IntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
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IntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
With the desire to make book publishing more relevant for the digital age and offer innovative Open Access publishing options, we are thrilled to announce the launch of our new publishing format: IntechOpen Book Series.
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Designed to cover fast-moving research fields in rapidly expanding areas, our Book Series feature a Topic structure allowing us to present the most relevant sub-disciplines. Book Series are headed by Series Editors, and a team of Topic Editors supported by international Editorial Board members. Topics are always open for submissions, with an Annual Volume published each calendar year.
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After a robust peer-review process, accepted works are published quickly, thanks to Online First, ensuring research is made available to the scientific community without delay.
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Our innovative Book Series format brings you:
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Topic Focused Publications - Each topic showcases high impact subject areas
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Renowned Editorial Expertise - Series Editors, Topic Editors, and a team of international Board Members that permanently support each Book Series
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Fast Publishing - quick turnaround which is unique for book publishing
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The benefit of ISSN and ISBN for increased citation and indexing possibilities
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IntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
\n\n
IntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
We invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
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Note: Edited in October 2021
\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"5150",leadTitle:null,fullTitle:"Electronics Cooling",title:"Electronics Cooling",subtitle:null,reviewType:"peer-reviewed",abstract:"Featuring contributions from the renowned researchers and academicians in the field, this book covers key conventional and emerging cooling techniques and coolants for electronics cooling. It includes following thematic topics:\n - Cooling approaches and coolants\n - Boiling and phase change-based technologies\n - Heat pipes-based cooling\n - Microchannels cooling systems\n - Heat loop cooling technology\n - Nanofluids as coolants\n - Theoretical development for the junction temperature of package chips. This book is intended to be a reference source and guide to researchers, engineers, postgraduate students, and academicians in the fields of thermal management and cooling technologies as well as for people in the electronics and semiconductors industries.",isbn:"978-953-51-2406-1",printIsbn:"978-953-51-2405-4",pdfIsbn:"978-953-51-5780-9",doi:"10.5772/61407",price:119,priceEur:129,priceUsd:155,slug:"electronics-cooling",numberOfPages:182,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"b95856cfcc87ef3cb7d7c7c7bac4010d",bookSignature:"S M Sohel Murshed",publishedDate:"June 15th 2016",coverURL:"https://cdn.intechopen.com/books/images_new/5150.jpg",numberOfDownloads:24128,numberOfWosCitations:91,numberOfCrossrefCitations:70,numberOfCrossrefCitationsByBook:5,numberOfDimensionsCitations:129,numberOfDimensionsCitationsByBook:7,hasAltmetrics:1,numberOfTotalCitations:290,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"September 30th 2015",dateEndSecondStepPublish:"October 31st 2015",dateEndThirdStepPublish:"January 17th 2016",dateEndFourthStepPublish:"February 16th 2016",dateEndFifthStepPublish:"April 30th 2016",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"24904",title:"Prof.",name:"S. M. Sohel",middleName:null,surname:"Murshed",slug:"s.-m.-sohel-murshed",fullName:"S. M. Sohel Murshed",profilePictureURL:"https://mts.intechopen.com/storage/users/24904/images/system/24904.jpg",biography:"Prof. S. M. Sohel Murshed was born in Bangladesh and obtained his Ph.D. in Mechanical and Aerospace Engineering from Nanyang Technological University, Singapore. He is currently a professor in the Mechanical Engineering Department, University of Lisbon, Portugal, and a visiting professor at Rochester Institute of Technology, New York. Previously he worked as a postdoctoral fellow and visiting professor and scientist at different universities in Singapore, the United States, the United Kingdom, and India. In 2020, he received the prestigious DUO-India Professorial Fellowship Award. Dr. Murshed has authored/co-authored 10 books, 30 book chapters, and more than 180 papers in leading international journals and conferences. His current Google scholar citation counts: 7560. He was recently named one of the World\\'s Top 2% Scientists by Stanford University.",institutionString:"Rochester Institute of Technology",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"8",totalChapterViews:"0",totalEditedBooks:"6",institution:{name:"University of Lisbon",institutionURL:null,country:{name:"Portugal"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"554",title:"Electronics",slug:"electronics"}],chapters:[{id:"50535",title:"Introductory Chapter: Electronics Cooling — An Overview",doi:"10.5772/63321",slug:"introductory-chapter-electronics-cooling-an-overview",totalDownloads:3579,totalCrossrefCites:7,totalDimensionsCites:10,hasAltmetrics:1,abstract:null,signatures:"S M Sohel Murshed",downloadPdfUrl:"/chapter/pdf-download/50535",previewPdfUrl:"/chapter/pdf-preview/50535",authors:[{id:"24904",title:"Prof.",name:"S. M. Sohel",surname:"Murshed",slug:"s.-m.-sohel-murshed",fullName:"S. M. Sohel Murshed"}],corrections:null},{id:"50131",title:"Boiling of Immiscible Mixtures for Cooling of Electronics",doi:"10.5772/62341",slug:"boiling-of-immiscible-mixtures-for-cooling-of-electronics",totalDownloads:2144,totalCrossrefCites:2,totalDimensionsCites:7,hasAltmetrics:0,abstract:"To satisfy the requirements for the cooling of small and large semiconductors operated at high heat flux density, an innovative cooling method using boiling heat transfer to immiscible liquid mixtures is proposed. Immiscible liquid mixtures discussed here are composed of more-volatile liquid with higher density and less-volatile liquid with lower density, and appropriate volumetric ratios become a key to realize high-performance cooling. The chapter reviews the experimental results obtained by the present authors, where critical heat flux accompanied by the catastrophic surface temperature excursion is increased up to 300 W/cm2 for FC72/water by using a flat heating surface of 40 mm in diameter facing upwards under the pressure 0.1 MPa.",signatures:"Haruhiko Ohta, Yasuhisa Shinmoto, Daisuke Yamamoto and\nKeisuke Iwata",downloadPdfUrl:"/chapter/pdf-download/50131",previewPdfUrl:"/chapter/pdf-preview/50131",authors:[{id:"178953",title:"Prof.",name:"Haruhiko",surname:"Ohta",slug:"haruhiko-ohta",fullName:"Haruhiko Ohta"},{id:"192761",title:"Dr.",name:"Yasuhisa",surname:"Shinmoto",slug:"yasuhisa-shinmoto",fullName:"Yasuhisa Shinmoto"},{id:"192762",title:"Dr.",name:"Daisuke",surname:"Yamamoto",slug:"daisuke-yamamoto",fullName:"Daisuke Yamamoto"}],corrections:null},{id:"50699",title:"Heat Pipe and Phase Change Heat Transfer Technologies for Electronics Cooling",doi:"10.5772/62328",slug:"heat-pipe-and-phase-change-heat-transfer-technologies-for-electronics-cooling",totalDownloads:3555,totalCrossrefCites:4,totalDimensionsCites:4,hasAltmetrics:0,abstract:"The heat pipe is a well-known cooling module for advanced electronic devices. The heat pipe has many applications, particularly in electronics and related area such as PC, laptop, display, artificial satellite, and telecommunication modules. The heat pipe utilizes phase change heat transfer inside enveloped structures, where the working fluid evaporates in heated zone, and vapor moves to the condenser, and the condensed liquid is pumped back through microporous structure call wick. The performance of applicability in electronics of heat pipe is strongly dependent on the geometry, working fluid, and microstructure of wick. Therefore, it is worth considering the theory and technologies related to heat pipes for advanced electronics cooling. According to the purpose of this chapter mentioned above, the author considers fundamental aspects regarding heat pipe and phase change phenomena. First, the working principle of heat pipe is introduced. Important parameters in heat pipe are considered, and theoretical model for predicting the thermal performance of the heat pipe is introduced. In addition, design method for heat pipe is presented. Finally, applications of heat pipe to electronics cooling are presented. This chapter covers knowledge and state-of-art technologies in regard to heat pipe and phase change heat transfer. For a reliable operation of future electronics that have ultra-high heat flux amounts to 1000 W/m2, heat pipe and phase change heat transfer are essential. This chapter provides the most valuable opportunity for all readers from industry and academia to share the professional knowledge and to promote their ability in practical applications.",signatures:"Chan Byon",downloadPdfUrl:"/chapter/pdf-download/50699",previewPdfUrl:"/chapter/pdf-preview/50699",authors:[{id:"178434",title:"Prof.",name:"Chan",surname:"Byon",slug:"chan-byon",fullName:"Chan Byon"}],corrections:null},{id:"50065",title:"Heat Pipes for Computer Cooling Applications",doi:"10.5772/62279",slug:"heat-pipes-for-computer-cooling-applications",totalDownloads:5159,totalCrossrefCites:4,totalDimensionsCites:10,hasAltmetrics:0,abstract:"There is an increasing demand for efficient cooling techniques in computer industry to dissipate the associated heat from the newly designed and developed computer processors to accommodate for their enhanced processing power and faster operations. Such a demand necessitates researchers to explore efficient approaches for central processing unit (CPU) cooling. Consequently, heat pipes can be a viable and promising solution for this challenge. In this chapter, a CPU thermal design power (TDP), cooling methods of electronic equipments, heat pipe theory and operation, heat pipes components, such as the wall material, the wick structure, and the working fluid, are presented. Moreover, we review experimentally, analytically and numerically the types of heat pipes with their applications for electronic cooling in general and the computer cooling in particular. Summary tables that compare the content, methodology, and types of heat pipes are presented. Due to the numerous advantages of the heat pipe in electronic cooling, this chapter definitely leads to further research in computer cooling applications.",signatures:"Mohamed H.A. Elnaggar and Ezzaldeen Edwan",downloadPdfUrl:"/chapter/pdf-download/50065",previewPdfUrl:"/chapter/pdf-preview/50065",authors:[{id:"178453",title:"Dr.",name:"Mohamed",surname:"Elnaggar",slug:"mohamed-elnaggar",fullName:"Mohamed Elnaggar"},{id:"184278",title:"Dr.",name:"Ezzaldeen",surname:"Edwan",slug:"ezzaldeen-edwan",fullName:"Ezzaldeen Edwan"}],corrections:null},{id:"50421",title:"MEMS-Based Micro-heat Pipes",doi:"10.5772/62786",slug:"mems-based-micro-heat-pipes",totalDownloads:2765,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:0,abstract:"Micro-electro-mechanical systems (MEMS)-based micro-heat pipes, as a novel heat pipe technology, is considered as one of the most promising options for thermal control applications in microelectronic circuits packaging, concentrated solar cells, infrared detectors, micro-fuel cells, etc. The operating principles, heat transfer characteristics, and fabrication process of MEMS-based micro-grooved heat pipes are firstly introduced and the state-of-the-art of research both experimental and theoretical is thoroughly reviewed. Then, other emerging MEMS-based micro-heat pipes, such as micro-capillary pumped loop, micro-loop heat pipe, micro-oscillating heat pipe, and micro-vapor chamber are briefly reviewed as well. Finally, some promising and innovatory applications of the MEMS-based micro-heat pipes are reported. This chapter is expected to provide basic reference for future researches.",signatures:"Qu Jian and Wang Qian",downloadPdfUrl:"/chapter/pdf-download/50421",previewPdfUrl:"/chapter/pdf-preview/50421",authors:[{id:"178950",title:"Associate Prof.",name:"Jian",surname:"Qu",slug:"jian-qu",fullName:"Jian Qu"},{id:"184907",title:"Prof.",name:"Qian",surname:"Wang",slug:"qian-wang",fullName:"Qian Wang"}],corrections:null},{id:"50801",title:"Performance Evaluation of Nanofluids in an Inclined Ribbed Microchannel for Electronic Cooling Applications",doi:"10.5772/62898",slug:"performance-evaluation-of-nanofluids-in-an-inclined-ribbed-microchannel-for-electronic-cooling-appli",totalDownloads:2509,totalCrossrefCites:52,totalDimensionsCites:95,hasAltmetrics:0,abstract:"Nanofluids are liquid/solid suspensions with higher thermal conductivity, compared to common working fluids. In recent years, the application of these fluids in electronic cooling systems seems prospective. In the present study, the laminar mixed convection heat transfer of different water–copper nanofluids through an inclined ribbed microchannel––as a common electronic cooling system in industry––was investigated numerically, using a finite volume method. The middle section of microchannel’s right wall was ribbed, and at a higher temperature compared to entrance fluid. The modeling was carried out for Reynolds number of 50, Richardson numbers from 0.1 to 10, inclination angles ranging from 0° to 90°, and nanoparticles’ volume fractions of 0.0–0.04. The influences of nanoparticle volume concentration, inclination angle, buoyancy and shear forces, and rib’s shape on the hydraulics and thermal behavior of nanofluid flow were studied. The results were portrayed in terms of pressure, temperature, coefficient of friction, and Nusselt number profiles as well as streamlines and isotherm contours. The model validation was found to be in excellent accords with experimental and numerical results from other previous studies.",signatures:"Mohammad Reza Safaei, Marjan Gooarzi, Omid Ali Akbari, Mostafa\nSafdari Shadloo and Mahidzal Dahari",downloadPdfUrl:"/chapter/pdf-download/50801",previewPdfUrl:"/chapter/pdf-preview/50801",authors:[{id:"178854",title:"Dr.",name:"Mohammad Reza",surname:"Safaei",slug:"mohammad-reza-safaei",fullName:"Mohammad Reza Safaei"},{id:"179807",title:"Dr.",name:"Mostafa",surname:"Safdari Shadloo",slug:"mostafa-safdari-shadloo",fullName:"Mostafa Safdari Shadloo"},{id:"179809",title:"Dr.",name:"Mahidzal",surname:"Dahari",slug:"mahidzal-dahari",fullName:"Mahidzal Dahari"},{id:"179813",title:"MSc.",name:"Marjan",surname:"Goodarzi",slug:"marjan-goodarzi",fullName:"Marjan Goodarzi"},{id:"185093",title:"MSc.",name:"Omid",surname:"Ali Akbari",slug:"omid-ali-akbari",fullName:"Omid Ali Akbari"}],corrections:null},{id:"50219",title:"Reciprocating Mechanism–Driven Heat Loop (RMDHL) Cooling Technology for Power Electronic Systems",doi:"10.5772/62518",slug:"reciprocating-mechanism-driven-heat-loop-rmdhl-cooling-technology-for-power-electronic-systems",totalDownloads:2021,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"The most significant hindrances to the technological advances in high power electronics (HPE) and digital computational devices (DCD) has always been the issue of effective thermal management. Energy losses during operation cause heat to build up in these components, resulting in temperature rise. Finding effective thermal solutions will become a major constraint for the reduction of cost and time-to-market, two governing factors between success and failure in commercial evolution of technology. Even when high temperatures are not reached, high thermal stresses because of temperature variations are major causes of failure in electronic components mounted on circuit boards. An effective electronic cooling technique, which is based on reciprocating heat pipe, is the so-called reciprocating mechanism–driven heat loop (RMDHL) that has a heat transfer mechanism different from those of traditional heat pipes. Experimental results show that the heat loop worked very effectively and a heat flux as high as 300 W/cm2 in the evaporator section could be handled. In addition to eliminating the cavitation problem associated with traditional two-phase heat loops, the RMDHL also provides superior cooling advantage with respect to temperature uniformity. Considering the other advantages of coolant leakage free and the absence of cavitation problems for aerospace-related applications, the single phase RMDHL could be an alternative of a conventional liquid cooling system (LCS) for electronic cooling applications. This chapter will provide insight into experimental, numerical and analytical study undertaken for RMDHL in connection with high heat and high heat flux thermal management applications and electronic cooling. In addition to clarifying the fundamental physics behind the working mechanism of RMDHLs, a working criterion has also been derived, which could provide a guidance for the design of a reciprocating mechanism–driven heat loop.",signatures:"Olubunmi Popoola, Soheil Soleimanikutanaei and Yiding Cao",downloadPdfUrl:"/chapter/pdf-download/50219",previewPdfUrl:"/chapter/pdf-preview/50219",authors:[{id:"178841",title:"Ph.D.",name:"Soheil",surname:"Soleimanikutanaei",slug:"soheil-soleimanikutanaei",fullName:"Soheil Soleimanikutanaei"},{id:"179928",title:"Prof.",name:"Yiding",surname:"Cao",slug:"yiding-cao",fullName:"Yiding Cao"},{id:"179929",title:"Dr.",name:"Olubunmi",surname:"Popoola",slug:"olubunmi-popoola",fullName:"Olubunmi Popoola"}],corrections:null},{id:"50240",title:"Theoretical Derivation of Junction Temperature of Package Chip",doi:"10.5772/62570",slug:"theoretical-derivation-of-junction-temperature-of-package-chip",totalDownloads:2396,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Junction temperature is the highest operating temperature of the actual semiconductor in an electronic device. In operation, junction temperature is higher than the case temperature and the temperature of the part’s exterior. The difference is equal to the amount of heat transferred from the junction to case multiplied by the junction-to-case thermal resistance. When designing integrated circuits, predicting and calculating the chip junction temperature is a very important task. This chapter describes how to derive the junction temperature from the thermal transport model.",signatures:"Professor Wei-Keng Lin",downloadPdfUrl:"/chapter/pdf-download/50240",previewPdfUrl:"/chapter/pdf-preview/50240",authors:[{id:"178475",title:"Prof.",name:"Wei-Keng",surname:"Lin",slug:"wei-keng-lin",fullName:"Wei-Keng Lin"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:[{id:"65",label:"highly cited contributor"}]},relatedBooks:[{type:"book",id:"5395",title:"Heat Exchangers",subtitle:"Design, Experiment and Simulation",isOpenForSubmission:!1,hash:"2df2e51f2bb427d6a50b215ac8d1e68c",slug:"heat-exchangers-design-experiment-and-simulation",bookSignature:"S M Sohel Murshed and Manuel Matos Lopes",coverURL:"https://cdn.intechopen.com/books/images_new/5395.jpg",editedByType:"Edited by",editors:[{id:"24904",title:"Prof.",name:"S. M. 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\n\t\t\t
1. Introduction
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Most of the drugs that are available in the marketplace are administered via the oral route, which is a convenient and cost effective route of administration (Lipinski 1995, Lipinski 2000, Lipinski et al. 2001, Lipinski 2004, Abrahamsson and Lennernas 2005). Thus, oral bioavailability is one of the key considerations for discovery and development of a new chemical entity (NCE). It is well recognized that poor oral bioavailability is one of the major causes of therapeutic variability, associated with the variable drug exposure (Beierle et al. 1999, Bardelmeijer et al. 2000, Katsura and Inui 2003). This is particularly important for drugs with narrow therapeutic window or potential for resistance development such as antibiotics and cytotoxic drugs (Bardelmeijer et al. 2000). Hellriegel et al. reported a significant inverse relationship between the oral bioavailability of drugs from several therapeutic classes and the coefficient of inter-individual variability in their oral bioavailability (Hellriegel et al. 1996).
