The observed k value and t1/2 of atenolol
1. Introduction
The palatability of the active ingredient of a drug is a significant obstacle in developing a patient friendly dosage form. Organoleptic properties, such as taste, are an important factor when selecting a certain drug from the generic products available in the market that have the same active ingredient. It is a key issue for doctors and pharmacists administering the drugs and particularly for the pediatric and geriatric populations. Nowadays, pharmaceutical companies are recognizing the importance of taste masking and a significant number of techniques have been developed for concealing the objectionable taste [1].
The word “medicine” for a child is considered a bad thing to administer because of its aversive taste. Medicines dissolve in saliva and bind to taste receptors on the tongue giving a bitter, sweet, salty, sour, or umami sensation. Sweet and sour taste receptors are concentrated on the tip and lateral borders of the tongue respectively. Bitter taste is sensed by the receptors on the posterior part of the tongue and umami taste receptors are located all over the tongue. A short period after birth, infants reject bitter tastes and prefer sweet and umami tastes[1]. Children have larger number of taste buds than adults which are responsible for sensitivity toward taste. These taste buds regenerate every two weeks. Taste becomes altered as a function of the aging process, which explains why most children find certain flavors to be too strong when adults do not. The American Academy of Pediatrics estimates that compliance in children is as low as 53%, indicating that children frequently fail to take medications properly. Noncompliance can lead to: (1)persistent symptoms, (2) need for additional doctor visits or even hospitalizations, (3) worsening of condition, (4) need for additional medications, (5) increased healthcare costs and (6) development of drug-resistant organisms in cases of infectious diseases [2].
In mammals, taste buds are groups of 30-100 individual elongated "neuroepithelial" cells which are often embedded in special structure in the surrounding epithelium known as papillae. Just below the taste bud apex, taste cells are joined by tight junctional complexes that prevent gaps between cells. Food molecules cannot therefore squeeze between taste cells and get into the taste bud.
Taste papillae located on the tongue appear as little red dots, or raised bumps, particularly at the front of the tongue called "fungi form" papillae. There are three other kinds of papillae, foliate, circumvallates and the non-gustatory fili form. In mammals taste buds are located throughout the oral cavity, in the pharynx, the laryngeal epiglottis and at the entrance of the esophagus. Taste perception fades with age; on average, people lose half their taste receptors by time they turn 20 [3].The sensation of taste can be categorized into five basic tastes: sweetness, sourness, saltiness, bitterness, and umami. Taste buds are able to differentiate among different tastes through detecting interaction with different molecules or ions. Sweet, umami, and bitter tastes are triggered by the binding of molecules to G protein-coupled receptors on the cell membranes of taste buds. Saltiness and sourness are perceived when alkali metal or hydrogen ions enter taste buds, respectively [4].As taste senses both harmful and beneficial things, all basic tastes are classified as either aversive or appetitive, depending upon the effect the things they sense have on our bodies [5].Sweetness helps to identify energy-rich foods, while bitterness serves as a warning sign of poisons [6].
For a long period, it was commonly accepted that there is a finite and small number of "basic tastes" of which all seemingly complex tastes are ultimately composed. As of the early twentieth century, physiologists and psychologists believed there were four basic tastes: sweetness, sourness, saltiness, bitterness. At that time umami was not proposed as a fifth taste but now a large number of authorities recognize it as the fifth taste [7]. In Asian countries within the sphere of mainly Chinese and Indian cultural influence, pungency (piquancy or hotness) had traditionally been considered a sixth basic taste. Today, the consensus is that sweet,amino acid (umami), and bitter taste converge one common transduction channel, the transient receptor potential channel TRPM5,
2. Taste masking
There are numerous pharmaceutical and over the counter (OTC) preparations that contain active ingredients, which are bitter in taste. With respect to OTC preparations, such as cough and cold syrups, the bitterness of the preparation leads to lack of patient compliance. Among examples that are commonly used drugs with bitter taste: (1) pseudoephedrine (1) (Figure 1),a sympathomimetic drug of the phenethylamine (2) (Figure 1) and amphetamine (3) (Figure 1) chemical classes. It may be used as a nasal/sinus decongestant, as a stimulant, or as a wakefulness-promoting agent [19], (2) dextromethorphan (4) (Figure 1), an antitussive (cough suppressant) drug. It is one of the active ingredients in many over-the-counter cold and cough medicines. Dextromethorphan has also found other uses in medicine, ranging from pain relief to psychological applications. It is sold in syrup, tablet, spray, and lozenge forms. In its pure form, dextromethorphan occurs as a white powder [20], (3) dyphylline (5) (figure1) also known as dipprophyllinea xanthine derivative withbronchodilatorandvasodilator effects. It is used in the treatment of respiratory disorders like asthma, cardiac, and bronchitis. It acts as an adenosine receptor antagonist and phosphodiesterase inhibitor [21].