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Clinical Relevance of Medicinal Plants and Foods of Vegetal Origin on the Activity of Cytochrome P450

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Xóchitl S. Ramírez-Gómez, Sandra N. Jiménez-García, Vicente Beltrán Campos, Esmeralda Rodríguez Miranda, Gabriel Herrera Pérez and Rafael Vargas-Bernal

Submitted: 11 April 2018 Reviewed: 05 July 2018 Published: 05 November 2018

DOI: 10.5772/intechopen.79971

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Medicinal Chemistry

Edited by Janka Vašková and Ladislav Vaško

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Drug metabolism is a pharmacokinetic process whose main objective is to modify the chemical structure of drugs to easily excretable compounds. This process is carried out through phase I and phase II reactions. The enzymes of cytochrome P450 (CYP450) participate in phase I reactions, and their activity can be inhibited or induced by xenobiotics. The aim of this chapter is to study the clinical relevance of the induction and inhibition of CYP450, by describing the effect that some bioactive compounds present in medicinal plants or foods can modify, either increasing or decreasing the activity of CYP450 enzymes and with it modify the bioavailability and depuration of drugs. Examples will be described on the interaction of medicinal plants and foods of vegetal origin that when combined with some drugs can generate toxicity or therapeutic failure; this will allow gathering relevant information on the adequate pharmacological management in different clinical situations.


  • cytochrome P450
  • drug metabolism
  • medicinal plants
  • foods of vegetal origin toxicity
  • therapeutic failure

1. Introduction

When a patient is in pharmacological treatment, and at some point a pharmacological response different from the expected one is observed, it is possible to think that a pharmacological interaction occurred. This occurs when a drug is administered or consumed in combination with other drugs, foods, or medicinal plants. In this context, changes in responses to drugs can be positive or negative for the patient. However, it is of particular interest to study the negative changes in pharmacological responses such as intoxication or therapeutic failure.

In this chapter, we focus on describing the effect of the interaction between drugs, medicinal plants, and foods of vegetable origin on the activity of cytochrome P450. Due to the natural products may modify the plasmatic concentrations of the drugs, either by inhibition or induction enzymatic, respectively.

In clinical practice, it is very important to know this topic to identify which medicinal plants and foods of vegetable origin should not be consumed when the patient is in pharmacological treatment and to avoid suffering a change in the response to medications that they consume by prescription and that could put their lives at risk.


2. General aspect of pharmacokinetics

To understand the effect of the chemical compounds, present in some medicinal plants and foods of vegetable origin on the activity of cytochrome P450 (CYP450), we will start with a brief description of the pharmacokinetics because the CYP450 participates in the phase I reactions of drug metabolism.

Pharmacokinetics is the branch of pharmacology that is responsible for studying and explaining the processes by which drugs are absorbed, distributed, metabolized, and eliminated from organism [1, 2]. It is important to know these pharmacokinetics processes and how they influence the bioavailability of drugs [2].

Bioavailability refers to the amount of drug found in the bloodstream and is available to exert its pharmacological effect [3]. However, if the plasma quantity of a drug is modified, the pharmacological response will be modified [1, 2, 3]. The four pharmacokinetic processes influence the bioavailability of the drugs. In the process of metabolism, the plasma concentrations of the drugs can be modified, either by inhibition or by induction of different CYP isoenzymes, as shown in Figure 1.

Figure 1.

Effect of drug metabolism on the pharmacological response.

The following example makes it easier to understand the importance of adherence to treatment to avoid fluctuations in plasmatic concentration. When patients are in pharmacological treatment, it is important that dosage regimen be complied. For example, if the prescription is 500 mg of acetaminophen every 8 h, this patient should be taken exactly three tablets of 500 mg of acetaminophen per day.

In order for patient has an adequate pharmacological response to acetaminophen, and a lower probability of presenting adverse effects or therapeutic failure, the amount of drug and the time of administration indicated in each shot must be respected. If, patient modifies any of these two variables, the plasma concentration of the drug changes and with it its response also changes [4].

When a single dose of drug is administered orally, after a certain time, the plasma concentrations of the drug are enlarged until reaching a maximum level. This maximum point is known as maximum plasma concentration (Cmax), and it is reached in a determined maximum time (tmax). These parameters are specific for each drug [6]. The Cmax of a drug is within the therapeutic range [4].