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Oral bioavailability is a product of fraction absorbed, fraction escaping gut-wall elimination, and fraction escaping hepatic elimination; and the factors that influence bioavailability can be divided into physiological, physicochemical, and biopharmaceutical factors. It has been well established that physicochemical properties determine oral absorption and drug metabolism. The “rule-of-five” devised by Lipinski and co-workers provided an important advance, with analysis of a large data set showing that compounds within certain physicochemical space tended to be more successful in clinical development than others. Using a dataset of 309 drugs, Varma et al. studied the interrelation of physicochemical properties and the individual parameters of oral absorption to define the physicochemical space for optimum human oral bioavailability (Varma et al. 2010). This analysis, which may provide a rational judgment on the physicochemical space to optimize oral bioavailability, will be discussed. Furthermore, the solubility and permeability as the fundamental properties of oral absorption will be discussed in-line with biopharmaceutics classification system. Uptake and efflux transporters are implicated as facilitating or limiting intestinal absorption. This book chapter will touch up on the latest findings on several chemistry approaches that has be directed to target the uptake transporters and circumvent the efflux transporters. Overall, this chapter will provides a better understanding of the interplay between gastrointestinal tract physiology/anatomy and drug physicochemical /biopharmaceutical factors in the absorption and metabolism mechanisms that affect oral bioavailability humans; and enable a rational approach to design NCE with better absorption in humans.
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2. Concepts and theoretical calculations of oral bioavailability
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Bioavailability (F) is the extent to which an active moiety is absorbed from a pharmaceutical dosage form and becomes available in the systemic circulation (Thomas et al. 2006). Bioavailability is usually determined by calculating the respective plasma drug exposure assessed as the total area under the drug plasma concentration versus time curve (AUC) after oral and intravenous administration as:
In general, determinants of oral drug bioavailability include fraction of dose absorbed in the gastrointestinal tract (GIT) and fraction of dose that escapes elimination by the intestinal tract, liver, and lung. Thus, oral bioavailability can be defined mathematically by the following equation:
Where Fabs is the fraction of the dose that is absorbed from the intestinal lumen to the intestinal enterocytes; Fg is the fraction of the dose that escapes pre-systemic intestinal first pass elimination; and Fh is the fraction of the dose that passes through the liver and escapes pre-systemic liver first-pass elimination. The fraction of the dose that escapes first-pass elimination across the intestine (Fg) and liver (Fh) can be estimated experimentally via the comparison of systemic exposures (AUC ratios) where the dosing routes are selected to isolate the contribution by a particular organ.
\n\t\t\t
Fg can be estimated (Eq. 3) for a compound when doses are given orally and via a cannulated hepatic portal vein (h.p.v.) with the fraction absorbed (Fabs) either assumed to be complete or is known.
The details on scientific background and factors that influence Fh are outside the scope of this book chapter; interested readers are encouraged to refer to our recent reviews in these areas (Thomas et al. 2006, Hurst et al. 2007, Varma et al. 2010) and other chapters in this book that focus on metabolism and related topics such as induction and inhibition of drug metabolism, pharmacogenetics and metabolism: past, present and future, and effect of pharmaceutical excipients on drug metabolism.
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3. Mechanism of oral absorption
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Following oral dosing, drug molecules can cross the luminal membrane through various mechanisms that involve passive diffusion or active transport. Passive diffusion is comprised of two pathways: the paracellular pathway, in which drug diffuses through the aqueous pores at the tight junctions between the intestinal enterocytes; and the transcellular (lipophilic) pathway, which requires drug diffusion across the lipid cell membrane of the enterocyte. The active transport pathway is mediated by transporters and is divided into active drug influx and efflux. It is important to note that the relevance of each route is determined by the compound’s physicochemical properties and its potential affinity for various transport proteins (Thomas et al. 2006, Hurst et al. 2007, Varma et al. 2010, Varma et al. 2010).
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3.1. Passive diffusion
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In paracellular diffusion, drug molecules are absorbed by diffusion and convective volume flow through the water-filled intercellular space (Lennernas 1995). In general, drugs that are absorbed through this pathway are small molecules (e.g., molecular weight [MW] < 250 g/mol) and hydrophilic in nature (Log P < 0). Because the junctional complex has a net negative charge, positively charged molecules pass through more readily, whereas negatively charged molecules are repelled (Karlsson et al. 1999). Furthermore, the paracellular pathway offers a limited window for absorption since it accounts for < 0.01% of the total surface area of intestinal membrane. In addition, the tight junctions between cells become tighter traveling from the jejunum towards the colon.
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The transcellular pathway is the major route of absorption for most of drug molecules. In general, the rate of passive transcellular permeability is mainly determined by the rate of transport across the apical cell membrane, which is controlled by the physicochemical properties of the absorbed compound. Unlike the paracellular pathway, compounds that are absorbed through the transcellular pathway are unionised, with lipophilicity of Log P > 0 and MW > 300 g/mole. In addition, the hydrogen-bonding capacity determined by the number of hydrogen bond donors and hydrogen bond acceptors is < 10 and 5, respectively (Lipinski 1995, Lipinski 2000, Avdeef 2001).
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3.2. Active transport
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Enterocytes express several transporters, belonging to the adenosine triphosphate (ATP) binding cassette (ABC) superfamily and the solute carrier (SLC) superfamilies, on the apical and basolateral membranes for the influx or efflux of endogenous substances and xenobiotics (Table 1). Although a variety of transporters are expressed in the enterocytes, only a few are known to play a key role in the intestinal absorption of drugs. ABC transporters utilize ATP to drive the transport and are called primary active transporter. However, SLC transporters majorly use the ion gradients (H+, Na+ and Ca++ gradients) created across the membrane by primary active carriers (Na+/K+-ATPase, Na+/H+-ATPase) (Tsuji and Tamai 1996). ABC transporters expressed in the intestine include P-glycoprotein (P-gp; ABCB1), breast cancer resistance protein (BCRP; ABCG2), multidrug resistance proteins (MRP1-6; ABCC1-6). P-gp, BCRP, MRP2 and MRP4 are localized on brush-border (apical) membrane while certain MRPs are expressed on the basolateral membrane of the enterocytes. These efflux transporters functionally limit the enterocytic levels of their substrates by reducing uptake and facilitating efflux. SLC transporters suggested as relevant at the intestinal apical surface of epithelial cells include, peptide transporter (PepT1; SLC15A1), organic anion polypeptide transporters (OATP1A2, SLCO1A2; OATP2B1,SLCO2B1), monocarboxylate transporters (MCT1; SLC16A1), sodium-multivitamin transport (SMVT; SLC5A6) and organic cation/zwitterion transporters (OCTN1, SLC22A4; OCTN2, SLC22A5). Several other SLC transporters including organic anion or cation transporters (OATs or OCTs; SLC22) have also been identified in the intestine, but seem to be of less importance in oral drug absorption (Englund et al. 2006, Seithel et al. 2006).
When an active uptake process is involved, the overall transport of a drug across the intestinal enterocytes can be defined by model incorporating saturable and nonsaturable components (Eq. 5).
As outlined in the equation above, the total flux (J) of a compound across intestinal membrane is determined by four variables: J\n\t\t\t\t\n\t\t\t\t\tmax\n\t\t\t\t, which is the maximal uptake rate, K\n\t\t\t\t\n\t\t\t\t\tm\n\t\t\t\t, which is the transporter substrate binding affinity, K\n\t\t\t\t\n\t\t\t\t\tD\n\t\t\t\t, which is the kinetic constant for nonsaturable transport, and C, which is the luminal drug concentration. The impact of intestinal transporters on the overall absorption of drug across the intestine is determined by the percentage component of the active process (J\n\t\t\t\t\n\t\t\t\t\tmax\n\t\t\t\t\n\t\t\t\tC/(K\n\t\t\t\t\n\t\t\t\t\tm\n\t\t\t\t\n\t\t\t\t+C)) to the total flux, J, of the drug molecule. In general hydrophilic drug have low KD values and therefore there transport rates are mainly driven by the transporter activity, while for lipophilic drugs the passive component is usually high and the role of transporters is expected to be minimal.
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5. Physiological, physicochemical and biopharmaceutical factors that impact oral drug absorption
5.1. Physiological factors that impact oral drug absorption
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5.1.1. Gastro-intestine anatomy and physiology
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In humans, the GIT consists mainly of the stomach, small intestine (the duodenum, jejunum, and ileum) and large intestine (cecum, colon and rectum). The total length of the human GIT is 8.35 m and the relative size of the human small intestine, which is considered the primary site of drug absorption, to the total length of the GI tract is 81%. As for the large intestine, its relative size in humans is 19%. It may also be pointed out that the cecum, which is the major site of microbial digestion, forms only 5% of the length of the human large intestine (DeSesso and Jacobson 2001).
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The surface area is attributed to the fact that the human small intestine has three anatomical modifications that significantly increase the surface area of the human small intestine (Shargel and Yu 1999). The human small intestine has grossly observable folds of mucosa (plicae circularis or folds of kerckring) that increase the surface area threefold. From the plicae circularis, microscopic finger-like pieces of tissue called villi project, which increase the surface area by 10-fold for humans. Each villus is covered in microvilli, which increase the surface area by 20-fold. Unlike the small intestine, the large intestine surface area does not have villi and is divided into geographical areas by transverse furrows. In addition, the large intestine enterocytes differ slightly from that of the small intestine and its microvilli are less packed (Kararli 1995). Overall, this significantly contributes to the smaller surface area of the large intestine in humans and is consistent with the fact that small intestine is the major site of drug absorption in humans.
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5.1.2. Unstirred water layer
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Adjacent to the intestinal membrane is an unstirred water layer, which is a potential barrier for the absorption of various drug molecules across the intestinal membrane (Winne 1976, Hayton 1980). The thickness of this layer in humans is only 25 μm (Strocchi et al. 1996). Chiou et al. quantitatively studied the impact of the unstirred water layer adjacent to the intestinal membrane on the rate and extent of absorption of passively absorbed drugs with different membrane absorption half-lives (10 – 300 min) in humans (Chiou 1994). Results of this analysis suggested that the presence of the unstirred water layer is generally expected to have a relatively mild or insignificant effect on the rate of absorption and an insignificant effect on the extent of absorption (Kimura and Higaki 2002).
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5.1.3. Gastrointestinal transit times
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The absorption rate of a drug molecule is generally a function of drug absorption through the GIT, which is determined by the residence time and absorption in each GIT segment (Kimura and Higaki 2002). In general, gastric transit time impacts the systemic exposure of rapidly dissolved and well absorbed drugs. However, intestinal transit time influences the absorption of drugs with limited mucosal permeability, carrier mediated uptake, drugs subject to intestinal degradation, or products whose dissolution is the rate limiting step for systemic absorption (Martinez and Amidon 2002). In contrast to gastric transit time, intestinal transit time is independent of the feeding conditions and the physical composition of the intestinal contents (Garanero et al. 2005). The human intestinal transit time is ~3 – 4 h (DeSesso and Jacobson 2001, Kimura and Higaki 2002). Several studies suggested that in human small intestine, there is a gradient of velocity where the small intestinal transit in the proximal intestine was faster compared with the distal intestine. The transit time in human large intestine can vary in the range of 8 – 72 h (DeSesso and Jacobson 2001).
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5.1.4. The GIT pH
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The extent of ionization plays a pivotal role in determining the drug dissolution rate and passive permeability across the GIT. Therefore, it becomes clear that the pH at the absorption site is a critical factor in facilitating or inhibiting the dissolution and absorption of various ionizable drug molecules (DeSesso and Jacobson 2001). It should be stressed that the pH of the luminal content (chyme) is altered by the luminal secretions. The pH of chyme is acidic and can be as low as 2.3. When the chyme arrives in the duodenum, it is quickly neutralized by the secretion of the pancreatic bicarbonate and bile. The pH values of chyme become progressively more alkaline in the distal portion of the small intestine in humans. However, the pH of chyme in the large intestine is generally more acidic than the pH observed in the small intestine in humans, possibly due to the fermentation mediated by the microbial flora (Kararli 1995).
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5.1.5. Bile fluid
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Bile is produced by hepatocytes and drained through the many bile ducts that penetrate the liver (DeSesso and Jacobson 2001). During this process, the epithelial cells add a watery solution that is rich in bicarbonates which increases the alkalinity of the solution. In humans, the bile is stored and concentrated up to five times its original potency in the gall bladder. It is to be noted that the human gall bladder secrets bile at a rate of 2 – 22 ml/kg/day. In humans, bile acts as a detergent to emulsify fats by increasing the surface area to help enzyme action, and thus aid in their absorption in the small intestine. In addition to bicarbonate solution, bile is composed of bile salts, such as the salts of taurocholic acid and deoxycholic acid, which are combined with phospholipids to break down fat globules in the process of emulsification by associating their hydrophobic side with lipids and the hydrophilic side with water. Emulsified droplets are then organized into many micelles which increases their absorption. Because bile increases the absorption of fats, it also plays a pivotal role in the absorption of the fat-soluble vitamins and steroids (Hanano 1993, Kirilenko and Gregoriadis 1993).
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5.1.6. Bacterial microflora
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In humans, bacterial microflora exists in most of the GIT and become an important component of the luminal content. However, there is no bacterial microflora in the stomach and upper small intestine. This is mainly attributed to the low pH of the human gastric content. However, a large number of bacterial microflora populates the human’s distal small and large intestines (Cummings and Macfarlane 1997). These bacterial microflora play a role in the metabolism of various chemicals and xenobiotics through hydrolysis, dehydroxylation, deamidation, decarboxylation and reduction of azide groups (Lichtenstein 1990, Cummings and Macfarlane 1997, Blaut et al. 2003). Among these reactions, hydrolysis of the glucuronide conjugates is the most important metabolic reaction that is mediated by the glucronidase enzyme and produced by the bacterial microflora found in the GIT of humans.
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5.1.7. Lymphatic absorption
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The intestinal lymphatic route plays a key role in the absorption of drugs that are highly lipophilic. It has many advantages, such as increase in the oral bioavailability of highly lipophilic drugs by avoiding hepatic first pass effect, direct targeting of lymphoid tissue, indirect targeting of specific sites associated with low-density lipoprotein receptors, and alteration in the rate of oral drug input to the systemic circulation thereby providing opportunity for controlled release drug formulation (Cheema et al. 1987, Trevaskis et al. 2005, Trevaskis et al. 2006, Trevaskis et al. 2006).
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5.1.8. Intestinal drug transporters
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P-glycoprotein (P-gp)
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P-gp (MDR1; ABCB1), an ATP-dependent transmembrane efflux pump belonging to ABC superfamily, shows affinity to a wide variety of structurally unrelated compounds (Juliano and Ling 1976). It is expressed as a 1280 amino acid long (MW ~170 kDa) single chain glycoprotein with two homologous portions of equal length, each containing six transmembrane (TM) domains and two ATP binding regions separated by a flexible linker polypeptide region (Schinkel et al. 1993, Ambudkar et al. 1999).
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Immunohistochemical analysis using monoclonal antibody provided evidence for localization of P-gp in a wide range of tissues, particularly in columnar epithelial cells of the lower GIT, capillary endothelial cells of brain and testis, canalicular surface of hepatocytes and apical surface of proximal tubule in kidney (Thiebut et al. 1987). Due to selective distribution at the port of drug entry and exit, P-gp has been speculated to play a major physiological role in the absorption, distribution and excretion of xenobiotics and endogenous substrates. Overall, P-gp functions as a biochemical barrier for entry of drugs across intestine and brain, as well as a vacuum cleaner to expel drugs from the intestine, liver, kidney, etc. A number of clinically important drugs are P-gp substrates (Table 1), which are as diverse as anthracyclines (doxorubicin, daunorubicin), alkaloids (reserpine, vincristine, vinblastine), specific peptides (valinomycin, cyclosporine), steroid hormones (aldosterone, hydrocortisone) and local anesthetics (dibucaine) (Polli et al. 2001, Mahar Doan et al. 2002, Varma et al. 2003, Takano et al. 2006). P-gp substrates, digoxin and talinolol, show pharmacokinetic changes in human upon coadministration with P-gp inhibitors (Gramatte et al. 1996, Fenner et al. 2009). Greiner et al., studied the effect of rifampicin pretreatment on the oral pharmacokinetics of digoxin and suggested that rifampicn induced duodenal P-gp expression and thus significantly reduced AUC of digoxin (Greiner et al. 1999). Similarly, rifampicn decreased talinolol oral exposure, which is consistent with ~4 fold increase in duodenal P-gp expression (Westphal et al. 2000).