(4) phenylephrine (6) (Figure 1), is a selective α1-adrenergic receptor agonist used primarily as a decongestant, as an agent to dilate the pupil, and to increase blood pressure [22]. Phenylephrine is marketed as a substitute for the decongestant pseudoephedrine, (5) chlorhexidine (7) (Figure 1), a chemical antiseptic. It is effective on both Gram-positive and Gram-negative bacteria, although it is less effective with some Gram-negative bacteria. It has both bactericidal and bacteriostatic mechanisms of action, the mechanism of action being membrane disruption, not ATPase inactivation as previously thought [23]. It is also useful against fungi and enveloped viruses, though this has not been extensively investigated, (6) atorvastatin (8) (Figure 1), a member of the drug class known as statins, used for lowering blood cholesterol. It also stabilizes plaque and prevents strokes through anti-inflammatory and other mechanisms. Like all statins, atorvastatin works by inhibiting HMG-CoA reductase, an enzyme found in liver tissue that plays a key role in production of cholesterol in the body [22], (7) loperamide (9) (Figure 1),a piperidine derivative, is an opioid drug used against diarrhea resulting from gastroenteritis or inflammatory bowel disease. In most countries it is available generically [24].(8) terfenadine (10) (Figure 2), was an antihistamine formerly used for the treatment of allergic conditions. It was brought to market by Hoechst Marion Roussel (now Sanofi-Aventis) and marketed under various brand names. According to its manufacturer, terfenadine had been used by over 100 million patients worldwide as of 1990 [25]. It was superseded byfexofenadine (11) (Figure 2) in the 1990s due to the risk of a particular type of disruption of the electrical rhythms of the heart (specifically cardiac arrhythmia caused by QT interval prolongation) [22], (9) prednisolone (12) (Figure 2), is a synthetic glucocorticoid, a derivative of cortisol, which is used to treat a variety of inflammatory and auto-immune conditions. It is the active metabolite of the drug prednisoneand is used especially in patients with hepatic failure, as these individuals are unable to metabolize prednisone into prednisolone [22], (10) salbutamol (13) (Figure 2), or albuterol (USAN) is a short-acting β2-adrenergic receptor agonist used for the relief of bronchospasm in conditions such as asthma and chronic obstructive pulmonary disease. It is marketed as Ventolin among other brand names. Salbutamol was the first selective β2-receptor agonist to be marketed – in 1968. It was first sold by Allen & Hanburys under the brand name Ventolin. The drug was an instant success, and has been used for the treatment of asthma ever since [26]. (11) guaifenisen (14) (Figure 2), or guaiphenesin (former BAN), also glyceryl guaiacolate, is an expectorant drug sold over the counter and usually taken orally to assist the bringing up (expectoration) of phlegm from the airways in acute respiratory tract infections [22] and (12) amoxicillin (15) (Figure 2), a moderate-spectrum, bacteriolytic, β-lactam antibiotic used to treat bacterial infections caused by susceptible microorganisms. It is usually the drug of choice within the class because it is better absorbed, following oral administration, than other β-lactam antibiotics. Amoxicillin is one of the most common antibiotics prescribed for children. The drug became available in 1972 [22].
3. Challenges and criteria for pursuing masking bitter taste approaches
The most significant challenges that facing developers when pursuing masking bitter taste drugs approaches are: (i) Safety, tolerability and efficacy of the compound which are based on non-clinical testing, and physicochemical properties such as solubility, permeability and stability, (ii) lack of robust and reliable techniques for early taste screening of compounds with limited toxicity data, (iii) structure–taste relationships of pharmaceutically active molecules is limited, (iv) The perception of taste of pharmaceuticals has been shown to be different between adults and children and it might differ between healthy and patient children [4] and (v) ethical concerns to perform taste studies in healthy children unless the study is a ‘swill and spit’ one with drugs known to have a good safety profile [27-29].
4. Bitter taste masking approaches (techniques)
A variety of taste masking approaches has been used to address the patient compliance problem. With strongly bad tasting medications even a little exposure is sufficient to perceive the bad taste. Conventional taste masking methods such as the use of sweeteners, amino acids and flavoring agents alone are often inadequate in masking the taste of highly bitter drugs. Drugs such as macrolide antibiotics, non-steroidal anti-inflammatory such as ibuprofen (
Although the mentioned approaches have helped to improve the taste of some drugs formulations, the problem of the bitter taste of drugs in pediatric and geriatric formulations still creates a serious challenge to pharmacists. Thus, different strategies should be developed in order to overcome this serious problem. The novel chemical approach discussed in this chapter involves the design of prodrugs for masking bitter taste of pharmaceuticals based on intramolecular processes using density functional theory (DFT) and ab initio methods [43] and correlations of experimental and calculated reactions rates. No enzyme is needed to catalyze the interconversion of a prodrug to its corresponding drug. The rate of drug release is controlled by the nature of the linker bound to the drug. Bitter tastant molecules interact with taste receptors on the tongue to give bitter sensation. Altering the ability of the drug to interact with bitter taste receptors could reduce or eliminate its bitterness. This could be achieved by an appropriate modification of the structure and the size of a bitter compound. Bitter molecules bind to the G-protein coupled receptor-type T2R on the apical membrane of the taste receptor cells located in the taste buds [44,45].