On the other hand, after several administrations of a drug, the final concentration begins to increase due to the remainder of the previous dose, until reaching a constant concentration called the equilibrium state [1]. Steady state is usually achieved after four to five half-lives [1, 2]. The half-life (t1/2) is defined as the time required by a drug to decrease its initial concentration by half [1].

In the equilibrium state, the drug plasmatic concentrations are within the range of therapeutic effect. If the patient suspends the administration of the drug, the plasma levels fall to concentrations below the therapeutic level causing therapeutic failure. Generally, the elimination of a drug is carried out after four to five half-lives [1, 2, 3].

When the patient does not remember if took the dose of the drug and decides to take the dose thinks was needed, the concentration of that drug will accumulate, then the plasma concentration reaches levels above the therapeutic concentration, and additionally, some signs of toxicity begin to appear [5].

In this chapter, we will focus on describing the effect that some compounds present in medicinal plants and some foods of vegetable origin can have on the activity of cytochrome P450 enzymes. The World Health Organization (WHO) estimates that more than 80% of the population of developed and underdeveloped countries use medicinal plants as a first resource for their health care and, on the other hand, there is a context cultural acceptance of the traditional practice with herbs, which makes its use popular and that in many cases patients combine their pharmacological treatment with herbal treatment [6, 7, 8, 9, 10].

On the other hand, the consumption of certain foods of vegetable origin with nutraceutical properties has increased considerably in recent years, especially to treat and prevent conditions such as cancer, diabetes, hypertension, hypercholesterolemia, obesity, among others. Therefore, by combining these foods with the pharmacological treatment indicated in the abovementioned conditions, they can significantly modify the plasma levels of some drugs and put the patient’s life at risk, either due to therapeutic failure (decrease in plasma concentration) or toxicity (increased plasma concentration) [11, 12, 13, 14, 15].

2.1. Pharmacokinetic process of drug metabolism

The drugs are defined chemically as acids or weak bases, and during the absorption process, the nonionized fraction of a drug is the one that crosses the biological membranes, due to its lipid solubility. Until the condition of lipid solubility is not lost, the drug will continue remaining in the body, by means of processes of reabsorption at the renal level or the enterohepatic circuit and redistribution from drug deposits in adipose tissue [16, 17, 18, 19].

If this lipid solubility condition is not lost, the drug will not be able to be eliminated [2, 18]. Fortunately, the pharmacokinetic process of the metabolism helps to modify the chemical structure of drugs into structures more polar, so that these can be more easily excreted [2, 18, 19].

The main organ that participates in the metabolism of drugs and other xenobiotics is the liver. However, other tissues also have metabolic capacity such as the gastrointestinal tract, lungs, skin, kidneys, and brain [20, 21, 22, 23].

The functional unit of this organ is the hepatocyte, and it contains different enzymes that are in the mitochondria, smooth and rough reticulum membrane, cytosol, etc. [23].

During this process of drug metabolism, the following may occur:

  1. Transform to a more active molecule [1, 2, 3].

  2. Transform to give biological activity (prodrug) [1, 2, 3].

  3. Transform to an inactive molecule [1, 2, 3].

  4. Transform to a toxic molecule [1, 2, 3].

It is important to mention that there are drugs that do not transform. Their chemical structure is not modified, and they are eliminated unaltered [2].

2.1.1. Effect of metabolism of the first step

When drugs are administered orally, they suffer a phenomenon of elimination prior to the process per se of the metabolism. This effect is known as first-pass metabolism and occurs in the epithelial cells of the gastrointestinal tract mainly in the small intestine [24]. Subsequently, the amount of drug that was not biotransformed enters the liver through the portal circulation, and there in the hepatocytes the metabolism process per se is carried out [24]. The amount of drug remaining after liver extraction is bioavailable to give an adequate pharmacological response. It is important not to modify this bioavailability because the effective doses of the drugs used in the clinical ready are considered as the effect of metabolism of the first step. Above all, caution should be exercised in drugs with a narrow safety margin, such as barbiturates [1, 2].