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P-gp affinity screening using various in vitro culture models is now an integral part of drug discovery due to wide substrate specificity and clinical relevance in drug disposition and associated drug-drug interactions (DDIs) (Varma et al. 2004a). Tailoring of molecules to reduce substrate specificity to P-gp may help in improving the oral bioavailability of drugs. Seelig and coworkers suggested that the partitioning into the lipid membrane is the rate-limiting step for the interaction of a substrate with P-gp and that dissociation of the P-gp-substrate complex is determined by the number and strength of the hydrogen bonds formed between the substrate and the transporter (Seelig and Landwojtowicz 2000). Several studies have related the binding affinity (K\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tm\n\t\t\t\t\t\t) of P-gp for substrates and modulators to their lipid-water partition coefficient (Log P). Evidence suggests that a drug with high Log P will accumulate to a high concentration within the cytoplasmic membrane and favors binding to P-gp with low K\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tm\n\t\t\t\t\t\t value, while a drug with low partitioning will have a lower membrane concentration and a high K\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tm\n\t\t\t\t\t\t value. Three-dimensional structures of a large number of drugs revealed that the minimal common binding element consisting of two or three hydrogen bond acceptor (HBA) groups in a specific spatial distance. Since the TM sequences of P-gp are rich in hydrogen bond donor (HBD) groups, it is hypothesized that P-gp recognizes the HBA groups of the substrates through hydrogen bond formation in the lipid membrane environment (Seelig 1998, Seelig 1998). Didziapetris et al. studied 220 substrates and 1000 non-substrates and proposed the ‘rule of four’, which states that compounds with the HBA ≥ 8, a molecular weight (MW) > 400 g/mol and most acidic pK\n\t\t\t\t\t\ta< 4 are likely to be P-gp substrates, while compounds with HBA ≤ 4, MW < 400 g/mol and most basic pK\n\t\t\t\t\t\ta> 8 are not substrates to P-gp (Didziapetris et al. 2003). Although many such models describe the physicochemical attributes of P-gp interaction and are shown to have high predictability, existence of multiple binding sites and other complicating factors has prevented the development of a definitive SAR (Stouch and Gudmundsson 2002).
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Breast Cancer Resistance Protein (BCRP)
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BCRP (ABCP/MXR; ABCG2), a member of the ABC family of transporters, is considered a half-transporter with six TM domains and one ATP-binding domain at the amino terminus and is believed to homodimerize in order to function (Staud and Pavek 2005). It is composed of 655 amino acids with a MW of 72 kDa (Graf et al. 2003). An atomic model of BCRP was predicted by homology modeling based on the crystal structure of the bacterial multidrug exporter Sav1866, which suggested that BCRP had multiple drug binding sites (Hazai and Bikadi 2008, Muenster et al. 2008). BCRP expression can be traced to placenta, kidney, liver, testis, brain, mammary tissue, and intestine (Doyle and Ross 2003). Unlike P-gp, the expression of BCRP along the length of the small intestine does not vary significantly (Bruyere et al. 2010). Additionally, the mRNA level of BCRP is notably higher than other efflux transporters such as P-gp and MRP2 in the human intestine (Taipalensuu et al. 2001). Since BCRP is highly expressed on the apical membrane of enterocytes and effluxing substrates back into the lumen, it has been noted to play an important role as a detoxification efflux transporter and limiting drug absorption in the GIT (Zaher et al. 2006).
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BCRP exhibits broad substrate specificity and accepts diverse chemical space, as do other ABC transporters. Substrates to BCRP include (Table 1): chemotherapy agents (mitoxantrone, camptothecins, tyrosine kinase inhibitors), antivirals (zidovudine, lamivudine), HMG-CoA reductase inhibitors (statins), benzimidazoles, and antibiotics (ciprofloxacin, rifampicin) (Bailey et al. ; Merino et al. 2005, Huang et al. 2006, Takano et al. 2006, Ando et al. 2007, Dauchy et al. 2009, Ieiri et al. 2009). Some of the BCRP substrates are also effectively effluxed by P-gp. For example, etoposide, irinotecan and tamoxifen are substrates for both BCRP and P-gp (Table 1). In a clinical study, Kruijtzer et al. showed an increase in bioavailability of topotecan from 40% to 97% in the presence of GF120918, a potent inhibitor of BCRP and P-gp (Kruijtzer et al. 2002). Yamasaki et al. investigated the impact of genetic polymorphisms of ABCG2 (421c>A) and NAT2 on the pharmacokinetics of sulfasalazine, in 37 healthy volunteers and suggested sulfasalazine as a useful probe substrate for evaluating the role of BCRP in the intestinal disposition (Yamasaki et al. 2008). BCRP polymorphism significantly affects the pharmacokinetics of several HMG-CoA reductase inhibitors, including atrovastatin, rosuvastatin, fluvastatin and simvastatin lactone, but has no significant effect on pravastatin or simvastatin acid (Bailey et al. , Huang et al. 2006, Ieiri et al. 2009, Keskitalo et al. 2009, Keskitalo et al. 2009). For example, rosuvastatin AUC was 100% and 144% greater in the c.421AA genotype population than in those with c.421CA and the c.421CC genotypes, respectively. Although, few clinical studies have been reported on the role of BCRP in the intestinal absorption, several studies using BCRP knock-out mice suggest significant impact (Merino et al. 2006,Seamon et al. 2006,Zaher et al. 2006, Yamagata et al. 2007).
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Due to general selectivity, substrates of BCRP can be either negatively or positively charged, hydrophobic or hydrophilic, and unconjugated or conjugated. Several attempts were made to establish SAR for BCRP interaction, however, many analysis methods were based on the datasets of inhibitors (Saito et al. 2006, Matsson et al. 2007, Matsson et al. 2009, Nicolle et al. 2009). Yoshikawa et al. studied BCRP substrate specificity of 14 camptothecin (CPT) analogues, and noted that CPT analogues that showed ATP-dependent transport in BCRP-overexpressing membrane vesicles possess one –hydroxy or –amino group (Yoshikawa et al. 2004). Also CPT analogues showed a good correlation between polarity and BCRP-association, where highly polar compounds showed substrate specificity. It is likely that the presence of hydroxyl and amino functional groups facilitate hydrogen bonding with the amino acid residues at the binding site of BCRP. Furthermore, presence of a negative electrostatic potential area at position 10 for SN-38 and SN-398, but not in SN-22, suggests that CPT analogues with this feature are potential substrates for BCRP (Nakagawa et al. 2006). BCRP substrate specificity of a set of pyrrolobenzodiazepine (PBD) derivatives showed a good correlation with the electrostatic potential and aromaticity (Kaliszczak et al. 2010). PBDs with a greater number of HBA and the electronegativity and aromaticity of the C2 substitution show affinity to BCRP. Evidently, BCRP-mediated efflux could be circumvented by limiting C2 aryl substituents and the number of aromatic rings. In general, BCRP substrates share a same set of molecular properties as that of substrates to P-gp and other efflux pumps (Begley 2004, Kunta and Sinko 2004, Takano et al. 2006).
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Peptide transporter 1 (Pept1)
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PepT1 (SLC15A1), an electrogenic, H+-dependent transporter, was first cloned from the rabbit intestine and subsequently from both rat and human (Fei et al. 1994). The cloned human PepT1 cDNA sequence encodes a 708 amino acid protein (MW 79 kDa) with an isoelectric point of 8.6 and several putative glycosylation and phosphorylation sites. There are 12 putative -helical TM domains and a large extracellular loop between the IX and X TM domains, which possess intacellularly localized N- and C- termini (Liang et al. 1995, Rubio-Aliaga and Daniel 2008). Herrera-Ruiz et al. reported that PepT1 appears to be localized predominantly in the duodenum, with decreasing expression in the jejunum and ileum (Herrera-Ruiz et al. 2001).
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PepT1 has been shown to be independent of Na+ and uses H+-gradient and inside-negative membrane potential to provide the necessary driving force for substrate translocation. At the brush border membrane of enterocytes, an in-ward proton gradient is generated through the activity of an electroneutral proton/cation exchanger, Na+/H+ antiporter. This enables the uptake of PepT1 transporter substrates to be coupled with the influx of protons back into the enterocytes (Adibi 1997). The uptake of the PepT1 substrates is strongly dependent on the extracellular pH, where a pH of 4.5-6.5 (depending on the net charge of the substrate), is needed for optimal transport activity. Irie et al. investigated the transport mechanism of PepT1 for neutral and charged substrates by experimental studies and computational simulation (Irie et al. 2005). These uptake studies suggested that the K\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tm\n\t\t\t\t\t\t of glycylsarcosine (Gly-Sar), a neutral substrate, decreased as the pH dropped from 7.4 to 5.5, yet increased at a pH of 5.0. The K\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tm\n\t\t\t\t\t\t value of an anionic substrate, ceftibuten, declined steadily with a decreasing pH. Furthermore, the maximum transporter rate (V\n\t\t\t\t\t\tmax) values gradually increased with a fall in pH from 7.4 to 5.0, for both substrates. Consequently, the group hypothesized that unlike neutral and cationic substrates, negatively charged molecules not only require H+ binding to H+-binding site, but also to the substrate-binding site.
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The 3D structure of the substrate binding site of PepT1 is not yet known, but its template has been proposed by the large variety of substrates (Foley et al. ; Meredith and Price 2006). It is interesting to note that the peptide bond is not required for substrate binding specificity of PepT1 transporter (Brandsch et al. 2004). Only the two oppositely charged free head groups (carboxylic carbon and amino nitrogen) separated by a 4 spacer carbon unit were identified as a minimal structural feature requirement (Doring et al. 1998). In the presence of a peptide bond, it is only the backbone carbonyl that is functional. This minimal configuration also explains the efficient transport of -aminolevulinic acid, which serves as a precursor for the endogenous porphyrin accumulation on which photodynamic therapy of tumors is based. In addition, the side chains provided in both di and tripeptides and in xenobiotics with charge polarity and conformation are pivotal in determining the binding affinities. It should also be emphasized that for the di and tripeptides, only the trans-configuration of the peptide bond is transported. Besides a preferred free N-terminal amino group, a high electron density around the terminal carboxylic group in dipeptide, or alternatively around the carbonyl group of the second amino acid in a tripeptide structure, is needed to ensure optimum binding affinity. Furthermore, high electron densities at the first and third side chains, as well as the presence of hydrophobic side chains, significantly contribute to overall binding affinity (Brandsch et al. 1999).
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PepT1 is a low-affinity (K\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tm\n\t\t\t\t\t\t of 200 µM to 15 mM), high-capacity transporter and is known to play a pivotal role in the absorption and distribution of peptidomimetics that include β-lactam antibiotics such as cephalosporins and penicillins, angiotensin converting enzyme inhibitor such as zofenopril, fosinopril, benazepril, quinapril, trandolapril, spirapril, cilazapril, ramipril, moexipril, quinaprilat, and perindopril., selected rennin inhibitors, antitumor agents such as bestatin, and dopamine receptor antagonists such as sulpiride (Terada et al. 1997, Bretschneider et al. 1999, Watanabe et al. 2002, Watanabe et al. 2002, Watanabe et al. 2004, Knutter et al. 2008). Using PepT1 as an intestinal transporter to increase oral exposure of compounds with low oral bioavailability was shown to be an effective strategy (Kikuchi et al. 2009). For example, acyclovir is usually associated with suboptimal oral plasma exposure (oral bioavailability 15%) that can lead to resistant viral strains. To overcome this limitation, valacyclovir, a L-valine ester prodrug of acyclovir was effectively designed to increase the oral absorption and plasma exposure of acyclovir (Ganapathy et al. 1998).
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Organic Anion-Transporting Polypeptides (OATPS)
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OATPs (SLCO) are transmembrane solute carriers that mediate the proton-dependent transport of a wide range of amphipathic endogenous and exogenous organic compounds across the plasma membrane. Currently, 39 members of the OATP/SLCO superfamily have been identified in mammalian species (Hagenbuch and Meier 2004). The OATPs represent integral membrane proteins that contain 12 TM domains where amino and carboxy termini are oriented to the cytoplasmic spaces. There is limited information regarding the tertiary structures of OATPs, although more recent studies are beginning to address this aspect. In this book chapter, we focus on OATP2B1 (SLCO2B1) and OATP1A2 (SLCO1A2). OATP2B1 plays a key role in the uptake of various xenobiotics and was originally isolated from the human brain and named OATP-B (Tamai et al. 2000, Kullak-Ublick et al. 2001) or SLC21A9 (Hagenbuch and Meier 2003). OATP2B1 mRNA is expressed in the human small intestine (Tamai et al. 2000, Kullak-Ublick et al. 2001, Sai et al. 2006) and its protein is immunolocalised at the apical surface of human small intestine (Kobayashi et al. 2003) and Caco-2 cell monolayers (Sai et al. 2006).
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Similar to other OATPs, transport via OATP2B1 is generally considered to occur in a bidirectional fashion driven by the solute concentration gradient across the membrane. Heterologous expression of OATP2B1 produces a Na+-independent, pH-gradient dependent transporter with a relatively narrow substrate specificity compared to other OATPs (Nozawa et al. 2004). Extracellular acidification promoted solute uptake, a property of OATP2B1 that bears relevance to the small intestinal environment in which the transporter is expressed on the apical membrane of the enterocytes. Kobayashi et al. studied the impact of pH on the uptake of both estrone-3-sulfate and pravastatin in OATP-2B1 transfected HEK 293 cells. The group reported that the uptake of both compounds were pH dependent, where higher uptake at pH 5.5 relative to that at 7.4 pH was reported. It is interesting to note that an increase was only observed in V\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tmax\n\t\t\t\t\t\t with a decrease of pH from 7.4 to 5.0 and a negligible change was observed in K\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tm\n\t\t\t\t\t\t at studied pH (Kobayashi et al. 2003). In a recent study, our group examined the role of OATP2B1 in the intestinal absorption and tissue uptake of 3-hydroxy-3-methylglutaryl-CoenzymeA (HMG-CoA) reductase inhibitors (statins) (Varma et al. Accepted). We first investigated impact of extracellular pH on the functional affinity of statins to the transporter using OATP2B1-transfeced HEK293 cells. The results indicated that OATP2B1-mediated transport is significant for rosuvastatin, fluvastatin and atorvastatin, at neutral pH. However, OATP2B1 showed broader substrate specificity as well as enhanced transporter activity at acidic pH consistent with other research groups’ findings (Kobayashi et al. 2003). Furthermore, uptake at acidic pH was diminished in the presence of proton ionophore, suggesting proton-gradient as the driving force for OATP2B1 activity. Notably, passive transport rates are predominant or comparable to active transport rates for statins, except for rosuvastatin and fluvastatin. Second, we studied the effect of OATP modulators on statins uptake. At pH 6.0, OATP2B1-mediated transport of atorvastatin and cerivastatin was not inhibitable, while rosuvastatin transport was inhibited by E-3-S, rifamycin SV and cyclosporine with IC50 values of 19.7±3.3μM, 0.53±0.2μM and 2.2±0.4μM, respectively. Rifamycin SV inhibited OATP2B1-mediated transport of E-3-S and rosuvastatin with similar IC50 values at pH 6.0 and 7.4, suggesting that the inhibitor affinity is not pH-dependent. Finally, we noted that OATP2B1-mediated transport of E-3-S, but not rosuvastatin, is pH-sensitive in intestinal epithelial (Caco-2) cells. However, uptake of E-3-S and rosuvastatin by Caco-2 cells was diminished in the presence of proton ionophore (FCCP). The present results indicate that OATP2B1 may be involved in the tissue uptake of rosuvastatin and fluvastatin, while OATP2B1 may play a significant role in the intestinal absorption of several statins due to their transporter affinity at acidic pH.
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The physiological and pharmacological role played by OATP2B1 in intestinal absorption may also vary between individuals. For example, a single nucleotide polymorphism (SNP) (found in 31% of the Japanese population investigated within the referenced study) leads to an amino acid change in the OATP2B1 protein (S486F), which is associated with a greater than 50% reduction in transport capacity (Nozawa et al. 2002).
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Since the unavailability of crystal structures of OATPs and relative difficulties in validating their homology models, pharmacophore models have helped elucidate the key molecular features involved in the substrate/inhibitor and protein interactions. These models have demonstrated good structure and activity correlation within the studied chemical space. The proposed OATP2B1 pharmacophores may share the similar molecular features for the consideration of the substrate binding at the positively-charged region. Its substrates may have features such as a hydrophobic core to form the π-stacking interaction with the imidazole ring of H579, or a HBD to directly interact with the nitrogen atom of the imidazole ring, both of which should be oriented at the energetically favored position inside the pore. To model these interactions structurally using molecular docking and dynamics, the minimal requirement will be a validated homology model of OATP2B1. To date, the strategy to elucidate the SAR of OATP2B1 is the combination of QSAR, pharmacophore, and structure-based modeling with the support of in vitro and cell-based experimental data.
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Another OATP transporter that plays a role in the intestinal absorption of xenobiotics is OATP1A2 (also known as human OATP-A or SLCO1A2). This transporter consists of 670 amino acids and is expressed in the brain, kidney and apical membrane of the enterocytes (Kullak-Ublick et al. 1995). Unlike other OATP transporters, OATP1A2 possesses perhaps the broadest spectrum of solutes in that compounds of acidic, basic, and neutral character are substrates. It has been reported to transport bile salts and bromosulfophtalein (BSP), steroid sulfates, thyroid hormones [triiodothyronine (T3), thyroxine (T4), and reverse T3], prostaglandin E2, fexofenadine, opioid peptides [e.g., deltorphin II and (d-penicillamine)enkephalin], rocuronium, N-methylquinine and N-methylquinidine, ouabain, the endothelin receptor antagonist BQ-123, talinolol, and the thrombin inhibitor CRC-220 (Ianculescu et al. ; Loubiere et al. ; Kullak-Ublick et al. 1995, Hsiang et al. 1999, Gao et al. 2000, Geyer et al. 2004, Schwarz et al. 2005, Shimizu et al. 2005, Kalliokoski and Niemi 2009). Similar to OATP2B1, genetic variations has been reported in SLCO1A2. For example, Lee et al. identified six non-synonymous SNPs in the coding region of SLCO1A2. The c.516A>C (p.Glu172Asp) variant had markedly reduced uptake capacity for the OATP1A2 substrates estrone 3-sulfate and the d-opioid receptor agonists, deltorphin II and [D-penicillamine2,5]-enkephalin in vitro. The group concluded that considering its substrate specificity and expression in organs such as the brain, kidney and intestine, genetic variations in SLCO1A2 may be an important contributor to inter-individual variability in drug disposition and central nervous system entry of OATP1A2 substrate drugs (Lee et al. 2005).
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In the clinic, the effect of grapefruit juice on the oral exposure of fexofendadine was evaluated. The oral plasma exposure of fexofenadine was decreased 63%. This seems likely to be mediated by inhibition of intestinal absorption via OATP1A2. (Dresser et al. 2005, Bailey et al. 2007). Similar findings were reported in a study that evaluated the effect of single and repeated grapefruit juice ingenstion on the oral plasma exposure of talinolol in humans. The decrease in the oral plasma exposure of talinolol (44%) was attributed to the inhibition of OATP1A2 (Shirasaka et al., Schwarz et al. 2005). Overall, these findings identify OATP1A2 as a potential site for diet-drug interactions and clearly demonstrate the potential role of OATP1A2 in the absorption of xenobiotics.