Due to the large variation of structural features of bitter tasting molecules, it is difficult to generalize the molecular requirements for bitterness. Nevertheless, it was reported that a bitter tastant molecule requires a polar group and a hydrophobic moiety. A quantitative structure activity relationship (QSAR) model was developed and has been established for the prediction of bitterness of several tastant analogues. For example, it was reported that the addition of a pyridinium moiety to an amino acid chain of a variety of bitter amino acid compounds decreases bitterness, such as in the case of glycine. Other structural modifications, such as an increase in the number of amino groups/residues to more than 3 and a reduction in the poly-hydroxyl group/ COOH, have been proven to decrease bitterness significantly. Moreover, changing the configuration of a bitter tastant molecule by making isomer analogues was found to be important for binding affinity to enhance bitterness agonist activity (e.g. L-tryptophan is bitter while D-tryptophan is sweet) [46].
Our recent studies on intramolecularity have demonstrated that there is a necessity to further explore the mechanisms for the intramolecular processes to be utilized in the design for determining the factors playing dominant role in determining the reaction rate. Unraveling the reaction mechanism would allow for an accurate design of an efficient chemical device to be used as a prodrug linker that can be covalently linked to a drug which can chemically, and not enzymatically be cleaved to release the active parent drug in a controlled manner. For instance, exploring the mechanism for a proton transfer in Kirby’s acetals [47] has led to a design and synthesis of novel prodrugs of aza-nucleosides to treat myelodysplastic syndromes [48] and statins to treat high cholesterol levels in the blood [49]. In the above mentioned examples, the prodrug moiety was attached to the hydroxyl group of the active drug such that the drug promoiety (prodrug) has the potential to degrade upon exposure to physiological environment such as stomach, intestine, and/or blood circulation, with rates that are solely dependent on the structural features of the pharmacologically inactive promoiety (Kirby’s enzyme model). Other different linkers such as Kirby’s maleamic acid enzyme model [50] was also investigated for the design of some prodrugs such as tranexamic acid prodrugs to treat bleeding conditions [51] and acyclovir as anti-viral drug to treat Herpes Simplex [52]. Menger’s Kemp acid enzyme model [53] was also utilized for the design of dopamine prodrugs for the treatment of Parkinson’s disease [54]. Prodrugs for dimethyl fumarate to treat psoriasis were also designed, synthesized and currently under
The same approach was utilized for masking the bitter taste of antibacterial drugs such as cefuroxime (
In this chapter, the novel prodrug approach to be presented is based on enzyme models that have been made to understand the mechanism by which enzymes catalyze biochemical reactions. The tool exploited in the design is computational calculations using molecular orbital and molecular mechanics methods and correlations between experimental and calculated rate values for some intramolecular processes. In this approach, no enzyme is needed to catalyze the conversion of a prodrug to its active parent drug. The conversion rate is solely determined by the factors affecting the rate limiting step in the intramolecular (conversion) process. Knowledge gained from the mechanisms of the previously studied enzyme models was exploited in the design.
It is believed that the use of this approach might eliminate all disadvantages related to prodrug conversion by the metabolic (enzyme catalyzed process) approach. The bioconversion of prodrugs is perhaps the most vulnerable link in the chain, because there are many intrinsic and extrinsic factors that can affect the process. For example, the activity of many prodrug activating enzymes may be varied due to genetic polymorphisms, age-related physiological changes, or drug interactions, leading to adverse pharmacokinetic, pharmacodynamic, and clinical effects. In addition, there are wide interspecies variations in both the expression and function of the major enzymes activating prodrugs, and these can pose some obstacles in the preclinical optimization phase.
5. Enzyme models utilized for the design of potential bitterless prodrugs for bitter drugs such as atenolol, amoxicillin, cephalexin, paracetamol and guaiphenesin
Scholar studies of enzyme mechanisms by several chemists and biochemists, over the past five decades, have had a significant contribution for understanding the mode and scope of enzymes catalysis.