2.1.2. Enterohepatic circuit

When drugs are biotransformed by phase I reactions, and the molecule obtained is not polar enough to be eliminated, their biotransformation continues through phase II reactions. In this phase, the metabolites are generally conjugated with glucuronide acid, giving a polar molecule with a higher molecular weight [1, 2]. These conjugates are secreted from the hepatocyte into the bile and stored there in the form of a drug-glucuronide complex; when the bile is secreted in the intestine by some stimulus, the drug-bile complex is eliminated through the feces [25]. However, intestinal microorganisms produce various enzymes, such as beta-glucuronidases, which break the bond between the drug and glucuronide acid, leaving the drug free again, where it can be reabsorbed through the small intestine and enter the general circulation. In this case, the half-life of the drugs is increased [25].

2.1.3. Factors that affect the metabolism of drugs Physiological factors: age and pregnancy

In children and older adults, the metabolic rate is decreased compared to the metabolic rate of a young adult [1]. In the child, the microsomal enzymes are not yet fully induced [26]. In elderly people, the number of hepatocytes and blood flow that reaches this organ is reduced [27]. So, there are fewer cytochrome P450 enzymes available to metabolize drugs. In pregnancy, there is greater hepatic flow and greater activity of cytochrome P450, which increases the metabolic rate [28]. Pathological factors: liver disease

The number of hepatocytes decreases, and the metabolic rate also decreases. In addition, there is an increase in the plasmatic concentrations and half-life of drugs. Therefore, it is necessary to adjust the dose, to prevent toxicity [2]. Drugs, medicinal plants, and foods

Some drugs and phytochemical compounds present in medicinal plants and foods of plant origin can induce or inhibit the activity of cytochrome P450 [29].

2.2. Phases of drug metabolism

Biotransformation reactions of drugs are divided into reactions of phase I or functionalization and reactions of phase II or conjugation [2].

The chemical reactions of phase I allow the introduction of functional groups such as –OH, –COOH, –SH, –O–, or –NH2. Phase I reactions are very simple chemical reactions such as oxidation, reduction, hydrolysis, alkylation, and dealkylation [2]. Of these chemical reactions, the most important in the metabolism of drugs and that occur more frequently are the oxidation reactions performed by the cytochrome P450 enzymes (CYP450). These enzymes are located mainly in the smooth endoplasmic reticulum [1, 2].

When the addition of the functional groups (–OH, –COOH, –SH, –O–, –NH2) to the drug molecule is not enough to transform it to a more polar molecule, the molecule continues its modification through reactions of phase II. Phase II reactions are called also conjugation reactions. In these reactions, the molecule of the drug or metabolite previously formed in the reactions of phase I is conjugated with a large molecule of polar nature (hydrophilic) as the acid glucuronide, or acetyl Co-A, glycine, glutathione, phosphoadenosyl phosphosulfate, and S-adenosylmethionine [2]. These reactions are carried out by means of specific enzymes called transferases that are generally located in the microsomes and in the cytosol [1, 2, 3].

2.3. Role of cytochrome P450 (CYP450) in drug metabolism

Cytochrome P450 (CYP450) is a superfamily of enzymes that contain a heme group, so they are hemoproteins. The iron in the heme group is reduced and forms complexes with the carbon monoxide that absorbs light at a wavelength of 450 nm [30]. They have identified more than 8700 genes that code for their proteins and are found in eukaryotic and prokaryotic cells [31]. They are responsible for metabolizing or biotransforming endogenous substances in the body such as hormones, and different xenobiotics such as drugs. These enzymes perform oxidation reactions and participate in the phase I reactions of drug metabolism [1, 2, 3]. They are also known as mixed function oxidases or monooxygenases; they require a reducing agent such as NADPH and molecular oxygen [32].

They have different patterns of specificity for the substrate; for example, acetaminophen is a substrate of both CYP1A2 and CYP2E1, while halogenated anesthetics are substrate only of CYP2E1 [2, 34, 35, 36]. This enzyme system is found in different tissues such as kidney, lung, skin, brain, adrenal cortex, placenta, testicles, and other tissues, but the liver and small intestine are the organs that have more CYP450 [33, 34].