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Monocarboxylate transporter 1 (MCT1)
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The bi-directional movement of monocarboxylic acids across the plasma membrane is catalyzed by a family of proton-linked monocarboxylate transporters (MCTs). MCTs are encoded by the SLC16A gene family, of which there are 14 known members that were identified through screening genomic and expressed sequence tag databases (Halestrap and Meredith 2004). Only MCTs 1-4 have been shown to catalyze the proton-coupled transport of metabolically important monocarboxylates such as lactate and pyruvate (Halestrap and Meredith 2004). This book chapter will focus on the first member of the MCT family, MCT1 (SLC16A1), which is well characterized and known to play a role in the intestinal drug absorption.
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MCT1 consists of 12 TM α-helical domains with a large intracellular loop between TM segments VI and VII and intracellular C- and N- termini (Poole et al. 1996, Halestrap and Price 1999). MCT1 is expressed in most tissues and is especially prominent in the heart, red skeletal muscle, erythrocytes, and all cells under hypoxic conditions, where it can either be involved in the uptake or efflux of glycolytically produced lactic acid. MCT1 is also highly expressed in the small and large intestine (Gill et al. 2005), where it is responsible for the absorption of short chain fatty acids such as acetate, propionate and butyrate, produced from microbial fermentation of dietary fiber (Cummings and Macfarlane 1991).
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MCT1 catalyses the facilitative diffusion of substrate across the plasma membrane, coupled with the translocation of a proton. The driving force for transport is provided by both the substrate and H+-concentration gradients, with the pH gradient determining the extent of transport activity (Juel 1997, Halestrap and Price 1999). Based on the reported crystal structures of two members of the major facilitator superfamily, the Escherischia coli glycerol-3-phosphate transporter (G1pT) and lactose permease (Lac Y) (Abramson et al. 2003, Huang et al. 2003), the structure of MCT1 has been modelled (Manoharan et al. 2006). Futhermore, site-directed mutagenesis identifying key substrate-binding residues together with structural modeling has lead to the suggestion of a translocation cycle as the mechanism of transport for MCT1 (Wilson et al. 2009). This mechanism of transport is consistent with the “Rocker Switch” mechanism (Law et al. 2008). This model describes MCT1 existing in an open and closed conformation, with the N- and C-terminal halves tilting against each other along an axis that separates the two domains, allowing the substrate binding site alternating access to the either side of the membrane (Wilson et al. 2009). MCT1 also requires an ancillary protein, CD147, for correct trafficking to the plasma membrane as well as functional activity (Wilson et al. 2005). CD147 is a member of the immunoglobulin gene superfamily, and has been shown to closely interact with both MCT1 and MCT4 (Kirk et al. 2000).
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MCT1 is a low affinity, high capacity transporter that has been shown to transport unbranched aliphatic monocarboxylates such as acetate and proprionate and substituted monocarboxylates pyruvate, lactate, acetoacetate and β-hydroxybutyrate, with the K\n\t\t\t\t\t\tm values for pyruvate and lactate about 0.7 and 3-5 mM, respectively (Halestrap and Meredith 2004). Other MCT1 monocarboxylate substrates include the branched chain keto-acids (formed from the transamination of leucine, isoleucine and valine) and the ketone bodies acetoacetate, β-hydroxybutyrate and acetate (Poole and Halestrap 1993), and exogenous acids p-aminohippuric acid, benzoic acid, γ-hydroxy butyrate, foscarnet, mevolonic acid, and salicylic acid (Enerson and Drewes 2003, Lam et al. 2010). MCT1 is also thought to be responsible for the intestinal absorption of the β-lactam antibiotics such as carbenicillin indanyl sodium as well as phenethicillin and propicillin (Li et al. 1999). The targeting of MCT1 by pharmacologically active drugs has been shown to result in enhanced intestinal drug uptake. For example, XP13512 is rapidly absorbed along the length of the intestine via MCT1 (as well as the SMVT). XP13512 is an anionic compound produced by the reversible modification of the amine group of gabapentin (which has limited oral absorption), with an acyloxyalkylcarbamate promoeity (Cundy et al. 2004). Overall, prototypical substrates of MCT1 generally consist of weak organic acids with the carboxyl group attached to a relatively small R group containing lipophilic or hydrophilic properties (Enerson and Drewes 2003).
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5.2. Physicochemical factors that impact oral drug absorption
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Our group recently investigated the interrelation of physicochemical properties and individual parameters for a database comprised of Fa, Fg, Fh, and F values for 309 drugs in humans (Varma et al. 2010). The aim is to define the physicochemical space for optimum human oral bioavailability. The current data set suggested an even distribution of the bioavailability values, with about 17% of compounds showing F less than 0.2 and 34% of compounds showing F more than 0.8. However, the vast majority of compounds showed Fa (71%), Fg (70%), and Fh (73%) more than 0.8. The current data set indicated that bioavailability is mainly limited by absorption as evident from the subset of compounds showing bioavailability less than 0.2, where mean and median values suggest the rank-order of limiting parameters as Fa > Fg > Fh.
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The distribution of the data set in physicochemical space is heterogeneous and thoroughly covered the range of conventional small molecule marketed drugs. Trend analysis clearly indicate that ionization state, molecular weight (MW), lipophilicity, polar descriptors, and free rotatable bonds (RB) influence bioavailability. For example, ionization state analysis of compounds studied indicate that although bases tend to have higher Fa, they are relatively less bioavailable as compared to acids and neutrals. MW trends suggest that increasing the size of molecules above 400 g/mol will on average lead to a steady decline in bioavailability, mainly due to the effect on Fa. Lipophilicity (cLog P and cLog D pH7.4) trends indicate that very hydrophilic compounds have drastically reduced intestinal absorption. On the other hands, RB and polar descriptors such as PSA, hydrogen bonding count (HBA + HBD) showed inverse relationship with Fa, in particular for compounds with RB > 12, PSA greater than 125 A 2, and hydrogen bond count more than 9.
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The scholarship outlined above is consistent with the finding of Lipinski et al, who introduced the rule of 5 (RO5), which is one of the most widely used concepts to qualitatively predict oral drug absorption. The group analyzed 2245 compounds from the World Drug Index (WDI) database that were either considered for, or entered into, Phase II clinical trials. Results indicate that good oral absorption is more likely with drug molecules that have less than 5 hydrogen bond donors (defined as NH or OH groups)/10 hydrogen bond acceptors (defined as oxygen or nitrogen atoms, including those that are part of hydrogen-bond donors), a molecular weight that is smaller than 500, and a calculated lipophilicity (cLog P) that is smaller than 5 (Lipinski 1995, Lipinski 2000, Lipinski et al. 2001). Poor bioavailability is more likely when the compounds violate two or more of the RO5. Using the current data set, we evaluated the relationships between number of violations and bioavailability and the individual processes. From Figure 1, it is evident that median bioavailability dropped considerably from 0.70 to 0.35 (p < 0.005) for the compound subsets with no violation and two violations, respectively. Compounds with three violations showed a further decline in median bioavailability (0.05). However, similar relationship was observed only with Fa but not with Fg and Fh, suggesting that relationship of rule-of-five and bioavailability is associated mainly with intestinal absorption.
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5.3. Biopharmaceutical factors that impact oral drug absorption
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5.3.1. Particle size
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Drug dissolution rate is an important parameter that affects oral drug absorption (Chaumeil 1998, Boobis et al. 2002, Hilgers et al. 2003). A drug is defined as being poorly soluble when its dissolution rate is so slow that dissolution takes longer than the transit time past its absorptive sites, resulting in incomplete oral absorption. Based on the Noyes-Whitney equation, many factors can affect a drug’s dissolution rate (Healy 1984, Frenning and Stromme 2003):
Where DR is the dissolution rate, A is the surface area available for dissolution, D is the diffusion coefficient of the drug, h is the thickness of the boundary diffusion layer adjacent to the dissolving drug surface, Cs, is the saturation solubility of the drug in the diffusion layer, C is the concentration of the drug in the bulk solution at time t. As shown in the equation above, the drug dissolution rate is directly proportional to the surface area of the drug particle, which in turn is increased with decreasing particle size. This can be accomplished by micronization or by the use of nanosuspension to reduce the particle size of the drug and therefore increases drug dissolution rate, which usually is associated with an increase in the extent as well as rate of oral absorption (Chaumeil 1998, Li et al. 2005, Borm et al. 2006). Examples on a drug for which reducing its particle size had significant impact on its dissolution rate is griseofulvin. This molecule has a particularly low solubility and was thus studied as a micronized powder with a median particle size of 3 M (Nystrom et al. 1985, Nystrom and Bisrat 1986). Measurement of the amount dissolved in water versus time using a micronized powder showed that the rate of dissolution depended on the area of contact, which is related to the particle size. Increasing this area was an effective way of increasing the rate of dissolution of this drug (Sjökvist et al. 1989).
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Figure 1.
Relationship between number of violations of rule-offive and bioavailability and individual processes. “n” is the number of compounds in each bin (Varma et al. 2010).
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5.3.2. Salt form
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As noted above, many drug molecules can be classified as either weak acids or bases that tend to form strong ionic interaction with an oppositely charged counter-ion and maintain that interaction through crystallization. The resulting solid comprises charged drug molecules and their associated oppositely charged counter-ions and is usually referred to as salt. The use of salt forms as active pharmaceutical ingredients is well established in the literature (Berge et al. 1977, Chowhan 1978). A salt form of a drug molecule changes the coulombic attraction between the drug molecule and its counterion and alters the potential energy of the solid state. This is usually associated with alteration of the pH of the diffusion layer at the surface of the dissolving solid, and therefore significantly increases the solubility of the parent drug molecule (Cs), in that layer over its inherent solubility at the pH of the dissolution medium (C). In general, these changes can result in a significant increase in the dissolution rates and higher apparent solubility of the drug molecules in physiologically relevant timescales. Overall, if other relevant factors such as chemical stability, permeability, intestinal and liver metabolism remain constant, the dissolution rate of a compound should determine the rate of build-up of blood levels with time and the maximal levels achieved (Nelson 1957, Chowhan 1978, Hendriksen et al. 2003, Huang and Tong 2004, Li et al. 2005).
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In summary, the drug salt form usually alters the drug dissolution rate by modifying the diffusion layer pH at the surface of the dissolving solid (Nelson 1957). Nelson was the first to report this phenomenon in which the salts of acidic theophylline with high diffusion layer pH’s had greater in vitro dissolution rates than those exhibiting a lower diffusion layer pH. In fact, the rank order of dissolution rates of theophylline was closely correlated with the clinical blood exposure. This report led many additional studies that demonstrated the influence of the salt form on drug dissolution and the benefit of changing nonionized drug to salts (Nelson 1957, Nelson 1958, Berge et al. 1977, Nang et al. 1977, Chowhan 1978, Chen et al. 2002, Hendriksen et al. 2003, Huang and Tong 2004, Strickley 2004, Li et al. 2005)
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5.3.3. Polymorphism and drug amorphous form
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Polymorphs of a drug substance are chemically identical. However, due to the differences in their molecular packing, they have different physical properties such as crystal shape, molecular density, melting temperature, hygroscopicity, and enthalpy of fusion (Huang and Tong 2004, Li et al. 2005). Albeit these differences, the various polymorphs tend to have comparable solubility profile. Pudipeddi and Serajuddin evaluated the effect of various polymorphs of drug molecules reported in the literature on their solubility profiles. The group reported that the solubility values of various polymorphs for these drug molecules did not differ more than two-folds. This difference in the solubility value is not expected to have profound impact on the compound biopharmaceutical profile depending on the doses used, particle sizes, and solubility values (Pudipeddi and Serajuddin 2005). However, polymorphism may influence the physical and chemical stability of various drug molecules by influencing the rate and mechanism of decay (Cohen and Green 1973, Matsuda et al. 1993, Singhal and Curatolo 2004). Examples are carbamezepine (Matsuda et al. 1993), indomethacin (Chen et al. 2002), furosemide (De Villiers et al. 1992), and enalapril maleate (Cohen and Green 1973, Eyjolfsson 2002).
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There are significant differences between crystalline polymorphs and the amorphous form of a drug. In general, the amorphous form tends to have significantly higher dissolution rate and solubility compared to their crystalline forms, which may significantly increase their rate and extent of oral absorption. However, the amorphous form is generally less chemically stable due to the lack of a three dimensional crystalline lattice, higher free volume, and greater molecular mobility. The chemical stability of amorphous systems has been discussed in detail elsewhere (Craig et al. 1999, Doelker 2002, Kaushal et al. 2004, Singhal and Curatolo 2004).
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5.3.4. Drug complexation
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The drug complexes of interest are generally divided into two major categories based on the energy of attraction between the components of the complexes. They are (1) covalently linked complexes, (2) ionic/inclusion complexes. It is interesting to note that the energy of attraction of covalently linked complexes is about 100 kcal/mol. Whereas; the latter type of complexes is less than 10 kcal/mol. Examples on covalently linked complexes are prodrugs that are prepared by chemical modification of the drug through the addition of a labile moiety, such as ester group (Van Gelder et al. 2000). This approach is widely used to increase drug solubility/permeability and thus improving drug bioavailability. The labile groups are usually broken by enzymatic action, and the parent drug is freed to produce its pharmacological action. The prodrug approach has been widely used in the development of bacampicillin, chloramphenicol, pivampicillin, and enalapril (Van Gelder et al. 2000, van De Waterbeemd et al. 2001, Beaumont et al. 2003).
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Inclusion compounds, which form the second category of complexes, result more from the architecture of molecules than from their chemical interaction. One of the constituents of the complex is trapped in the cage-like molecular structure of the other to yield a stable arrangement. Cyclodextrins have been most widely used for this purpose, since they can trap lipophilic drugs in their molecular envelope and form a complex having a comparatively more hydrophilic character (Shimpi et al. 2005). It is well established in the literature that a complex formation of a drug with cyclodextrin is known to improve drug solubility or dissolution rate, and thereby its oral bioavailability (Irie and Uekama 1997, Loftsson et al. 2002, Strickley 2004, Shimpi et al. 2005).
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It should be stressed that the drug molecules can also form complexes that may adversely affect their oral bioavailability. One widely reported example is the complexation of tetracycline with aluminum, calcium, or magnesium ions to form an insoluble complex that cannot be absorbed (Kakemi et al. 1968, Kakemi et al. 1968). Before the complexation phenomenon was known, the administration of antacids with tetracycline was suggested to minimize the gastrointestinal disturbance (nausea and vomiting) caused by the antibiotic (Gugler and Allgayer 1990). As most antacids contain aluminum or magnesium hydroxide and/or calcium carbonate ions, such coadministration have reduced greatly the bioavailability of the antibiotic. However, complexation can also arise due to the calcium ions present in milk and other dairy products (Jung et al. 1997). For example, for democycline, only 13% was absorbed when administered with milk. Doxycycline has been reported to be less prone to complexation with dairy products, yet only 10% was absorbed when coadministered with aluminum hydroxide gel (Gugler and Allgayer 1990).
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6. BCS and BDDCS
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Solubility and permeability are the fundamental properties determining the bioavailability of an orally active drug. Based on these properties Amidon et al. proposed biopharmaceutic classification system (BCS), which in present times is serving as a guide for regulatory and industrial purposes (Amidon et al. 1995). This concept exploring dose number, dissolution number, and absorption number of an orally administered drug clearly dictate its systemic availability. These three numbers are associated with a number of multifaceted hurdles, which include (i) physicochemical properties of the molecule (solubility/dissolution) (ii) stability of drug in GI environment (acid degradation) (iii) enzymatic stability in GI lumen, epithelium and liver (iv) permeability (molecular weight, log P, H-bonding efficiency) and (v) substrates specificity to various uptake and efflux transporters. The US FDA, other regulatory agencies, and healthcare organizations have implemented the BCS to enable the use of in vitro solubility and permeability data to waive conducting expensive bioequivalence clinical studies (BE) of high solubility-high permeability (Class I) drugs. While the pharmaceutical industry has taken advantage of BCS-based biowaivers, its principles are used throughout the drug discovery and development to drive oral active programs. On the basis of the apparent correlation between intestinal permeability rate and extent of drug metabolism, Benet and coworkers proposed biopharmaceutics drug disposition classification system (BDDCS), and suggested that the extent of drug metabolism may be used for characterizing high intestinal permeability drugs (Wu and Benet 2005, Benet 2009).
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7. Intestinal metabolism
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Small intestine has an ability to metabolize drugs by several pathways involving both phase I and phase II reactions and may lead to limited oral bioavailability. CYP3A4, the most abundant cytochrome P450 present in human hepatocytes and intestinal enterocytes is implicated in the metabolic elimination of many drugs (Paine et al. 2006; Thummel 2007). It has also been proposed that drug interactions involving CYP3A inhibition and induction may be largely occurring at the level of the intestine (Hebert et al. 1992, van Waterschoot et al. 2009). In a recent analysis of 309 drugs with intravenous and oral clinical pharmacokinetic data, we noted that roughly 30% of the drugs in the data set show more than 20% intestinal extraction, underscoring the importance of considering intestinal metabolism in predicting bioavailability and dose projections in drug discovery and development settings (Varma et al. 2010). Although, the average human intestinal content of CYP3A has been estimated to be only about 1% of the average hepatic content (Paine et al. 2006), the data set indicated that intestinal metabolism may contribute to first-pass extraction more than the hepatic metabolism for certain drugs. This could be a result of better access to the enzymes in the enterocytes; a function of transcellular flux and the large absorptive area, and/or due to reduced access to hepatic enzymes because of potential plasma protein binding (Thummel 2007).