Nowadays, the scientific community has reached to the conclusion that enzyme catalysis is based on the combined effects of the catalysis by functional groups and the ability to reroute intermolecular reactions through alternative pathways by which substrates can bind to preorganized active sites. It is believed that rate accelerations by enzymes can be proceed by (i) covalently enforced proximity, as seen in the case of chymotrypsin, [57] (ii) non-covalently enforced proximity, as represented in the catalysis of metallo-enzymes, [58] (iii) covalently enforced strain, [59], and (iv) non-covalently enforced strain, which has been extensively studied on models mimicking the lysozyme enzyme which is most closely associated with rate acceleration due to this kind of strain [60].
Rates for the majority of enzymatic reactions ranges between 1010 and 1018 fold their non-enzymatic bimolecular counterparts. For instance, biochemical reactions involving the catalysis of the enzyme cyclophilin are enhanced by105 and those by the enzyme orotidine monophosphate decarboxylase are accelerated by 1017 [61]. The significant enhancement in rate manifested by enzymes is a result of the substrate binding within the confines of the enzyme active site. The substrate-enzyme binding energy is the dominant driving force and the major contributor to catalysis. A consensus has been reached that in all enzymatic processes binding energy is used to overcome physical and thermodynamic factors that make barriers to the reaction (free energy). These factors are: (1) the change in entropy (ΔS˚), in the form of the freedom of motions of the reactants in solution; (2) the hydrogen bonding net around bio-molecules in aqueous solution; (3) a proper alignment of catalytic functional groups on the enzyme; and (4) the distortion of a substrate that must occur before the reaction takes place [62,63].
Scholarly studies have been done by Bruice, Cohen, Menger, Kirby and others to design enzyme models having the potential to reach rates comparable to rates of biochemical reactions catalyzed by enzymes. Examples for such models are those based on rate enhancements driven by covalently enforced proximity. The most cited example is the intramolecular cyclization of dicarboxylic semi esters to anhydrides advocated by Bruice
Other examples of rate acceleration based on proximity orientation include: (a) acid-catalyzed lactonization of hydroxy-acids as studied by Cohen et al.[66-68] and Menger [63, 69-75], (b) intramolecular SN2-based cyclization reactions as researched by Brown et al. [76] and Mandolini’s group [77], (c) proton transfer between two oxygens in Kirby’s acetals [78-84], and proton transfer between nitrogen and oxygen in Kirby’s enzyme models [78-84], (d) proton transfer between two oxygens in rigid systems as investigated by Menger [63, 69-75],and (e) proton transfer from oxygen to carbon in some of Kirby’s enol ethers [78-84]. The conclusions emerged from these studies are (1) the driving force for enhancements in rate for intramolecular processes are both entropy and enthalpy effects. In the cases by which enthalpy effects were predominant such as ring-closing and proton transfer reactions proximity or/and steric effects were the driving force for rate accelerations. (2) The nature of the reaction being intermolecular or intramolecular is determined on the distance between the two reacting centers. (3) In SN2-based ring-closing reactions leading to three-, four-and five-member rings the
In the past few years some prodrugs based on the trimethyl lock system have been reported. Borchardt et al. has shown that the pro–prodrug 3-(2’-acetoxy-4’, 6’-dimethyl dimethyl)-phenyl-3, 3-dimethylpropionamide is capable of releasing the biologically active amine drug upon acetate hydrolysis by enzyme triggering. Another successful example exploiting a stereopopulation control model is the prodrug Taxol which enhances the drug water solubility and hence affords it to be administered to the human body
6. Computational methods used in the design of bitterless prodrugs for bitter tastant drugs
Nearly sixty five years ago, organic, bioorganic and medicinal chemists alike have started using computational methods for calculating molecular properties of ground and transition states. These computational methods use principles of computer science to aid in solving chemical problems. Theoretical results emerged from these methods, incorporated into efficient computer programs, for calculating the structures and physical and chemical properties of molecules.
Equilibriums energy-based and reactions rates calculations for systems having medicinal interests are of a vast importance to the health community. Today, quantum mechanics (QM) such as
Another widely used quantum mechanical method is the density functional theory (DFT). With this theory, the properties of many-electron systems can be determined by using functionals, i.e. functions of another function, which in this case is the spatially dependent electron density. Therefore, the name density functional theory comes from the use of functionals of the electron density. DFT is among the most popular and versatile methods available in condensed-matter physics, computational physics, and computational chemistry. The DFT method is adequate for calculating structures and energies for medium-sized systems (30-60 atoms) of biological, pharmaceutical and medicinal interest and is not restricted to the second row of the periodic table [43].
Although the use of DFT method is significantly increasing some difficulties still encountered when describing intermolecular interactions, especially van der Waals forces (dispersion); charge transfer excitations; transition states, global potential energy surfaces and some other strongly correlated systems. Incomplete treatment of dispersion can adversely affect the DFT degree of accuracy in the treatment of systems which are dominated by dispersion.