2.3.1. Nomenclature of CYP450

The CYP450 is grouped into families and subfamilies depending on the analogy in their amino acid sequences, such that CYPs that present 40% homology in their amino acids belong to a family, and when the analogy is greater than 55%, they form a subfamily, are named with the prefix CYP, and followed by the family number, a capital letter indicating the subfamily, and a number that marks the individual form: for example, CYP1A1, in this way, represents the individual form 1 of subfamily A of family 1 [35]. Eighteen families, 42 subfamilies, and more than 50 individual genes of human origin have been described. However, the most important in the metabolism of drugs are CYP1A1/2, CYP1B1, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, CYP3A4,5,7 [1, 2, 3]. CYP3A4,5,7 is the most abundant and participates in the metabolism of more than 50% of the drugs currently used in the clinic [1, 2, 3, 35].

2.4. Induction and Enzymatic inhibition

Many substances such as drugs, environmental toxins, and phytochemicals present in medicinal plants and some foods of plant origin contain substances that act as inhibitors or inducers of cytochrome P450 enzymes; this induction and inhibition can be strong or weak so it can sometimes have relevant clinical implications such as producing toxicity or therapeutic failure [36].

Enzymatic induction refers to the increase of enzymes and/or their activity. Additionally, it increases the metabolic rate of CYP450, and therefore, the concentrations of the drug in blood will decrease, which can cause a decrease in pharmacological effects and with it a therapeutic failure (Figure 2) [37].

Figure 2.

Effect of medicinal plants and foods of vegetable origin on CYP450 activity.

In enzymatic inhibition, the number of enzymes and/or their activity decreases. There are fewer enzymes available to biotransform the drugs and increase their plasma levels with each administration of the drug will produce toxicity (Figure 2) [33].

It is important not to induce or inhibit the activity of CYP450; they directly influence the bioavailability of the drugs. On the other hand, the genetic polymorphism of CYP450 is also responsible for the variability in the response to drugs between each individual [34, 35]. Genetic variability, especially of CYP2C9, CYP2C19, CYP2D6, and CYP3A5, is known to have an important clinical impact on drugs that are metabolized by these enzymes [38, 39, 40].

2.5. Effect of bioactive compounds of medicinal plants and foods of vegetable origin on the activity of CYP450

In the literature, there is a lot of information about the effect of drugs to inhibit or induce certain CYP450 isoenzymes. Recently the study of the effect of some phytochemical components that are present in medicinal plants and foods of vegetable origin on the activity of CYP450 has been increasing, because the population makes use of herbal medicine in its traditional practice and, on the other hand, it consumes foods with nutraceutical properties, either to prevent or to control any disease.

Tables 1 and 2 show the effect of the phytochemical compounds present in medicinal plants and foods of vegetable origin. We mentioned principally those natural products that have an important effect on the induction and inhibition of different CYP450 isoenzymes and that have clinical relevance to produce toxicity or therapeutic failure.