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The intestinal first-pass metabolism in humans is indirectly estimated under certain assumption, by comparing the plasma AUCs following intravenous and oral dosing. Early studies in liver transplant patients during the anhepatic phase indicated the relative importance of the gut extraction to the first-pass metabolism for drugs such as midazolam and cyclosporine (Paine et al. 1996). Further clinical evidences were obtained in the grape-fruit juice interaction studies, where coadministration of grape-fruit juice result in the inhibition of gut CYP3A4 without significantly affecting the hepatic metabolism of drugs like felodipine (Gertz et al. 2008). However, assessment of the quantitative contribution of intestinal and hepatic extraction in first-pass metabolism is limited by ethical and technical challenges. There exist gaps in predicting the gut extraction before the clinical development stage due to shortcomings in the in vitro-in vivo extrapolation (Eg. utilizing human intestinal microsomal stability). Also species differences exist where rat and monkey typically under-predicts the fraction escaping gut extraction (Fg) in human (Cao et al. 2006, Nishimuta et al. 2010). Recently, transgenic mice model with constitutive expression of human CYP3A4 in liver or intestine that provides quantitative estimation of the contribution of hepatic and gut extraction to the first-pass metabolism has been generated (van Waterschoot et al. 2009). Overall, due to limited access to the sophisticated models and complexities with in vitro in vivo extrapolation and species differences, intestinal metabolic disposition is far from consistently predictable.
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Recent studies demonstrated that efflux transporters present on the apical membrane of enterocytes, in particular Pgp, can affect the intestinal metabolism by prolonging the enterocytic transit time and consequent exposure to CYP3A enzymes (Wacher et al. 2001). A significant overlap has also been identified between substrates and inhibitors of CYP3A4 and Pgp, suggesting that these two proteins may act complementarily in further limiting Fg of CYP3A substrates. Due to the complexity in these biochemical processes and the lack of availability of extensive experimental models, application of physiologically-based pharmacokinetic (PBPK) models and systems biology seem to provide quantitative prediction of first-pass metabolism. These emerging tools aim towards appropriate reconstruction of the physicochemical, anatomical and biochemical complexities in mathematical terms.
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8. Conclusions
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Reliable delivery of drugs via oral administration is most sort after in drug industry. Consequently, the design and development of orally active drugs has to take into account a plethora of factors which may include the physicochemical, biopharmaceutical and physiological determinants. While, solubility and permeability, are fundamental biopharmaceutical parameters that determine the oral absorption, physicochemical and drug substance properties are directly or indirectly associated with these parameters. Lipophilicity, hydrogen bonding ability and number of rotatable bonds are generally identified as critical molecular properties of drugs influencing the rate of membrane transport and thus the intestinal absorption (Fa). However, for drugs with low membrane permeability, role of uptake and efflux transporters may become significant and thus need appropriate characterization. It is believed that targeting intestinal uptake transporter and circumventing efflux transporters may be an useful strategy to design drugs with oral activity. Understanding the contribution of intestinal metabolism to the oral bioavailability is also key in projecting clinical pharmacokinetics and doses. Modeling intestinal absorption and metabolism is complicated due to variability in the physiology and gradient enzyme and transporter localization. Nevertheless, better characterization of factors influencing intestinal absorption and metabolism might result in improved pharmacokinetic optimization in discovery and development settings.
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\n\t\n',keywords:null,chapterPDFUrl:"https://cdn.intechopen.com/pdfs/29240.pdf",chapterXML:"https://mts.intechopen.com/source/xml/29240.xml",downloadPdfUrl:"/chapter/pdf-download/29240",previewPdfUrl:"/chapter/pdf-preview/29240",totalDownloads:27094,totalViews:4608,totalCrossrefCites:27,totalDimensionsCites:57,totalAltmetricsMentions:0,impactScore:40,impactScorePercentile:100,impactScoreQuartile:4,hasAltmetrics:0,dateSubmitted:"March 25th 2011",dateReviewed:"September 28th 2011",datePrePublished:null,datePublished:"February 22nd 2012",dateFinished:null,readingETA:"0",abstract:null,reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/29240",risUrl:"/chapter/ris/29240",book:{id:"672",slug:"topics-on-drug-metabolism"},signatures:"Ayman El-Kattan and Manthena Varma",authors:[{id:"85539",title:"Dr.",name:"Ayman",middleName:null,surname:"El-Kattan",fullName:"Ayman El-Kattan",slug:"ayman-el-kattan",email:"Ayman.El-Kattan@pfizer.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"88221",title:"Dr.",name:"Manthena",middleName:null,surname:"Varma",fullName:"Manthena Varma",slug:"manthena-varma",email:"Manthena.V.Varma@pfizer.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Concepts and theoretical calculations of oral bioavailability",level:"1"},{id:"sec_3",title:"3. Mechanism of oral absorption",level:"1"},{id:"sec_3_2",title:"3.1. Passive diffusion",level:"2"},{id:"sec_4_2",title:"3.2. Active transport",level:"2"},{id:"sec_6",title:"4. Absorption kinetics",level:"1"},{id:"sec_7",title:"5. Physiological, physicochemical and biopharmaceutical factors that impact oral drug absorption ",level:"1"},{id:"sec_7_2",title:"5.1. Physiological factors that impact oral drug absorption ",level:"2"},{id:"sec_7_3",title:"5.1.1. Gastro-intestine anatomy and physiology",level:"3"},{id:"sec_8_3",title:"5.1.2. Unstirred water layer",level:"3"},{id:"sec_9_3",title:"5.1.3. Gastrointestinal transit times",level:"3"},{id:"sec_10_3",title:"5.1.4. The GIT pH",level:"3"},{id:"sec_11_3",title:"5.1.5. Bile fluid",level:"3"},{id:"sec_12_3",title:"5.1.6. Bacterial microflora",level:"3"},{id:"sec_13_3",title:"5.1.7. Lymphatic absorption",level:"3"},{id:"sec_14_3",title:"5.1.8. Intestinal drug transporters ",level:"3"},{id:"sec_16_2",title:"5.2. Physicochemical factors that impact oral drug absorption ",level:"2"},{id:"sec_17_2",title:"5.3. Biopharmaceutical factors that impact oral drug absorption",level:"2"},{id:"sec_17_3",title:"5.3.1. Particle size",level:"3"},{id:"sec_18_3",title:"5.3.2. Salt form",level:"3"},{id:"sec_19_3",title:"5.3.3. Polymorphism and drug amorphous form",level:"3"},{id:"sec_20_3",title:"5.3.4. Drug complexation",level:"3"},{id:"sec_23",title:"6. BCS and BDDCS",level:"1"},{id:"sec_24",title:"7. Intestinal metabolism",level:"1"},{id:"sec_25",title:"8. Conclusions",level:"1"}],chapterReferences:[{id:"B1",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAbrahamsson\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLennernas\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005 Application of the biopharmaceutic classification system now and in the future. Drug Bioavailability, Estimation of Solubility, Permeability, Absorption, and Bioavailability. 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Adv Drug Deliv Rev, 46\n\t\t\t\t\t1-3 , 89\n\t\t\t\t\t102 .\n\t\t\t'},{id:"B194",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWatanabe\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSawano\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEndo\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSakata\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSato\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2002 Studies on intestinal absorption of sulpiride (2): transepithelial transport of sulpiride across the human intestinal cell line Caco-2. 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A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPalandra\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBrayman\n\t\t\t\t\t\t\tT. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYu\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWare\n\t\t\t\t\t\t\tJ. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006 Breast cancer resistance protein (Bcrp/abcg2) is a major determinant of sulfasalazine absorption and elimination in the mouse. Mol. Pharm., 3\n\t\t\t\t\t1\n\t\t\t\t\t55\n\t\t\t\t\t61 .\n\t\t\t'},{id:"B207",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhou\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2003 Pharmacokinetic strategies in deciphering atypical drug absorption profiles. J. Clin. Pharmacol., 43\n\t\t\t\t\t3\n\t\t\t\t\t211\n\t\t\t\t\t227 .\n\t\t\t'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Ayman El-Kattan",address:null,affiliation:'
Pharmacokinetics, Dynamics and Metabolism Department, Pfizer Inc., USA
Pharmacokinetics, Dynamics and Metabolism Department, Pfizer Inc., USA
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1. Introduction
The goal in this chapter is to contribute to theories of consumer behavior in the context of the psychological experience of choice under the conditions of an explosive and expansive sphere of consumption opportunities against the backdrop of the COVID-19 pandemic. During this pandemic, shopping has become much more intensely concentrated in the online virtual environment consisting of digital formats of commercial transactions, and the space of choice for consumers in that online environment has expanded extensively. During the coronavirus crisis, the volume of e-commerce sites offering an assortment of products grew rapidly and their overall activity increased rapidly [1]. Not only did the number of e-shops and online supermarkets increase, but at the same time the sales offering of individual retailers also grew, no longer limited by the physical space of shelves and counters. “Digital tools enable reduced searching costs and provide instant access to a much wider variety of products and services…” [2]. It is this fact of extending the range of shopping options within the digitized formats of eshops that positively contributed during the COVID-19 pandemic to ensuring the availability of requisite supplies and the possibility of their convenient transport directly to homes, during both personal quarantines and area lockdowns. On the other hand, however, in such a situation of abundant choices, what is known as the Schwartz paradox of choice comes into play [3]. Schwartz’s basic thesis assumes that an overabundance of choices contributes to a decrease in happiness and reduces customers’ motivation to buy. This idea is echoed by other authors. “Not only does offering more options lead to higher costs for the company, larger assortments often lead to lower probability of purchase and decreased satisfaction due to choice overload” [4]. Kinjo and Ebina [5] developed a proprietary mathematical model to calculate the optimal quantity of products offered by retailers in order to maximize sales, depending on the size of customers’ invested costs in product selection. These authors confirm the thesis that markets in the real world and in cyberspace should adapt to a moderately sized product offering, which would lead not only to higher sales but also to much more favorable psychological effects on customer behavior. “Other studies show that people actually experience the greatest satisfaction when choosing from intermediate set of choices, not too small and not too big” [6]. More recently, the problem of the paradox of choice has been addressed at the meta-analytic level of interdisciplinary research in the behavioral and social sciences by Zhang and Xu [7]. In the process they arrived at the surprising finding of a high degree of inconsistency in academic results at both the theoretical and empirical levels of research. In doing so, they applied their own mathematical analysis and extensive simulation theories.
COVID-19 significantly reduced the possibilities of conventional offline shopping and limited the volumes of product offerings for some time [2]. However, business transactions moved rapidly to the online environment and supply chains quickly adapted to the indicators of consumer market demand [8]. The temporary problem of lack of product supply due to the reduction of offline shopping was quickly resolved by the rapid conversion to online sales [9]. Thus, COVID-19 did not significantly restrict freedom of consumer choice, but merely triggered its horizontal transformation and shifted its application to the digitalized sphere of shopping. The paradox of choice, originally elaborated by Schwartz [3] and developed in various contexts by a number of other authors [10, 11, 12], applied universally even in the era of the coronavirus crisis, inaccurately equated with the drastic reduction of consumer freedom of choice and the associated frustration of customers.
In this context, I will expose and evaluate the more general and apparently universally operating foci of tension and conflict generated in an environment of an increasingly dense network of consumption opportunities, in which the decisions of actors and the outcomes of choices are confronted with negative subjective experiences of regret, anxiety, or disappointment. Last, I will identify and sequentially explain the main sources reducing satisfaction from consumer choices made in an environment of abundant opportunities. I will focus on the circumstances of the influence of information, aspirations, and hedonistic adaptation as potential sources of their psychological discomfort. These are firmly integrated in the sphere of consumer decisions yet, I presume, are only minimally reflected in the everyday activities of consumers.
2. Methods
This chapter presents a theoretical study based on critical reflection on the discourse regarding changing consumer behavior during the COVID-19 pandemic. The method used to achieve the stated objectives consisted of critical literature review, comparative analysis, and meta-analytical evaluation of selected review and empirical studies aimed at understanding changes in consumer culture and consumer behavior. The critical literature review mainly reflects studies with a sociological, behavioral economic, social psychological, psychological, and partly anthropological focus. At the same time, more detailed attention has been devoted to a critical review of sociological studies from 2020 to 2022 referencing current transformations of consumer behavior during the time of the COVID-19 crisis. Relevant scholarly sources were identified using the ProQuest and ProquestEbooks databases. The methodological framework is built on an attempt to create a theoretical platform of arguments, insights, critical perspectives, and opinions, challenging some stereotypically accepted conceptions of consumer decision-making and freedom of consumer choice in the era of the COVID-19 pandemic. This chapter is intended to prompt future scholarly efforts to empirically investigate patterns of consumption behavior internalized during the COVID-19 crisis and the dynamics of their further strengthening or, conversely, weakening in the post-COVID period. The theoretical conclusions that follow can be developed and further verified through experimental studies and quantitative and qualitative research methods.
3. Sociological reflection on the transformation of consumer behavior against the backdrop of the COVID-19 pandemic
Consumption levels fell by around 25% in some European countries (e.g. UK, Spain, Italy, and France) during the coronavirus crisis, while in the USA a 10% drop in consumption was recorded during this period [13]. Over the last 2 years, the COVID-19 pandemic has produced not only dramatic economic but also psychosocial effects, transforming many parameters of consumption behavior and more general lifestyle standards [14]. “Among the consequences of the COVID-19 pandemic, we have seen the closing of shops and other business for months. Consumers have avoided public places, stores, and cultural events, even when such establishments were open. As a result, consumers began to change their purchasing behaviors and habits in a sustainable way” [15].
There is now a relatively rich empirical record from 2020 and 2021 documenting the impact of the COVID-19 pandemic as a source of significant changes in consumer decision-making, shopping patterns, and other characteristics, traits, and manifestations of people’s lifestyles. Silva et al. [16] conducted a detailed review of published scientific studies in journals indexed in the WOS and Scopus databases between 2020 and 2021 with the common research topic of changes in consumer behavior and consumption patterns during the COVID-19 pandemic. The study authors identified a total of 416 relevant articles according to the defined selection criteria (87 from 2021 and 329 from 2020). Based on bibliometric, thematic, and content analysis, the authors identified 7 main topical units referencing lifestyle changes related to consumption behavior during the coronavirus crisis: Changes in consumer behavior; Coping with the lockdowns; Information seeking and sharing; Psychological effects; Addictive behavior; Changes in food consumption; Panic buying and hoarding behavior [16]. Interesting data was also provided by their analysis of the keywords of the studies examined, through which the authors identified three main clusters. In this context of examining the ambivalent nature of proliferation of consumer choices, the following frequently occurring keywords in these clusters are relevant: Consumers; Decision-making; Information-seeking behavior; Stress [16]. In this study, the authors simultaneously addressed the question of other topics and issues that should be explored in greater detail in the context of the effects of the COVID-19 pandemic on changes in consumption behavior. One such key question is the problem of consumer choice and strategies for making purchasing decisions.
An even more extensive theoretical study was conducted by Yin, Yu, and Xu [17] on a robust sample of academic studies published between 1981 and 2021 that report on consumer behavior issues. They analyzed very rich research material, which enabled them to reveal changes in consumption behavior in modern societies over the relatively long time frame of the last decades. The authors point out that the COVID-19 pandemic marked an unexpected, rapid step change in lifestyle and consumption changes. According to their analysis of secondary data, the most significant changes in consumption behavior will occur in the sphere of an increased preference for online shopping or increased interest in healthy foods. They also highlight the importance of the more intensive mix of online and offline commerce, which allows consumers to shop more seamlessly and conveniently from anywhere and at any time. In the context of psychological effects during the coronavirus crisis, other authors confirm the increase in feelings of anxiety and insecurity that stems from online panic shopping and stockpiling, especially of food [18].
A similar meta-analysis was conducted by Smith and Machová [19], who analyzed empirical data from the research agencies Ipsos, KPMG, Roland Berger and Potloc, Salesforce, Worldpay/FIS, and YouGov and reported on actual changes in consumer behavior and attitudes during the COVID-19 pandemic. The authors systematize the analyzed data to identify the main foci of changes in people’s lifestyles and daily practices, including consumption behavior, and describe their key attributes [19]. It is confirmed here that the introduction of restrictive measures in the form of home quarantines and blanket lockdowns has produced dramatic social and economic effects in the populations studied, including a fundamental transformation of consumption practices. Consumer activities have shifted massively to virtual environments, with an increased preference for digital shopping via mobile devices and much greater use of online supermarket delivery apps. It has become clear that shoppers have become much more discerning in their product selection and have reorganized their purchasing decision-making strategies in the course of online shopping. It can be assumed that one of the reasons for this change may be that customers are confronted with a concentration of larger volumes of goods and services in the virtual shopping environment. It is here that potentialities complicating the decision-making process and choice have most likely been amplified for the segment of the population that had been accustomed to the conditions of conventional shopping with a more limited range of offerings in the period before the coronavirus crisis.
Šimić and Pap [13] empirically observed changes in consumption behavior during the coronavirus crisis in Croatia within the Generation Z population, whose members are often referred to as “digital natives”. Based on a quantitative data analysis conducted on a sample of 422 respondents, they showed that the consumption behavior of Generation Z during the coronavirus crisis led to much more stockpiling and overbuying. At the same time, they typically concentrated their consumption activities ever more frequently online, which became a global trend during the COVID-19 pandemic. And yet there was no correlation between changes in consumption behavior and perceived quality of life, which the study authors explain by the fact that for Generation Z, online shopping was already the norm in the pre-COVID-19 era, and as such the reduction in physical shopping options was not perceived negatively as a factor reducing their quality of life. The findings of an empirical study by Wang and Na [20] conducted during the COVID-19 pandemic in three Chinese cities confirm that panic shopping and hoarding, especially of food, is a significant manifestation of similar crises, triggering growing feelings of insecurity and fear of the future. Hesham, Riadh, and Sihem [15] empirically demonstrate statistical associations between age and gender moderating specific changes in consumption behavior in a sample of 360 respondents in Saudi Arabia. According to their findings, interest in healthy foods increased sharply during the coronavirus crisis, especially among women and the elderly population, who were observed to have higher levels of anxiety and psychological distress during the pandemic. Gupta, Nair, and Radhakrishnan [21] offer similar empirical conclusions by looking at changes in consumption behavior in India. There, the COVID-19 pandemic initiated panic and impulse buying and the need to stockpile food. Veselovská, Závadský, and Bartková [22] conducted a sociological investigation on a representative sample of the Slovak population to identify and explain the main factors influencing changes in consumption behavior during the COVID-19 pandemic. By analyzing empirical data, they reach similar conclusions as other authors [23], that in times of crisis, the rate of consumption increases and the allocation of financial resources to savings or longer-term investments decreases. At the same time, the authors of the Slovak study stressed that hygiene/epidemiological restrictions and the related restriction of social interactions have significantly influenced people’s mentality, reorganized daily routines and motivations for action, and, last but not least, modified consumption patterns in terms of a transition to digital shopping formats, which was more evident in the female population than in the male population. A number of other similarly focused empirical and theoretical studies are emerging in the early months of 2022.