On the other hand, molecular mechanics is a mathematical approach used for the computation of structures, energy, dipole moment, and other physical properties. It is widely used in calculating many diverse biological and chemical systems such as proteins, large crystal structures, and relatively large solvated systems. However, this method is limited by the determination of parameters such as the large number of unique torsion angles present in structurally diverse molecules [117].
Molecular mechanics simulations, for example, use a single classical expression for the energy of a compound, for instance the harmonic oscillator. The database of compounds used for parameterization, i.e., the resulting set of parameters and functions is called the force field, is crucial to the success of molecular mechanics calculations. A force field parameterized against a specific class of molecules, for instance proteins, would be expected to only have any relevance when describing other molecules of the same class. These methods can be applied to proteins and other large biological molecules, and allow studies of the approach and docking of potential drug molecules Since the size of the system which
7. Mechanistic study of the acid-catalyzed hydrolysis of maleamic acids 34-42 used for the design of atenolol, amoxicillin and cephalexin prodrugs
The acid-catalyzed hydrolysis of
In order to utilize Kirby’s enzyme model [84] for the design of prodrugs of the following drugs: atenolol, amoxicillin and cephalexin, a mechanistic study using DFT calculation methods at B3LYP/6-31G (d,p), B3LYP/311+G (d,p) levels and hybrid GGA (MPW1k) on an intramolecular acid catalyzed hydrolysis of maleamic (4-amino-4-oxo-2-butenoic) acids (Kirby’s N-alkylmaleamic acids)
8. Bitterless atenolol prodrugs based on Kirby’s maleamic acids enzyme model
Atenolol is a relatively polar hydrophilic compound with water solubility of 26.5 mg/mL at 37 0C and a log partition coefficient (octanol/ water) of 0.23. Atenolol is a selective ß1-adrenoceptor antagonist, applied in the treatment hypertension, angina, acute myocardial infarction, supraventricular tachycardia, ventricular tachycardia, and the symptoms of alcohol withdrawal. The net effect of atenolol on controlling both the heart rate and blood pressure is the reduction in myocardial work and oxygen requirement which reduces cardiovascular stress, thereby preventing arrhythmia and angina attacks.
Atenolol has a pKa of 9.6; it undergoes ionization in the stomach and intestine thus its oral bioavailability is low due to inefficient absorption through membranes.
The bioavailability of atenolol is 45%-55% of the given dose and is not increased by administration of the drug in a solution form [123-125].About 50% of administered atenolol is absorbed; however, most of the absorbed quantity reaches the systemic circulation. Atenolol peak blood levels are reached within two to four hours after ingestion. Differently from propranolol or metoprolol, atenolol is resistant to metabolism by the liver and the absorbed dose is eliminated by renal excretion. More than 85% of I.V. dose is excreted in urine within 24 hours compared with 50% for an oral dose. Only 6-16% is protein-bound resulting in relatively consistent plasma drug levels with about a four-fold inter-patient variation. The elimination half-life of atenolol is between 6 to 7 hours and there is no alteration of kinetic profile of a drug by chronic administration.
Atenolol is one of the most important medicines used for prevention of several types of arrhythmias in childhood, but unfortunately it is still unlicensed [126]. On the other hand, atenolol is indicated as a first-step therapy for hypertension in elderly patients, who have difficulty in swallowing and, thus, tablets and capsules are frequently avoided.
Atenolol is available as 25, 50 and 100 mg tablets for oral administration. However, most of these medicines are not formulated for easy or accurate administration to children for the migraine indication or in elderly patients who may have a difficulty swallowing tablets. Attempts to prepare a liquid formulation was challenging because atenolol is unstable in solutions. Studies showed that the degradation rate of atenolol is dependent on the temperature, indicating higher stability at 4 ºC. Atenolol syrup is stable only for 9 days. Furthermore, oral doses of atenolol are incompletely absorbed (range 46-62%), even when formulated as a solution. Furthermore, atenolol bitterness is considered as a great challenge to health sector when used among children and geriatrics [125]. The main problem in oral administration of bitter drugs such as atenolol is incompliance by the patients [1] and this can be overcome by masking the bitterness of a drug either by decreasing its oral solubility on ingestion or eliminating the interaction of drug particles to taste buds [2].Thus the development of bitterless and more lipophilic prodrug that is stable in aqueous medium is a significant challenge. Improvement of atenolol pharmacokinetic absorption properties and hence its effectiveness may increase the absorption of the drug