Medicinal plant Tradicional uses Phytochemistry compounds Activity on CYP450 Clinical effect on substrates of CYP450 References
Artemisia annua L. Antimalaria effect Artemisinin ↑CYP2C19 ↓Plasmatic concentration of I [3, 41, 42]
Cimicifuga racemosa Are used as a hormone replacement and antiinflammatory Triterpene glycosides Fukinolic acid
Cimicifugic acid A
Cimicifugic acid B
↑Plasmatic concentration of II
↑Plasmatic concentration of III
↑Plasmatic concentration of IV
↑Plasmatic concentration of V
[3, 43]
Centella asiatica Used for wound healing and maintaining normal blood pressure. Flavonoids:
↑Plasmatic concentration of III
↑Plasmatic concentration of IV
↑Plasmatic concentration of V
[3, 44, 45]
Curcuma longa Antiinflammatory, anticancer and antiarthritic effect. Curcuminoids:
Methoxycurcumin, Bisdemethoxy-curcumin
↑Plasmatic concentration of II
↓Plasmatic concentration of VI
↑Plasmatic concentration of IV
↑Plasmatic concentration of V
[3, 46, 47, 48]
Echinacea purpurea (L.) It is used to treat colds, upper respiratory infections, and dermatologic issues Cichoric acid
Caftaric acid
↓Plasmatic concentration of II
↑Plasmatic concentration of V
[3, 49, 50]
Garcinia cambogia Obesity treatment Extract crude ↓CYP2B6 ↑Plasmatic concentration of VII [3, 51]
Gardenia jasminoides Ellis. Is used as an antioxidant, hypoglycemic, antithrombotic, antiinflammatory, antidepression effect, and improved sleeping quality Geniposide
↓Plasmatic concentration of III
↑Plasmatic concentration of I
↑Plasmatic concentration of V
[3, 52, 53]
Gingko biloba It is used as an anti-hypertensive as well as to treat macular degeneration and tinnitus. Are effective in treating cerebral infarction Ginkgolide A
Ginkgolide B
↑Plasmatic concentration of VII
↓Plasmatic concentration of II
↓Plasmatic concentration of V
[3, 54, 55, 56]
Panax ginseng Is believed to enhance cognitive ability and to lower blood sugar levels Ginsenosides and gintonin
Ginsenoside F2 and protopanaxadiol
Ginsenosides ↓CYP2C9
↑Plasmatic concentration of IV
↑Plasmatic concentration of V
[3, 57]
Camellia sinensis It is consumed to treat cancer, cardiovascular disease, dyslipidemia, inflammation, and weight loss Catechin
(-)-Epigallocatechin -3-gallate
↑Plasmatic concentration of II
↑Plasmatic concentration of VII
↑Plasmatic concentration of VIII
↑Plasmatic concentration of IV
↑Plasmatic concentration of III
↑Plasmatic concentration of V
[3, 58, 59, 60]
Piper methysticum Anxiolytic effect Flavokawain A ↑CYP2C9
↓Plasmatic concentration of IV
↑Plasmatic concentration of II
↑Plasmatic concentration of V
[3, 61, 62, 63, 64]
Hypericum perforatum Is used to treat anxiety and depression Hyperforin ↑CYP2C9
↓Plasmatic concentration of IV
↓Plasmatic concentration of V
[3, 65, 66, 67]

Table 1.

Effect of medicinal plants on CYP450 activity.

I: Omeprazole, pantoprazole, diazepam, S-mephenytoin, amitriptyline, carisoprodol, citalopram, chloramphenicol, clomipramine, cyclophosphamide, indomethacin, moclobemide, nelfinavir, propranolol, progesterone.

II: Acetaminophen, amitriptyline, phenacetin, tacrine, theophylline, tamoxifen, (R)warfarin, caffeine, verapamil, ondansetron, haloperidol, naproxen, propanolol.

III: Propoxyphene, codeine, oxycodone, dextromethorphan, clozapine, timolol, tamoxifen, tramadol, seleglinide, fluoxetine, phenformin, paroxetine, risperidone, metoprolol, tricyclic antidepressants.

IV: Amitriptyline, celcoxib, ibuprofen, diclofenac, meloxicam, hexobarbital, losartan, S-warfarin, fluvastation, phenytoin, tolbutamide, glipizide, glibenclamide, fluoxetine, tamoxifen.

V: Acetaminophen, amiodarone, cisapride, astemizole, cocaine, cyclosporine, dapsone, diazepam, dihydroergotamine, diltiacem, felodipine, nifedipine, erythromycin, indinavir, lidocaine, methadone, miconazole, quinidine, paclitaxel, mifepristone, spironolactone, verapamil, trazolam, desametaxone, ritonavir, lovastatin, hydrocortisone.

VI: Nicotine.

VII: Bupropion, cyclophosphamide, efavirenz, ifosfamide, methadone.

VIII: Paclitaxel, torsemide, amodiaquine, cerivastatin, repaglinide.

Fruit or vegetable Phytochemistry compound Activity on CYP450 Clinical effect on substrates of CYP450 References
Broccoli Sulforaphane ↑CYP1A2
↓Plasmatic concentration of II
↑Plasmatic concentration of III
[3, 68, 69]
Grapefruit Furanocoumarin ↓CYP3A4 ↑Plasmatic concentration of V [3, 65, 70, 71]
Pomegranate Flavonoids
Phenolic acids
↑Plasmatic concentration of IV
↑Plasmatic concentration of V
[3, 72]
Sevillian orange Furanocoumarin ↓CYP3A4 ↑Plasmatic concentration of V [3, 73]
Star fruit Catechin Epicatechin ↓CYP3A4 ↑Plasmatic concentration of V [3, 74, 75, 76]

Table 2.