4. The ambivalence of freedom of choice
In post-industrial societies, the values of material well-being and rising living standards are closely intertwined with the notion of simultaneously maximizing people’s individual freedoms [3]. In other words, existential security and its further strengthening and affirmation in a spiral of increasing abundance should be echoed in parallel at a similarly accelerated and progressive existential level in terms of the emancipation of human freedoms. An integral part of such freedoms is the fulfillment of the premise of a proliferation of choices and decisions in a variety of life situations. It is therefore true that the greater the plurality of choice in each individual decision-making situation, the more intense the personal freedoms people achieve. It should be added that the more freedoms there are, the greater the well-being.
An unbridled offering of products is intended to liberate and emancipate consumers in their ability to make free and authentic choices. In particular, some optimistic scenarios attribute to technological innovation an important function in the creation of abundance in the sense of the ever more voluminous generation of value from fewer resources, but also abundance represented by a more robust selection and variety of options in the areas of everyday consumption, education, and health [24].
There is no doubt that significant expansion of choice as one of the pillars of emancipation of individual freedoms is one of the defining features of the consumer culture of late modern societies. According to Lury [25], it is precisely the trend of accelerated growth in the quantity of types and classes of contemporary goods and the contemporary proliferation of sales and purchasing platforms that forms part of the fundamental parameters of contemporary consumer culture of societal well-being. The expansion of consumption opportunities is fundamentally driven by the increasingly massive conversion of conventional product offerings traditionally determined by the physical context of points of sale, dependent on the personal interactions of sellers and buyers, into the virtual environment of digitized shopping. The online environment of consumer activities is not limited by the space or physical capacity of points of sale and shelves. On the contrary, the virtual shopping environment accelerates the quantitative potential of the assortment of goods on offer and the variability in the selection of types and classes of different products. The digitalization of shopping formats not only contributes to an increase in the quantitative volume of product and service choices, but also to a more creative and personalized shopping experience overall. Thus, consumers are reorganizing their life standards and consumption preferences as a result of the introduction of the technological innovations of digitized shopping [19].
The COVID-19 pandemic has contributed substantially to the speed of these changes, accelerated by the reorganization of consumer shopping patterns and the redefinition of consumption behavior. Everyday life was significantly transformed as a result of widespread lockdowns and home quarantines, as were routine consumer activities. Thus, opportunities for socially interactive individual shopping were reduced, leading to a massive shift of product offerings and sales to online virtual environments [26]. The digitalization of shopping formats has thus directly and indirectly influenced customers’ consumption habits and decision-making strategies [27].
As such, the empirically identified and explicitly described causes of changes in consumption behavior thus undoubtedly include the fact of the forced conversion of conventional shopping to the virtual environment, where the confrontation of customers with the abundance of offerings was intensified and had essentially no other alternative. We can also see changes in the decision-making strategies of customers according to a meta-analysis of empirical data from various reputable public opinion research agencies that tracked various parameters of changes in consumer behavior during the COVID-19 pandemic. “Consumer decision-making and behavior change have rapidly adapted based on a range of individual and contextual characteristics” [19]. At the same time, there should also be evidence of higher levels of customer procrastination and even more demanding product selection criteria from shoppers.
In the spirit of rational choice theory, this is an uncomplicated situation, since every concrete decision and choice made is the result of a stable and reliably functioning hierarchy of the social actor’s priorities and preferences of a social actor, who rationally applies such a system in every similar situation requiring an act of choice, regardless of the number of options needing to be compared and evaluated with each other as part of the implementation of the choice [28].
According to other behavioral economic studies, the conditions of such shopping are not only potentially more creative, varied, and comfortable, but also much more psychologically complicated and even reduce the level of positive feelings about shopping. Masatlioglu and Suleymanova [29] for example, address questions related to the adequate decision-making strategies of consumers and the dangers of procrastination or shopping resignation under the conditions of a dense network of product offerings that should psychologically facilitate choice and practically optimize its outcome. After all, consumers are confronted with numerous psychological and cognitively distorting elements of human thought [30]. While consumers seek to maximize their own utility and assume that their choices in acts of decision-making will lead to this maximization, the outcomes of choice often do not produce the expected effects. In fact, the little-considered reality of the ambivalent nature of consumer culture, sometimes referred to and interpreted as the “culture of overchoice” [31], fundamentally casts doubt on optimistic scenarios referencing theses of increasing consumer comfort and growing feelings of freedom, independence, authenticity, and pleasure resulting from accelerating consumer product choices [24], as assumed, for example, by economic theories of rational choice [32]. While acts of decision-making in an environment of growing choices increase the potential to achieve objectively better, i.e., higher quality, more useful, or more advantageous outcomes, they often instead paradoxically awaken feelings of uncertainty, anxiety, internal tension, disappointment, remorse, or regret [33, 34]. The thesis of a relationship between the escalation of the range of options, the growth of demands for continuous decision-making, and the increasing level of consumer dissatisfaction is also considered at a more general level by other authors [35, 36, 37].
5. Why less can be more
In the conditions of a performance consumer society, active participation in consumption is an indicator of individual success, prestige, and recognition [38]. The function of consumption is simultaneously to construct and reconstruct identities and to model social roles. It is becoming a source of self-reflection and the formation and sharing of symbolic worlds [39]. The consumer culture of affluent societies is equated with a culture of “many opportunities”, providing ever greater volumes of choices and consumption goals in an expanding variety of product offerings. “There are millions of products available on store shelves nowadays” [40]. These conditions then contribute to a conviction that individual freedoms are continually increasing, both in the sphere of the material consumption of shopping itself, and in the dimension of symbolic values and signs, achieved and (re-)defined through different models of consumption behavior.
Consumer culture is characterized by an ambivalent nature. The more diverse and voluminous offering of choices on one hand raises optimistic expectations of expanding individual freedom and independence, while on the other hand it leads to high demands for individual responsibility in making choices and experiencing the outcomes of choices. According to some authors, this very fact leads to negative effects in the form of psychological discomfort, when the degree of inner anxiety and uncertainty and feelings of self-defeat increase as a result of a more complex decision-making process in an environment of many opportunities. Motivations grow stronger to postpone the decision or completely resign from making a choice [41]. On the contrary, similar experiences of negative emotions in the form of remorse and dissatisfaction might not occur in conditions of limited choices. In fact, the outcome of a choice in a situation of limited choices significantly relativizes the feeling of personal responsibility. Each individual decision takes place against a background of minimized consumer choice, and responsibility for the outcome in a context of limited choice can be at least partially shifted to the external circumstances of the system. For example, until the late 1980s, the range of consumer goods in socialist Czechoslovakia was dramatically reduced as the result of its centrally planned state economy to such an extent that something like the psychological discomfort of consumer choice was almost unknown. In such a world, part of the personal responsibility for choices made was thus transferred to an anonymous system of political, economic, cultural, or social parameters of society. Thus, every disadvantageous decision or bad choice need not be experienced as a personal failure. In contrast, a world of hypertrophy of opportunity delegates this responsibility strictly to individuals, who have to deal with the consequences of their own decisions independently. This has not ceased to be the case even during the COVID-19 pandemic, when freedom of consumer choice was preserved in spite of certain expectations and intensively exercised in the online environment of digital shopping formats. For some types of products in particular, freedom of choice was maintained and, in some cases, even enhanced due to the virtual environment.
Feelings of psychological discomfort under conditions of abundant choice are partially caused by opportunity cost. This is a situation where the satisfaction of each individual decision decreases as the number of options increases. For each individual choice at the same time means the rejection of other opportunities that remain unused and untried. Consumers develop fictions and fantasies, imagining hypothetical situations of alternative choices and comparing these with the outcome of a real choice that may appear disadvantageous or unattractive compared to similar imaginings. For example, the average supermarket today offers around 40,000 different items, but the average household needs on average around 150 products to ensure normal operations [42]. This means that the vast majority of the products offered by the average supermarket pass through the filters of consumer choice, at the cost of increasing opportunity cost. In the COVID-19 era, it is possible to consider some reduction in opportunity cost (and a reduced sense of “feeling of missing out”) when consumer choice did not only focus on mainstream consumer products (food, clothing, electronics) but also, for example, on various activities and entertainment requiring social contacts. During the lockdown in particular, the options for paid and unpaid leisure activities were very limited and the space for choice drastically restricted.
In the post-COVID era, we are now witnessing the rapid revitalization of the space of choice in various areas of consumption, which reinforces feelings of individual freedom, yet also implies an increase in transaction costs. According to Mlčoch [43], the decision-making process and each choice made place considerable demands on the time, energy, and cognitive abilities of consumers seeking and comparing information about products, their prices, quality, and countless other characteristics. The increasing transaction costs associated with choice may ultimately lead consumers to resign and definitively refuse to make the planned choice. Vardi [44] illustrates such a situation with the example of Jewish emigrants from the Soviet Union who, after very difficult negotiations with the Soviet authorities, were allowed to emigrate to Israel on a limited basis in the early 1970s. Smaller groups of Soviet emigrants were confronted in Israel with a Western-style economy and a standard of living equivalent to Western welfare standards. According to some memoirs, Jewish emigrants accustomed to the conditions of shopping in the Soviet Union found it difficult to navigate the goods on offer in Israeli supermarkets and often left without making a purchase.
This brings us to the problem where the principle of “more is better” moves actors not toward liberation but rather closer to states of paralysis and passivity. Czech [6] reached conclusions supporting this thesis in the present when studying the functioning of Swedish pension funds in recent decades. While 70 financial companies in Sweden had offered a total of 465 pension funds in 2000, this increased to 800 in 2006; by 2015, 102 companies were involved in the administration of a total of 843 pension funds in Sweden [6]. The consequence of the increasing options for types of pension savings was a delay in potential buyers pursuing such savings and an overall decline in pension savings contracts. For example, Google, following the recommendation of the results of one of its marketing studies, decided to increase the number of links listed on a single page when a specific password was entered. This move was oriented toward accommodating Google’s customers, who had repeatedly expressed in surveys a desire to increase the amount of input when searching for information. When Google tripled the number of links per page, search and information tracking through Google began to plummet [45].
And yet other, namely behavioral economics studies consider this type of paralysis and resignation from making decisions due to being overwhelmed with large volumes of choices to be rather rare [46]. The more significant problem, as they see it, is the implementation of decisions that are not only disadvantageous, but often fatally damaging to the interests of the actors themselves. This is attributed to people’s limited attention spans, their easy manipulability, and the underestimation or unintentional disregard of important product parameters, referencing their price or quality. In general, the behavioral economics perspective accepts the thesis that freedom of choice is not a guarantee of an efficient decision-making process, but only the potential to achieve optimized choice outcomes in terms of pursuing one’s own goals and priorities. The reason is that the effectiveness of the decision-making process is significantly impaired by the limits of people’s cognitive capacities and limited attention. When cognitive resources are depleted and attention is declining, the decision-making process turns into a shallow, intuitive affair, generating many missteps. This is especially true when dealing with information, where increasing volumes of information often do not lead to more efficient solutions and decisions, but rather to suboptimal outcomes and higher overall transaction costs [47].
6. The problem of choice and reduced satisfaction: Information, aspiration, adaptation
At a general level, the behavioral and social sciences confirm the thesis that the proliferation of choices fundamentally complicates acts of decision-making, increases costs for consumers, and leads to an increase in indecision and feelings of dissatisfaction. Yet consumers reject potential and actual reductions in choice and experience them as a threat to their freedom of choice, especially for certain types of products [48]. This was confirmed during the COVID-19 pandemic, when the reduction of offline shopping options triggered a strong psychological response from consumers [2, 26]. As a result, business activities were concentrated in the online virtual shopping environment while more or less maintaining the abundance of product choices that consumer markets demanded. At the same time, due to health concerns, consumer demand grew for non-standard distribution channels for the goods purchased [49].
Let us next attempt to summarize and briefly describe the possible effects that may act as complementary and interrelated forces in the extensive field of consumer choices. Why, then, might we feel worse off in situations “when we have more”?
First of all, this is a problem of information. The easy availability and abundance of information is not only a more general defining feature of a contemporary technologically advanced society [50] and a common attribute of everyday behavior, but also an elementary principle of the functioning of consumer culture, where it is reproduced and confirmed by a globally functioning and operating platform of information flows from producers, sellers, and consumers. Decision-making based on easy and quick access to large volumes of information should, according to all the assumptions of rational choice theory, optimize choice or lead consumers to favorable or desirable choice outcomes in terms of their own expectations and desires. And yet behavioral economists point to the practical problem of people’s cognitive limits and their declining ability to gather, organize, compare, and evaluate all available information on different products of interest in a comprehensible way. Thus, more information and escalating choices may not necessarily lead in a linear fashion to greater efficiency in achieving individual goals and making the most advantageous decisions. “However, because of limited attention and cognitive resources, people are not able to use all available information and freedom of choice effectively to achieve their own best interests” [40]. Imagine the amount of information that customers must accumulate, evaluate, and compare in their search for the best possible product choice when, for example, even a single brand of sporting goods in a retailer’s catalog represents more than two dozen different individual parameters in an offering of tens and hundreds of other models of a similar product from other brands [33]. Is it even possible to organize and mutually compare hundreds and perhaps thousands of pieces of information from different quality parameters and features among such a wide range of product offerings?
Consumers are sensitive to this fact; as early as at the stage of decision and the making of the choice itself, they may be anticipating the inner turmoil and uncertainty of the final choice. Recall that this anticipation of internal tension due to a lack of options and means to evaluate all the information available to retailers is based on the knowledge that every choice made also implies a decision not to make alternative choices that may be more advantageous overall or that may prove after some time to have been more advantageous. The fact that consumers decide for the best possible option out of the available choices based of the amount of information available to them is thus accompanied by ongoing uncertainty and doubt, which also reduces the subjective feelings of satisfaction in and enjoyment of the product purchased. “However, the increasing personal anxiety and rising transaction costs associated with informing oneself about choices from an ever-larger set of goods on offer can still be ‘incorporated’ into a standard theory of consumer behavior” [42].
There are, however, at least two other reasons whose functions and meanings are somewhat outside the scope of research attention and are generally neglected even by the “standard” theories of consumer behavior. These are the issues of aspirations and hedonistic adaptation.
We examine the question of aspirations in the form of hopes and expectations of what we want to achieve in the area of consumer welfare. As a rule, these tend to increase in situations of high material security, accompanied by a proliferation of consumption opportunities as an inseparable feature of the rising standard of living in affluent societies. Furthermore, consumer aspirations are systematically and programmatically initiated by a dense network of information flows, images, and messages produced by the advertising industry’s media apparatus and by advanced tools of integrated marketing communication, including the use of sophisticated artificial intelligence technologies. In the media-amplified hedonistic orientation of life, complete with examples and presentations of different variants and models of the attractiveness of lifestyles, the ethos of “a life of unlimited possibilities”, “a world without limits”, “a life of infinite opportunities” is awakened, which inevitably widens the gap between the reality (what we actually achieve) and the possibility (what we would like to achieve).
Lastly, there is the problem of (hedonistic) adaptation, which is closely related to the effects of increasing aspirations. Hedonistic adaptation, in the case of consumption, is what subsequently weakens the intensity of the initial enjoyment and the pleasure from the goods acquired (we find interesting similarities here with Weber-Fechner’s law defining the relationship between psychic stimulus and perceived change—if the intensity of a stimulus grows by a geometric order of magnitude, then the intensity of the sensation grows by an arithmetic order of magnitude).
Behavioral economics here assumes that people are emotionally adaptive, finding support for this claim in Brickman and Campbell’s psychological theory of hedonistic adaptation [51]. Thus, achieving a higher degree of consumer well-being may cause a certain fluctuation or deflection in the level of subjective happiness, however this returns to its original level after a certain period of time. Many consider that the achievement of a feeling of happiness lies in notions of fulfillment of aspirations, and yet once the goalposts are passed and these aspirations realized, they are quickly forgotten and cast into the past as unnecessary artifacts of one’s own biography. This explains why there is such fervent pursuit of ever higher standards of living in affluent societies, why people endeavor to make their material comfort even more “comfortable” and convenience ever more “convenient”. The past is always judged from the perspective of a higher aspirational level, and perhaps we too easily succumb to the illusion of the added value of well-being to a future from which perhaps too much is expected.
Hedonistic adaptation seems to operate at another level as well. Namely, consumers may exhibit a decreased ability to predict the chilling effect of adaptation due to higher expectations, also based on their own belief that their choice will be the “best” choice (depending on their ability to obtain, compare, and evaluate information). This contributes to the optimistic scenario of hoping that the choice will not bring disappointment, but rather longer-term feelings of satisfaction. However, these aspirations mean that the effects of hedonistic adaptation will weigh all the more heavily on this group of consumers. When one considers how quickly the costs associated with seeking the best price for a product are “amortized” over time as a result of hedonistic adaptation, their losses seem all the greater.
7. Conclusion
Consumer culture does not consist solely of a specific type of material culture and does not only express systems of relationships to material values. It represents a world of symbols and signs that transforms material goods into their immaterial meanings, including the creation of identities, sources of self-reflection, and modifications of social roles, including the definition and redefinition of social relationships. Consumer culture is subject to changes of varying intensity, depth, and duration. The most significant transformations of recent decades would include not only the democratization of consumerism, but also the expansion of consumption opportunities and the unprecedented abundance of consumer choices. Consumer culture is characterized by its ambivalent nature. In the spirit of rational choice theory, the proliferation of choices is a positive and universally useful phenomenon, which also promotes a desired emancipation of individual freedoms. However, from the perspective of behavioral economists and many sociologists and social psychologists, this phenomenon is problematic and highly ambiguous, as it generates social and psychological risks that are unseen and difficult to predict. What was originally a rational and generally accepted requirement for the constant expansion of the space of choice has become an irrational desire with considerable potential to harm all those concerned. In this context, the “more is better” principle is a significant complication for consumers, where it is increasingly difficult to operate without experiencing cognitive dissonance, self-blame, regret, and feelings of self-defeat. Moreover, empirical research during the COVID-19 pandemic has demonstrated the importance to consumers of feelings of safety and security, which will likely be a central theme of the shopping experience in the post-COVID era [22]. At the same time, there are many overlooked arguments to support the claim that the limitation of consumer choice during the COVID-19 crisis occurred only partially and only in the conventional shopping environment. And yet the freedom of consumer choice for certain types of products was maintained and even enhanced in the virtual shopping environment. The psychological discomfort associated with choice in an environment of many opportunities was therefore not eliminated and may have contributed to the overall psychological discomfort and mental distress during the lockdown. However, during the COVID-19 era opportunity cost was decreasing, particularly for paid forms of entertainment and leisure activities involving social contact (concerts, sports matches, etc.).