The proposed atenolol prodrugs that were designed based on the acid-catalyzed hydrolysis reactions of N-alkyl maleamic acids
As shown in Figure 7, the only difference exists between the proposed atenolol prodrugs and their parent drug is that the amine group of atenolol was replaced with an amide moiety. Replacing the free amine in atenolol with an amide is expected to increase the stability of the prodrug thus formed due to general chemical stability for tertiary alcohols over amine alcohols. In addition, recent stability studies on atenolol esters have demonstrated that the esters were more stable than their corresponding alcohol, atenolol, when formulating in aqueous solutions. Furthermore, kinetic study on atenolol and propranolol demonstrated that increasing the lipophilicity of the drug leads to an increase in the stability of its aqueous solutions. Based on that, it is expected that atenolol prodrugs shown in Figure 7 will have the potential to be more resistant to heat or/oxidation when formulated in aqueous solutions [128-131]. Atenolol’s bitter-taste can be masked by using the prodrug chemical approach. For example, paracetamol (
The proposed atenolol prodrugs, atenolol
It is worth noting that the HLB value of atenolol prodrug will be largely determined on the pH of the physiological environment by which the prodrug is exposed to. For example, in the stomach pH, the atenolol prodrugs,
9. Calculation of the t1/2 values for the cleavage reactions of atenolol prodrugs ProD 1-2
The effective molarity (EM) parameter is a commonly tool used to predict the efficiency of intramolecular reactions when bringing two functional groups such as an electrophile and a nucleophile in a close proximity. Intramolecularity is usually measured by the effective molarity parameter. The effective molarity is defined as the rate ratio (kintra/kinter) for corresponding intramolecular and intermolecular processes driven by identical mechanisms. Ring size, solvent and reaction type are the major factors affecting the EM value. Ring-closing reactions
For obtaining the EM values for processes
Using equations 1-4, equation 5 was derived, and describes the EM term as a function of the difference in the activation energies of the intra-and the corresponding inter-molecular processes. The calculated EM values for processes
Where T is the temperature in Kelvin and R is the gas constant.
The calculated EM values from eq. 5 for processes
In addition, for further support to the credibility of our DFT calculations the calculated free activation energies (∆GBW‡) were correlated with the corresponding experimental free activation energies (Exp ∆G‡). Good correlation was obtained with R value of 0.96 (Figure 9b).
Utilizing eq. 6 obtained from the correlation of log krelvs. ∆G‡ and the experimental t1/2 value measured for process
10. In vitro intraconversion of atenolol ProD 1 to the parent drug atenolol
Kinetics of the acid-catalyzed hydrolysis for atenolol
|
|
|
2.53 | 4.95 x 10 -4 | 1 N HCl |
3.82 | 2.22 x 10 -4 | Buffer pH 2 |
133 | 2.75 x 10-6 | Buffer pH 5 |
----- | No Reaction | Buffer pH 7.4 |
11. Bitterless amoxicillin and cephalexin prodrugs based on Kirby’s maleamic acids enzyme model
Most of the antibacterial agents that are commonly used suffer unpleasant taste and a respected number of them are characterized with bitter taste. For example, amoxicillin, cephalexin and cefuroxime axetil have an extremely unpleasant and bitter taste which is difficult to mask. This is a particular problem in geriatric patients who cannot swallow whole tablets or when small doses are required. Even the antibacterial suspension is difficult for pediatrics to administer due to its better and unpleasant taste [133-139].
It is widely assumed that the extremely bitter and unpleasant taste of these antibacterial drugs is due to a formation of intermolecular force/s between the drug and the active site of the bitter taste receptor/s. The intermolecular bond/s is/are most likely due to formation either
Antimicrobial agents are classified according to their specific mode of action against bacterial cell. By which these agents may interfere with cell wall synthesis, inhibit protein synthesis, interfere with nucleic acid synthesis or inhibit a metabolic pathway. They have a broad spectrum of activity against both gram-positive and gram-negative bacteria. Among these agents, β-lactams – penicillins, cephalosporins, carbapenems and monobactams, by which represent 60% of all antimicrobial use by weight. They are preferred because of their efficacy, safety, and because their activity can be extended or restored by chemical manipulation. Inevitably, however, their usage has been restricted because of their bacterial resistance.
11.1. Amoxicillin
Amoxicillin is an oral semi-synthetic penicillin, moderate-spectrum, bacteriolytic, β-lactam antibiotic used to treat bacterial infections caused by susceptible microorganisms by which it is susceptible to the action of the β-lactamases. Amoxicillin has a bactericidal action and acts against both Gram positive and Gram-negative microorganisms by inhibiting the biosynthesis and repair of the bacterial mucopeptide wall. It is usually the drug of choice within its class because it is well absorbed following oral administration. Amoxicillin presents some outstanding advantages in comparison with other amino-penicillins, such as: a better absorption from the intestinal tract, better capacity for reaching effective concentrations at the sites of action and a more rapid capacity for penetrating the cellular wall of Gram-negative microorganisms. Amino-penicillins are frequently prescribed agents for the oral treatment of lower respiratory tract infections and are generally highly effective against S. pneumonia and non-β-lactamase-producing H. influenza. Amoxicillin is mostly common antibiotics prescribed for children. It has high absorption after oral administration which is not altered and affected by the presence of food. Amoxicillin dose reaches Cmax about 2 hours after administration and is quickly distributed and eliminated by excretion in urine (about 60%-75%). The antibacterial effect of amoxicillin is extended by the presence of a benzyl ring in the side chain. Because amoxicillin is susceptible to degradation by β-lactamase-producing bacteria, which are resistant to a broad spectrum of β-lactam antibiotics, such as penicillin, for this reason, it is often combined with clavulanic acid, a β-lactamase inhibitor. This increases effectiveness by reducing its susceptibility to β-lactamase resistance. Amoxicillin has two ionizable groups in the physiological range (the amino group in α-position to the amide carbonyl group and the carboxyl group). Amoxicillin has a good pharmacokinetics profile with bioavailability of 95% if taken orally, its half-life is 61.3 minutes and it is excreted by the renal and less than 30 % bio-transformed in the liver [140-142].
11.2. Cephalexin
Cephalexin is a first-generation cephalosporin antibiotic, which was chosen as the model drug candidate to obtain dosage with improved stability, palatability and attractive pediatric elegance, cost effective with ease of administration. Cephalosporins are the most widely used for treatment of skin infections because of their safety profile, and their wide range of activity against both gram positive and gram negative microorganism. Cephalexin is also used for the treatment of articular infections as a rational first-line treatment for cellulitis, it is a useful alternative to penicillins hypersensitivity, and thought to be safe in a patient with penicillin allergy but caution should always be taken, that’s because cephalexin and other first-generation cephalosporins are known to have a modest cross-allergy in patients with penicillin hypersensitivity. In addition, cephalexin is also effective and used in the treatment of group A β-hemolytic streptococcal throat infections. Cephalexin works by interfering with the bacteria's cell wall formation, causing it to rupture, and thus killing the bacteria. The compound is zwitterion by which it contains both a basic and an acidic group, the isoelectric point of cephalexin in water is approximately 4.5 to 5. Cephalexin has a good pharmacokinetic profile by which it is well absorbed, 80% excreted unchanged in urine within 6 hours of administration. Cephalexin’s half-life is 0.5-1.2 hours and it is excreted
11.3. Cefuroxime axetil
Cefuroxime axetil is a semi-synthetic, broad-spectrum cephalosporin antibiotic for oral administration. Cefuroxime axetil is an orally active antibacterial agent though its absorption is incomplete. The range of its bioavailability is 25-52%. The axetil moiety is metabolized to acetaldehyde and acetic acid. Peak plasma concentration is reached 2-3 hours after an oral administration. Up to 50% of cefuroxime in the circulation is bound to plasma proteins. The plasma half-life is about 70 minutes and is prolonged in patients with renal impairments and in neonates. Cefuroxime axetil is widely distributed in the body including plural fluid, sputum bone synovial fluid, and aqueous humor, but only achieves therapeutic concentration in the CSF when the meninges are inflamed. It crosses the placenta and has been detected in breast milk. Cefuroxime is excreted unchanged, by glomerular filtration and renal tubular secretion, and high concentration is achieved in urine [146].
Amoxicillin, cephalexin and cefuroxime axetil as mentioned before suffer low stability and bitter taste sensation. Several attempts were made in order to enhance their aqueous solubility and bioavailability. Among several research approaches, the prodrug approach has been widely used for an improvement of drugs delivery to their site of action by physicochemical modulation properties that affect absorption or by targeting to specific enzymes or membrane transporters [147,148]. Generally, enzymatic catalysis is required for most of prodrugs that are in clinical use in order to be converted into the parent drug. This is mostly particular for those prodrugs designed to liberate the parent drug in the blood stream following gastro-intestinal absorption. These prodrugs are typically ester derivatives of drugs containing carboxyl or hydroxyl groups which are converted into the parent drug by esterase catalyzed hydrolysis. However, a high chemical reactivity that precludes either liquid or solid formulation of the prodrug (e.g. some phenol esters) or low chemical reactivity, resulting in reduced regeneration of the parent drug due to enzymatic activation for other functional groups. Thus, non-enzymatic pathways for some prodrugs that can regenerate the parent drug, have emerged as an alternative approach by which prodrug activation is not influenced by inter-and intra-individual variability that affects the enzymatic activity. In particular, since the middle-1980s, cyclization-activated prodrugs have been capturing the attention of medicinal chemists, and reached maturity in prodrug design in the late 1990s. Activation of prodrugs
Some ampicillin esters were prepared for improving the bioavailability of ampicillin. For example, the pivaloyloxyethyl (pivampicillin), phthalidyl (talampicillin), and ethoxycarbonyloxyethyl (bacampicillin)were found to have two fold the oral bioavailability of their parent drug, ampicillin. Complete hydrolysis of these esters was occurred in the gastrointestinal mucosa, whereas methoxymethyl ester of ampicillin was partially hydrolyzed by gut and hepatic first-pass metabolism and appears in the systemic circulation and tissues as intact ester [151-154].