At present, we have an opportunity to observe many social initiatives, the dematerialization movement, and numerous spontaneous civic manifestations whose appeals have intensified precisely at the time of the COVID-19 pandemic, and in recent weeks in the context of the war in Ukraine, rising inflation, and the scarcity of some strategic raw materials. These call for changes in the politics of lifestyles in the spirit of the principle of “less is more”, a transformation of value orientations appealing to ecological and environmental responsibility, solidarity, and accountability, voluntary frugality, life minimalism or alternative hedonism as a return to the roots of the philosophical agenda of Epicureanism, in which hedonism was defined by “modest materialism and tranquility”. The rule should be to live a rich life by modest means. In these transformations of life attitudes and value worlds, it is not only the actual patterns of consumption behavior and the motivations for consumption decisions that are fundamentally changing for individuals and groups, but also the deeper layers of their identities, which will seek new sources of affirmation in the environment of consumer culture markets. The question then remains as to what form these sources of identities will take and in what direction they will be further developed in terms of the interactions of markets and consumers, such that markets may retain the direction of “more is better” or all the preconditions of economic prosperity and growth as the condicio sine qua non of their existence, while at the same time offering sufficiently credible sources of social identities to newly emerging alternatives to (counter-) consumerism, intertwined in many ways with its radical reduction and rejection. Thus, it is not only consumers in decision-making and choice implementation situations that find themselves in an ambivalent situation, but also the markets themselves, as well as the accompanying systems of marketing support for consumer culture that respond to current and future lifestyle politics.
Acknowledgments
The result was created with the use of institutional support for long-term conceptual development of research of the University of Finance and Administration.
\n',keywords:"abundance, choice, consumer culture, consumer opportunities, decision making, consumer behavior, consumption, COVID-19",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/82289.pdf",chapterXML:"https://mts.intechopen.com/source/xml/82289.xml",downloadPdfUrl:"/chapter/pdf-download/82289",previewPdfUrl:"/chapter/pdf-preview/82289",totalDownloads:2,totalViews:0,totalCrossrefCites:0,dateSubmitted:"April 20th 2022",dateReviewed:"May 31st 2022",datePrePublished:"June 27th 2022",datePublished:null,dateFinished:"June 17th 2022",readingETA:"0",abstract:"The defining feature of contemporary consumer culture is the escalation of consumption opportunities and the expanding space for choice. An unbridled and unrestricted range of products is part of material prosperity, rising living standards, and emancipation of human freedoms. The growing demands for constant consumer decision-making in an increasingly opaque environment of potential targets of choice exposes consumers to the risk of procrastination, passivity, and resignation, as well as psychological discomfort. The goal here is to contribute to theories of consumer behavior in the context of the psychological experience of choice under the conditions of the accelerated quantity of consumption volumes against the backdrop of the COVID-19 pandemic. While conventional offline shopping was drastically curtailed during the coronavirus crisis, freedom of consumer choice was maintained despite many proclamations to the contrary. I seek to provide support to the claim that freedom of consumer choice was maintained and often amplified during the pandemic in the online virtual environment of digital commerce formats. Freedom of consumer choice has merely been transformed into a horizontal level of application by the relatively rapid and fluid conversion of market activities into the cyberspace of a growing number of e-stores and online supermarkets, unconstrained by the physical space of shelves and counters.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/82289",risUrl:"/chapter/ris/82289",signatures:"Ondřej Roubal",book:{id:"11581",type:"book",title:"A New Era of Consumer Behavior - Beyond the Pandemic",subtitle:null,fullTitle:"A New Era of Consumer Behavior - Beyond the Pandemic",slug:null,publishedDate:null,bookSignature:"Dr. Umut Ayman",coverURL:"https://cdn.intechopen.com/books/images_new/11581.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-80356-183-7",printIsbn:"978-1-80356-182-0",pdfIsbn:"978-1-80356-184-4",isAvailableForWebshopOrdering:!0,editors:[{id:"210632",title:"Dr.",name:"Umut",middleName:null,surname:"Ayman",slug:"umut-ayman",fullName:"Umut Ayman"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Methods",level:"1"},{id:"sec_3",title:"3. Sociological reflection on the transformation of consumer behavior against the backdrop of the COVID-19 pandemic",level:"1"},{id:"sec_4",title:"4. The ambivalence of freedom of choice",level:"1"},{id:"sec_5",title:"5. Why less can be more",level:"1"},{id:"sec_6",title:"6. The problem of choice and reduced satisfaction: Information, aspiration, adaptation",level:"1"},{id:"sec_7",title:"7. Conclusion",level:"1"},{id:"sec_8",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'Santo PE, Marques AMA. Determinants of the online purchase intention: hedonic motivations, prices, information and trust. Baltic Journal of Management. 2022;17:56-71. DOI: 10.1108/BJM-04-2021-0140'},{id:"B2",body:'Rydell L, Kucera J. Cognitive attitudes, behavioral choices, and purchasing habits during the COVID-19 pandemic. Journal of Self-Governance and Management Economics. 2021;9:35-47. 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DOI: 10.1145/3488554'},{id:"B45",body:'Graves P. Consumerology. In: The Truth about Consumers and the Psychology of Shopping. 2nd ed. London: Nicholas Brealey Publishing; 2013. p. 228'},{id:"B46",body:'Scheibehenne B, Greifeneder R, Todd PM. Can there ever be too many options? A meta-analytic review of choice overload. Journal of Consumer Research. 2010;37:409-425. DOI: https://doi.org/10. 1086/651235'},{id:"B47",body:'Campbell JY, Jackson HE, Madrian BC, Tufano P. Consumer financial protection. Journal of Economic Perspectives. 2011;25:91-114. DOI: 10.1257/jep.25.1.91'},{id:"B48",body:'Argouslidis PC, Skarmeas D, Kühn A, Mavrommatis A. Consumers’ reactions to variety reduction in grocery stores: a freedom of choice perspective. European Journal of Marketing. 2018;52:1931-1955. DOI: 10.1108/EJM-12-2016-0844'},{id:"B49",body:'Pantano E, Pizzi G, Scarpi D, Dennis C. Competing during a Pandemic? Retailers’ ups and downs during the COVID-19 outbreak. Journal of Business Research. 2020;116:209-213. DOI: 10.1016/j.jbusres.2020.05.036'},{id:"B50",body:'Leonhard G. Technológia vs. Humanita. 1st ed. Bratislava: Slovenská inovačná a energetická agentura; 2018. p. 360'},{id:"B51",body:'Brickman P, Campbell D. Hedonic relativism and planning the good society. In: Appley MH, editor. Adaptation-level theory: A symposium. 1st ed. New York: Academic Press; 1971. pp. 287-301'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Ondřej Roubal",address:"ondrej.roubal@vsfs.cz",affiliation:'
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AFFILIATION
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Authors are responsible for ensuring all addresses and emails provided are correct. Under affiliation(s) all Authors should indicate where the research was conducted. Please note that no changes to the affiliation(s) can be made after the chapter has been published.
Substantially contribute to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work
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Participate in drafting or revising the work
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All contributors who meet these criteria are listed as Authors. Their exact contributions should be described in the manuscript at the time of submission.
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Conversely, all contributors who do not meet these criteria should be listed in the Acknowledgments section of the manuscript, along with a short description of their specific contributions.
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CHANGES IN AUTHORSHIP
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If it is felt necessary to make changes to the list of Authors after a manuscript has been submitted or published, it is the responsibility of the Author concerned to provide a valid reason to amend the published list. Additionally, all listed Authors must verify and approve the proposed changes in order for any amendments to be made.
\n\n
AFFILIATION
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Authors are responsible for ensuring all addresses and emails provided are correct. Under affiliation(s) all Authors should indicate where the research was conducted. Please note that no changes to the affiliation(s) can be made after the chapter has been published.
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Policy last updated: 2017-05-29
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As in living creatures, activities inside the robot include behavior initiators: self-activating networks that burn energy and function without external stimulus. Autonomy is achieved by mimicking the dynamics of biological brains, in resting situations, a default state network (DSN), specialized set of energy burning neurons, assumes control and keeps the robot in a safe condition, where other behaviors can be brought to use. Our ANC contains several kinds of neural nets trained with gradient descent to perform specialized jobs. The first group generates moving wave activities in the robot muscles, the second yields basic position/presence prediction information about sensors, the third acts as timing masters, empowering sequential tasks. We add a fourth category of self-activating networks that push behavior from the inside. Through evolutive methods, the composed network share clue information along a few connecting weights, producing self-motivated robots, capable of achieving noticeable self-level of competence. 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He is also a faculty member in the Molecular Oncology Program. He obtained his MSc and Ph.D. at Oregon State University and Texas Tech University, respectively. He pursued his postdoctoral studies at Rutgers University Medical School and the National Institutes of Health (NIH/NIDDK), USA. His research focuses on biochemistry, biophysics, genetics, molecular biology, and molecular medicine with specialization in the fields of drug design, protein structure-function, protein folding, prions, microRNA, pseudogenes, molecular cancer, epigenetics, metabolites, proteomics, genomics, protein expression, and characterization by spectroscopic and calorimetric methods.",institutionString:"University of Health Sciences",institution:null},{id:"180528",title:"Dr.",name:"Hiroyuki",middleName:null,surname:"Kagechika",slug:"hiroyuki-kagechika",fullName:"Hiroyuki Kagechika",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180528/images/system/180528.jpg",biography:"Hiroyuki Kagechika received his bachelor’s degree and Ph.D. in Pharmaceutical Sciences from the University of Tokyo, Japan, where he served as an associate professor until 2004. He is currently a professor at the Institute of Biomaterials and Bioengineering (IBB), Tokyo Medical and Dental University (TMDU). From 2010 to 2012, he was the dean of the Graduate School of Biomedical Science. Since 2012, he has served as the vice dean of the Graduate School of Medical and Dental Sciences. He has been the director of the IBB since 2020. Dr. Kagechika’s major research interests are the medicinal chemistry of retinoids, vitamins D/K, and nuclear receptors. He has developed various compounds including a drug for acute promyelocytic leukemia.",institutionString:"Tokyo Medical and Dental University",institution:{name:"Tokyo Medical and Dental University",country:{name:"Japan"}}},{id:"94311",title:"Prof.",name:"Martins",middleName:"Ochubiojo",surname:"Ochubiojo Emeje",slug:"martins-ochubiojo-emeje",fullName:"Martins Ochubiojo Emeje",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94311/images/system/94311.jpeg",biography:"Martins Emeje obtained a BPharm with distinction from Ahmadu Bello University, Nigeria, and an MPharm and Ph.D. from the University of Nigeria (UNN), where he received the best Ph.D. award and was enlisted as UNN’s “Face of Research.” He established the first nanomedicine center in Nigeria and was the pioneer head of the intellectual property and technology transfer as well as the technology innovation and support center. Prof. Emeje’s several international fellowships include the prestigious Raman fellowship. He has published more than 150 articles and patents. He is also the head of R&D at NIPRD and holds a visiting professor position at Nnamdi Azikiwe University, Nigeria. He has a postgraduate certificate in Project Management from Walden University, Minnesota, as well as a professional teaching certificate and a World Bank certification in Public Procurement. Prof. Emeje was a national chairman of academic pharmacists in Nigeria and the 2021 winner of the May & Baker Nigeria Plc–sponsored prize for professional service in research and innovation.",institutionString:"National Institute for Pharmaceutical Research and Development",institution:{name:"National Institute for Pharmaceutical Research and Development",country:{name:"Nigeria"}}},{id:"268659",title:"Ms.",name:"Xianquan",middleName:null,surname:"Zhan",slug:"xianquan-zhan",fullName:"Xianquan Zhan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/268659/images/8143_n.jpg",biography:"Dr. Zhan received his undergraduate and graduate training in the fields of preventive medicine and epidemiology and statistics at the West China University of Medical Sciences in China during 1989 to 1999. He received his post-doctoral training in oncology and cancer proteomics for two years at the Cancer Research Institute of Human Medical University in China. In 2001, he went to the University of Tennessee Health Science Center (UTHSC) in USA, where he was a post-doctoral researcher and focused on mass spectrometry and cancer proteomics. Then, he was appointed as an Assistant Professor of Neurology, UTHSC in 2005. He moved to the Cleveland Clinic in USA as a Project Scientist/Staff in 2006 where he focused on the studies of eye disease proteomics and biomarkers. He returned to UTHSC as an Assistant Professor of Neurology in the end of 2007, engaging in proteomics and biomarker studies of lung diseases and brain tumors, and initiating the studies of predictive, preventive, and personalized medicine (PPPM) in cancer. In 2010, he was promoted to Associate Professor of Neurology, UTHSC. Currently, he is a Professor at Xiangya Hospital of Central South University in China, Fellow of Royal Society of Medicine (FRSM), the European EPMA National Representative in China, Regular Member of American Association for the Advancement of Science (AAAS), European Cooperation of Science and Technology (e-COST) grant evaluator, Associate Editors of BMC Genomics, BMC Medical Genomics, EPMA Journal, and Frontiers in Endocrinology, Executive Editor-in-Chief of Med One. He has\npublished 116 peer-reviewed research articles, 16 book chapters, 2 books, and 2 US patents. His current main research interest focuses on the studies of cancer proteomics and biomarkers, and the use of modern omics techniques and systems biology for PPPM in cancer, and on the development and use of 2DE-LC/MS for the large-scale study of human proteoforms.",institutionString:null,institution:{name:"Xiangya Hospital Central South University",country:{name:"China"}}},{id:"40482",title:null,name:"Rizwan",middleName:null,surname:"Ahmad",slug:"rizwan-ahmad",fullName:"Rizwan Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/40482/images/system/40482.jpeg",biography:"Dr. Rizwan Ahmad is a University Professor and Coordinator, Quality and Development, College of Medicine, Imam Abdulrahman bin Faisal University, Saudi Arabia. Previously, he was Associate Professor of Human Function, Oman Medical College, Oman, and SBS University, Dehradun. Dr. Ahmad completed his education at Aligarh Muslim University, Aligarh. He has published several articles in peer-reviewed journals, chapters, and edited books. His area of specialization is free radical biochemistry and autoimmune diseases.",institutionString:"Imam Abdulrahman Bin Faisal University",institution:{name:"Imam Abdulrahman Bin Faisal University",country:{name:"Saudi Arabia"}}},{id:"41865",title:"Prof.",name:"Farid A.",middleName:null,surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41865/images/system/41865.jpg",biography:"Farid A. Badria, Ph.D., is the recipient of several awards, including The World Academy of Sciences (TWAS) Prize for Public Understanding of Science; the World Intellectual Property Organization (WIPO) Gold Medal for best invention; Outstanding Arab Scholar, Kuwait; and the Khwarizmi International Award, Iran. He has 250 publications, 12 books, 20 patents, and several marketed pharmaceutical products to his credit. He continues to lead research projects on developing new therapies for liver, skin disorders, and cancer. Dr. Badria was listed among the world’s top 2% of scientists in medicinal and biomolecular chemistry in 2019 and 2020. He is a member of the Arab Development Fund, Kuwait; International Cell Research Organization–United Nations Educational, Scientific and Cultural Organization (ICRO–UNESCO), Chile; and UNESCO Biotechnology France",institutionString:"Mansoura University",institution:{name:"Mansoura University",country:{name:"Egypt"}}},{id:"329385",title:"Dr.",name:"Rajesh K.",middleName:"Kumar",surname:"Singh",slug:"rajesh-k.-singh",fullName:"Rajesh K. Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329385/images/system/329385.png",biography:"Dr. Singh received a BPharm (2003) and MPharm (2005) from Panjab University, Chandigarh, India, and a Ph.D. (2013) from Punjab Technical University (PTU), Jalandhar, India. He has more than sixteen years of teaching experience and has supervised numerous postgraduate and Ph.D. students. He has to his credit more than seventy papers in SCI- and SCOPUS-indexed journals, fifty-five conference proceedings, four books, six Best Paper Awards, and five projects from different government agencies. He is currently an editorial board member of eight international journals and a reviewer for more than fifty scientific journals. He received Top Reviewer and Excellent Peer Reviewer Awards from Publons in 2016 and 2017, respectively. He is also on the panel of The International Reviewer for reviewing research proposals for grants from the Royal Society. He also serves as a Publons Academy mentor and Bentham brand ambassador.",institutionString:"Punjab Technical University",institution:{name:"Punjab Technical University",country:{name:"India"}}},{id:"142388",title:"Dr.",name:"Thiago",middleName:"Gomes",surname:"Gomes Heck",slug:"thiago-gomes-heck",fullName:"Thiago Gomes Heck",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/142388/images/7259_n.jpg",biography:null,institutionString:null,institution:{name:"Universidade Regional do Noroeste do Estado do Rio Grande do Sul",country:{name:"Brazil"}}},{id:"336273",title:"Assistant Prof.",name:"Janja",middleName:null,surname:"Zupan",slug:"janja-zupan",fullName:"Janja Zupan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/336273/images/14853_n.jpeg",biography:"Janja Zupan graduated in 2005 at the Department of Clinical Biochemistry (superviser prof. dr. Janja Marc) in the field of genetics of osteoporosis. Since November 2009 she is working as a Teaching Assistant at the Faculty of Pharmacy, Department of Clinical Biochemistry. In 2011 she completed part of her research and PhD work at Institute of Genetics and Molecular Medicine, University of Edinburgh. She finished her PhD entitled The influence of the proinflammatory cytokines on the RANK/RANKL/OPG in bone tissue of osteoporotic and osteoarthritic patients in 2012. From 2014-2016 she worked at the Institute of Biomedical Sciences, University of Aberdeen as a postdoctoral research fellow on UK Arthritis research project where she gained knowledge in mesenchymal stem cells and regenerative medicine. She returned back to University of Ljubljana, Faculty of Pharmacy in 2016. She is currently leading project entitled Mesenchymal stem cells-the keepers of tissue endogenous regenerative capacity facing up to aging of the musculoskeletal system funded by Slovenian Research Agency.",institutionString:null,institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"357453",title:"Dr.",name:"Radheshyam",middleName:null,surname:"Maurya",slug:"radheshyam-maurya",fullName:"Radheshyam Maurya",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/357453/images/16535_n.jpg",biography:null,institutionString:null,institution:{name:"University of Hyderabad",country:{name:"India"}}},{id:"418340",title:"Dr.",name:"Jyotirmoi",middleName:null,surname:"Aich",slug:"jyotirmoi-aich",fullName:"Jyotirmoi Aich",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038Ugi5QAC/Profile_Picture_2022-04-15T07:48:28.png",biography:"Biotechnologist with 15 years of research including 6 years of teaching experience. Demonstrated record of scientific achievements through consistent publication record (H index = 13, with 874 citations) in high impact journals such as Nature Communications, Oncotarget, Annals of Oncology, PNAS, and AJRCCM, etc. Strong research professional with a post-doctorate from ACTREC where I gained experimental oncology experience in clinical settings and a doctorate from IGIB where I gained expertise in asthma pathophysiology. A well-trained biotechnologist with diverse experience on the bench across different research themes ranging from asthma to cancer and other infectious diseases. An individual with a strong commitment and innovative mindset. Have the ability to work on diverse projects such as regenerative and molecular medicine with an overall mindset of improving healthcare.",institutionString:"DY Patil Deemed to Be University",institution:null},{id:"349288",title:"Prof.",name:"Soumya",middleName:null,surname:"Basu",slug:"soumya-basu",fullName:"Soumya Basu",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035QxIDQA0/Profile_Picture_2022-04-15T07:47:01.jpg",biography:"Soumya Basu, Ph.D., is currently working as an Associate Professor at Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, India. With 16+ years of trans-disciplinary research experience in Drug Design, development, and pre-clinical validation; 20+ research article publications in journals of repute, 9+ years of teaching experience, trained with cross-disciplinary education, Dr. Basu is a life-long learner and always thrives for new challenges.\r\nHer research area is the design and synthesis of small molecule partial agonists of PPAR-γ in lung cancer. She is also using artificial intelligence and deep learning methods to understand the exosomal miRNA’s role in cancer metastasis. Dr. Basu is the recipient of many awards including the Early Career Research Award from the Department of Science and Technology, Govt. of India. She is a reviewer of many journals like Molecular Biology Reports, Frontiers in Oncology, RSC Advances, PLOS ONE, Journal of Biomolecular Structure & Dynamics, Journal of Molecular Graphics and Modelling, etc. She has edited and authored/co-authored 21 journal papers, 3 book chapters, and 15 abstracts. She is a Board of Studies member at her university. She is a life member of 'The Cytometry Society”-in India and 'All India Cell Biology Society”- in India.",institutionString:"Dr. D.Y. Patil Vidyapeeth, Pune",institution:{name:"Dr. D.Y. Patil Vidyapeeth, Pune",country:{name:"India"}}},{id:"354817",title:"Dr.",name:"Anubhab",middleName:null,surname:"Mukherjee",slug:"anubhab-mukherjee",fullName:"Anubhab Mukherjee",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y0000365PbRQAU/ProfilePicture%202022-04-15%2005%3A11%3A18.480",biography:"A former member of Laboratory of Nanomedicine, Brigham and Women’s Hospital, Harvard University, Boston, USA, Dr. Anubhab Mukherjee is an ardent votary of science who strives to make an impact in the lives of those afflicted with cancer and other chronic/acute ailments. He completed his Ph.D. from CSIR-Indian Institute of Chemical Technology, Hyderabad, India, having been skilled with RNAi, liposomal drug delivery, preclinical cell and animal studies. He pursued post-doctoral research at College of Pharmacy, Health Science Center, Texas A & M University and was involved in another postdoctoral research at Department of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute, Santa Monica, California. In 2015, he worked in Harvard-MIT Health Sciences & Technology as a visiting scientist. He has substantial experience in nanotechnology-based formulation development and successfully served various Indian organizations to develop pharmaceuticals and nutraceutical products. He is an inventor in many US patents and an author in many peer-reviewed articles, book chapters and books published in various media of international repute. Dr. Mukherjee is currently serving as Principal Scientist, R&D at Esperer Onco Nutrition (EON) Pvt. Ltd. and heads the Hyderabad R&D center of the organization.",institutionString:"Esperer Onco Nutrition Pvt Ltd.",institution:null},{id:"319365",title:"Assistant Prof.",name:"Manash K.",middleName:null,surname:"Paul",slug:"manash-k.-paul",fullName:"Manash K. Paul",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/319365/images/system/319365.png",biography:"Manash K. Paul is a Principal Investigator and Scientist at the University of California Los Angeles. He has contributed significantly to the fields of stem cell biology, regenerative medicine, and lung cancer. His research focuses on various signaling processes involved in maintaining stem cell homeostasis during the injury-repair process, deciphering lung stem cell niche, pulmonary disease modeling, immuno-oncology, and drug discovery. He is currently investigating the role of extracellular vesicles in premalignant lung cell migration and detecting the metastatic phenotype of lung cancer via machine-learning-based analyses of exosomal signatures. Dr. Paul has published in more than fifty peer-reviewed international journals and is highly cited. He is the recipient of many awards, including the UCLA Vice Chancellor’s award, a senior member of the Institute of Electrical and Electronics Engineers (IEEE), and an editorial board member for several international journals.",institutionString:"University of California Los Angeles",institution:{name:"University of California Los Angeles",country:{name:"United States of America"}}},{id:"311457",title:"Dr.",name:"Júlia",middleName:null,surname:"Scherer Santos",slug:"julia-scherer-santos",fullName:"Júlia Scherer Santos",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311457/images/system/311457.jpg",biography:"Dr. Júlia Scherer Santos works in the areas of cosmetology, nanotechnology, pharmaceutical technology, beauty, and aesthetics. Dr. Santos also has experience as a professor of graduate courses. Graduated in Pharmacy, specialization in Cosmetology and Cosmeceuticals applied to aesthetics, specialization in Aesthetic and Cosmetic Health, and a doctorate in Pharmaceutical Nanotechnology. Teaching experience in Pharmacy and Aesthetics and Cosmetics courses. She works mainly on the following subjects: nanotechnology, cosmetology, pharmaceutical technology, aesthetics.",institutionString:"Universidade Federal de Juiz de Fora",institution:{name:"Universidade Federal de Juiz de Fora",country:{name:"Brazil"}}},{id:"219081",title:"Dr.",name:"Abdulsamed",middleName:null,surname:"Kükürt",slug:"abdulsamed-kukurt",fullName:"Abdulsamed Kükürt",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/219081/images/system/219081.png",biography:"Dr. Kükürt graduated from Uludağ University in Turkey. He started his academic career as a Research Assistant in the Department of Biochemistry at Kafkas University. In 2019, he completed his Ph.D. program in the Department of Biochemistry at the Institute of Health Sciences. He is currently working at the Department of Biochemistry, Kafkas University. He has 27 published research articles in academic journals, 11 book chapters, and 37 papers. He took part in 10 academic projects. He served as a reviewer for many articles. He still serves as a member of the review board in many academic journals. He is currently working on the protective activity of phenolic compounds in disorders associated with oxidative stress and inflammation.",institutionString:null,institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"178366",title:"Dr.",name:"Volkan",middleName:null,surname:"Gelen",slug:"volkan-gelen",fullName:"Volkan Gelen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178366/images/system/178366.jpg",biography:"Volkan Gelen is a Physiology specialist who received his veterinary degree from Kafkas University in 2011. Between 2011-2015, he worked as an assistant at Atatürk University, Faculty of Veterinary Medicine, Department of Physiology. In 2016, he joined Kafkas University, Faculty of Veterinary Medicine, Department of Physiology as an assistant professor. Dr. Gelen has been engaged in various academic activities at Kafkas University since 2016. There he completed 5 projects and has 3 ongoing projects. He has 60 articles published in scientific journals and 20 poster presentations in scientific congresses. His research interests include physiology, endocrine system, cancer, diabetes, cardiovascular system diseases, and isolated organ bath system studies.",institutionString:"Kafkas University",institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"418963",title:"Dr.",name:"Augustine Ododo",middleName:"Augustine",surname:"Osagie",slug:"augustine-ododo-osagie",fullName:"Augustine Ododo Osagie",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/418963/images/16900_n.jpg",biography:"Born into the family of Osagie, a prince of the Benin Kingdom. I am currently an academic in the Department of Medical Biochemistry, University of Benin. Part of the duties are to teach undergraduate students and conduct academic research.",institutionString:null,institution:{name:"University of Benin",country:{name:"Nigeria"}}},{id:"192992",title:"Prof.",name:"Shagufta",middleName:null,surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192992/images/system/192992.png",biography:"Prof. Shagufta Perveen is a Distinguish Professor in the Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Dr. Perveen has acted as the principal investigator of major research projects funded by the research unit of King Saud University. She has more than ninety original research papers in peer-reviewed journals of international repute to her credit. She is a fellow member of the Royal Society of Chemistry UK and the American Chemical Society of the United States.",institutionString:"King Saud University",institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"49848",title:"Dr.",name:"Wen-Long",middleName:null,surname:"Hu",slug:"wen-long-hu",fullName:"Wen-Long Hu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49848/images/system/49848.jpg",biography:"Wen-Long Hu is Chief of the Division of Acupuncture, Department of Chinese Medicine at Kaohsiung Chang Gung Memorial Hospital, as well as an adjunct associate professor at Fooyin University and Kaohsiung Medical University. Wen-Long is President of Taiwan Traditional Chinese Medicine Medical Association. He has 28 years of experience in clinical practice in laser acupuncture therapy and 34 years in acupuncture. He is an invited speaker for lectures and workshops in laser acupuncture at many symposiums held by medical associations. He owns the patent for herbal preparation and producing, and for the supercritical fluid-treated needle. Dr. Hu has published three books, 12 book chapters, and more than 30 papers in reputed journals, besides serving as an editorial board member of repute.",institutionString:"Kaohsiung Chang Gung Memorial Hospital",institution:{name:"Kaohsiung Chang Gung Memorial Hospital",country:{name:"Taiwan"}}},{id:"298472",title:"Prof.",name:"Andrey V.",middleName:null,surname:"Grechko",slug:"andrey-v.-grechko",fullName:"Andrey V. Grechko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/298472/images/system/298472.png",biography:"Andrey Vyacheslavovich Grechko, Ph.D., Professor, is a Corresponding Member of the Russian Academy of Sciences. He graduated from the Semashko Moscow Medical Institute (Semashko National Research Institute of Public Health) with a degree in Medicine (1998), the Clinical Department of Dermatovenerology (2000), and received a second higher education in Psychology (2009). Professor A.V. Grechko held the position of Сhief Physician of the Central Clinical Hospital in Moscow. He worked as a professor at the faculty and was engaged in scientific research at the Medical University. Starting in 2013, he has been the initiator of the creation of the Federal Scientific and Clinical Center for Intensive Care and Rehabilitology, Moscow, Russian Federation, where he also serves as Director since 2015. He has many years of experience in research and teaching in various fields of medicine, is an author/co-author of more than 200 scientific publications, 13 patents, 15 medical books/chapters, including Chapter in Book «Metabolomics», IntechOpen, 2020 «Metabolomic Discovery of Microbiota Dysfunction as the Cause of Pathology».",institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"199461",title:"Prof.",name:"Natalia V.",middleName:null,surname:"Beloborodova",slug:"natalia-v.-beloborodova",fullName:"Natalia V. Beloborodova",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/199461/images/system/199461.jpg",biography:'Natalia Vladimirovna Beloborodova was educated at the Pirogov Russian National Research Medical University, with a degree in pediatrics in 1980, a Ph.D. in 1987, and a specialization in Clinical Microbiology from First Moscow State Medical University in 2004. She has been a Professor since 1996. Currently, she is the Head of the Laboratory of Metabolism, a division of the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, Russian Federation. N.V. Beloborodova has many years of clinical experience in the field of intensive care and surgery. She studies infectious complications and sepsis. She initiated a series of interdisciplinary clinical and experimental studies based on the concept of integrating human metabolism and its microbiota. Her scientific achievements are widely known: she is the recipient of the Marie E. Coates Award \\"Best lecturer-scientist\\" Gustafsson Fund, Karolinska Institutes, Stockholm, Sweden, and the International Sepsis Forum Award, Pasteur Institute, Paris, France (2014), etc. Professor N.V. Beloborodova wrote 210 papers, five books, 10 chapters and has edited four books.',institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"354260",title:"Ph.D.",name:"Tércio Elyan",middleName:"Azevedo",surname:"Azevedo Martins",slug:"tercio-elyan-azevedo-martins",fullName:"Tércio Elyan Azevedo Martins",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/354260/images/16241_n.jpg",biography:"Graduated in Pharmacy from the Federal University of Ceará with the modality in Industrial Pharmacy, Specialist in Production and Control of Medicines from the University of São Paulo (USP), Master in Pharmaceuticals and Medicines from the University of São Paulo (USP) and Doctor of Science in the program of Pharmaceuticals and Medicines by the University of São Paulo. Professor at Universidade Paulista (UNIP) in the areas of chemistry, cosmetology and trichology. Assistant Coordinator of the Higher Course in Aesthetic and Cosmetic Technology at Universidade Paulista Campus Chácara Santo Antônio. Experience in the Pharmacy area, with emphasis on Pharmacotechnics, Pharmaceutical Technology, Research and Development of Cosmetics, acting mainly on topics such as cosmetology, antioxidant activity, aesthetics, photoprotection, cyclodextrin and thermal analysis.",institutionString:null,institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"334285",title:"Ph.D. Student",name:"Sameer",middleName:"Kumar",surname:"Jagirdar",slug:"sameer-jagirdar",fullName:"Sameer Jagirdar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334285/images/14691_n.jpg",biography:"I\\'m a graduate student at the center for biosystems science and engineering at the Indian Institute of Science, Bangalore, India. I am interested in studying host-pathogen interactions at the biomaterial interface.",institutionString:null,institution:{name:"Indian Institute of Science Bangalore",country:{name:"India"}}},{id:"329248",title:"Dr.",name:"Md. Faheem",middleName:null,surname:"Haider",slug:"md.-faheem-haider",fullName:"Md. Faheem Haider",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329248/images/system/329248.jpg",biography:"Dr. Md. Faheem Haider completed his BPharm in 2012 at Integral University, Lucknow, India. In 2014, he completed his MPharm with specialization in Pharmaceutics at Babasaheb Bhimrao Ambedkar University, Lucknow, India. He received his Ph.D. degree from Jamia Hamdard University, New Delhi, India, in 2018. He was selected for the GPAT six times and his best All India Rank was 34. Currently, he is an assistant professor at Integral University. Previously he was an assistant professor at IIMT University, Meerut, India. He has experience teaching DPharm, Pharm.D, BPharm, and MPharm students. He has more than five publications in reputed journals to his credit. Dr. Faheem’s research area is the development and characterization of nanoformulation for the delivery of drugs to various organs.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"329795",title:"Dr.",name:"Mohd Aftab",middleName:"Aftab",surname:"Siddiqui",slug:"mohd-aftab-siddiqui",fullName:"Mohd Aftab Siddiqui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329795/images/system/329795.png",biography:"Dr. Mohd Aftab Siddiqui is an assistant professor in the Faculty of Pharmacy, Integral University, Lucknow, India, where he obtained a Ph.D. in Pharmacology in 2020. He also obtained a BPharm and MPharm from the same university in 2013 and 2015, respectively. His area of research is the pharmacological screening of herbal drugs/natural products in liver cancer and cardiac diseases. He is a member of many professional bodies and has guided many MPharm and PharmD research projects. Dr. Siddiqui has many national and international publications and one German patent to his credit.",institutionString:"Integral University",institution:null},{id:"255360",title:"Dr.",name:"Usama",middleName:null,surname:"Ahmad",slug:"usama-ahmad",fullName:"Usama Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255360/images/system/255360.png",biography:"Dr. Usama Ahmad holds a specialization in Pharmaceutics from Amity University, Lucknow, India. He received his Ph.D. from Integral University, Lucknow, India, with his work titled ‘Development and evaluation of silymarin nanoformulation for hepatic carcinoma’. Currently, he is an Assistant Professor of Pharmaceutics, at the Faculty of Pharmacy, Integral University. He has been teaching PharmD, BPharm, and MPharm students and conducting research in the novel drug delivery domain. From 2013 to 2014 he worked on a research project funded by SERB-DST, Government of India. He has a rich publication record with more than twenty-four original journal articles, two edited books, four book chapters, and several scientific articles to his credit. He is a member of the American Association for Cancer Research, the International Association for the Study of Lung Cancer, and the British Society for Nanomedicine. Dr. Ahmad’s research focus is on the development of nanoformulations to facilitate the delivery of drugs.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"333824",title:"Dr.",name:"Ahmad Farouk",middleName:null,surname:"Musa",slug:"ahmad-farouk-musa",fullName:"Ahmad Farouk Musa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333824/images/22684_n.jpg",biography:"Dato’ Dr Ahmad Farouk Musa\nMD, MMED (Surgery) (Mal), Fellowship in Cardiothoracic Surgery (Monash Health, Aust), Graduate Certificate in Higher Education (Aust), Academy of Medicine (Mal)\n\n\n\nDato’ Dr Ahmad Farouk Musa obtained his Doctor of Medicine from USM in 1992. He then obtained his Master of Medicine in Surgery from the same university in the year 2000 before subspecialising in Cardiothoracic Surgery at Institut Jantung Negara (IJN