12. In vitro intraconversion of amoxicillin and cephalexin prodrugs to their parent drugs
Based on our previously reported DFT calculations and on experimental data for the acid-catalyzed hydrolysis of amide acids
The combination of both, the hydrophilic and lipophilic groups provides a prodrug entity with a potential to be with a high permeability (a moderate HLB). It should be emphasized, that the HLB value of the prodrug entity will be determined upon the pH of the target physiological environment. In the stomach where the pH is in the range 1-2, it is expected that prodrugs, amoxicillin
The hydrolysis kinetic studies for amoxicillin
|
|
|
2.5 | 2.33x10 -4 | 1 N HCl |
7 | 9.60 x10 -5 | Buffer pH 2.5 |
81 | 7.55x10-6 | Buffer pH 5 |
---- | No reaction | Buffer pH 7.4 |
|
|
|
2.4 | 2.41x10 -4 | 1 N HCl |
14 | 4.17x10 -5 | Buffer pH 2.5 |
--- | No reaction | Buffer pH 5.5 |
--- | No reaction | Buffer pH 7.4 |
13. Mechanistic study of Bruice’s hydrolysis of di-carboxylic semi-esters 43-47 used for the design of bitterless paracetamol prodrugs
Five decades ago, Bruice and Pandit have investigated the kinetics of for the hydrolysis reaction of di-carboxylic semi-esters
Quantum molecular mechanics using DFT methods at B3LYP 6-31G (d,p) and B3LYP/311+G (d,p) levels were exploited to calculate the thermodynamic and kinetic parameters for all reactants, transition states, intermediates and products involved in the proposed mechanism for process
The phenomenon of rate enhancements in several intramolecular processes was ascribed by Bruice and Menger to the importance of the proximity of the nucleophile to the electrophile of the ground state molecules [64,65,155]. Menger in his “spatiotemporal” hypothesis advocated a mathematical equation correlating activation energy to distance and based on this that, he came to the conclusion that enormous rate accelerations in reactions catalyzed by enzymes are feasible when imposing short distances between the reactive centers of the substrate and enzyme [155]. Differently from Menger, Bruice attributed the catalysis by enzymes to favorable ‘near attack conformations’; systems that have a high quota of near attack conformations will have a higher intramolecular reaction rate and
In contrast to the proximity orientation proposal, others proposed the high rate enhancements in intramolecular processes to steric effects (relief of the strain energy of the reactant) [156].
To test whether the acceleration in rates for processes
14. Paracetamol Prodrugs Based on Bruice’s Enzyme Model
Paracetamol is an odorless, bitter crystalline compound used as an over the counter analgesic and anti-pyretic drug. Paracetamol is used to relief minor aches. it is used as pain killer by decreasing the synthesis of prostaglandin due to inhibiting cyclooxygenases (COX-1 and COX-2). Paracetamol is favored over aspirin as pain killer in patients have excessive gastric secretion or prolonged bleeding. It was approved to be used as fever reducer in all ages. Pharmacokinetic studies have shown that urine of patients who had taken phenacetin contained paracetamol. Later was demonstrated that paracetamol was a urinary metabolite of acetanilide. Phenacetin known historically to be one of the first non-opioid analgesics without anti-inflammatory properties lacks or has a very slight bitter taste [157,158]. Comparison of the structures of paracetamol and phenacetin shows that shows close similarity between both analgesics except of the nature of the group on the
Based on the DFT calculations on the cyclization of Bruice’s
15. In vitro intraconverion of Paracetamol ProD 1 to the parent drug paracetamol
The hydrolysis of paracetamol
|
|
|
1N HCl | No reaction | No reaction |
Buffer pH 3 | 6.3 x 10-5 | 3 |
Buffer pH 7.4 | 6.1 x 10-4 | 0.3 |
As shown in Table 4 the hydrolysis rate of paracetamol
At pH 7.4 and 6.6 paracetamol
16. Conclusions and future directions
The quantum mechanics (QM) calculations in different methods revealed that the acid-catalyzed hydrolysis efficiency of processes
Comparisons of the calculated DFT properties for processes
Comparison of the calculated t 1/2 value (63.2 hours) for atenolol
The experimental t 1/2 value for atenolol
In a similar manner to that observed in the intraconversion of atenolol
Acknowledgments
The author would like to acknowledge funding by the German Research Foundation (DFG, ME 1024/8-1). Special thanks are also given to Nardene Karaman, Angi Karaman, Donia Karaman, and Rowan Karaman for technical assistance.
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