Effect of fruits or vegetables on CYP450 activity.

II: Acetaminophen, amitriptyline, phenacetin, tacrine, theophylline, tamoxifen, (R)warfarin, caffeine, verapamil, ondansetron, haloperidol, naproxen, propanolol.

III: Propoxyphene, codeine, oxycodone, dextromethorphan, clozapine, timolol, tamoxifen, tramadol, seleglinide, fluoxetine, phenformin, paroxetine, risperidone, metoprolol, tricyclic antidepressants.

IV: Amitriptyline, celcoxib, ibuprofen, diclofenac, meloxicam, hexobarbital, losartan, S-warfarin, fluvastation, phenytoin, tolbutamide, glipizide, glibenclamide, fluoxetine, tamoxifen.

V: Acetaminophen, amiodarone, cisapride, astemizole, cocaine, cyclosporine, dapsone, diazepam, dihydroergotamine, diltiacem, felodipine, nifedipine, erythromycin, indinavir, lidocaine, methadone, miconazole, quinidine, paclitaxel, mifepristone, spironolactone, verapamil, trazolam, desametaxone, ritonavir, lovastatin, hydrocortisone.


3. Conclusions

The induction and inhibition of CYP450, by some bioactive compounds present in medicinal plants or foods, can modify the bioavailability of drugs. The changes in the bioavailability are important in the efficacy and safety of pharmacological management. It is important to consider that when a patient will be in a pharmacologic treatment, the patient should not use any medicinal plants or foods of vegetable origin that can induce or inhibit any CYP450 isoenzymes.

Especially, they should not use the St. John’s wort and grapefruit, as their phytochemical compounds have a potent effect to induce or inhibit, respectively, the activity of CYP3A4 with important clinical relevance.


  1. 1. Brunton LL, Chabner BA, Knollman B. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. United States: McGraw-Hill; 2012. pp. 123-143
  2. 2. Katzung BG, Masters SB, Trevor AJ. Basic & Clinical Pharmacology. 12th ed. United States: McGraw-Hill; 2013. pp. 37-68
  3. 3. Flórez J, Armijo JA, Mediavilla A. Human Pharmacology. 6th ed. Barcelona, Spain: McGraw-Hill; 2014. pp. 46-105
  4. 4. Mehrotra N, Gupta M, Kovar A, Meibohm B. The role of pharmacokinetics and pharmacodynamics in phosphodiesterase-5 inhibitor therapy. International Journal of Impotence Research. 2007;19:253-264. DOI: 10.1038/sj.ijir.3901522
  5. 5. Chawla PK, Udwadia ZF, Soman R, Mahashur AA, Amale RA, Dherai AJ, Lokhande RV, Naik PR, Ashavaid TF. Importance of therapeutic drug monitoring of rifampicin. The Journal of the Association of Physicians of India. 2016;64:68-72
  6. 6. World Health Organization. Traditional Medicine Strategy 2014-2023 [Internet]. Available from: [Accessed: April 01, 2018]
  7. 7. Brewer CT, Chen T. Hepatotoxicity of herbal supplements mediated by modulation of cytochrome P450. International Journal of Molecular Sciences. 2017;18:E2353. DOI: 10.3390/ijms18112353
  8. 8. Hua S, Zhang Y, Liu J, Dong L, Huang J, Lin D, Fu X. Ethnomedicine, phytochemistry and pharmacology of Smilax glabra: An important traditional Chinese medicine. The American Journal of Chinese Medicine. 2018;46:261-297. DOI: 10.1142/S0192415X18500143
  9. 9. Cruz EC, Andrade-Cetto A. Ethnopharmacological field study of the plants used to treat type 2 diabetes among the Cakchiquels in Guatemala. Journal of Ethnopharmacology. 2005;159:238-244. DOI: 10.1016/j.jep.2014.11.021
  10. 10. Martínez-Francés V, Hahn E, Ríos S, Rivera D, Reich E, Vila R, Cañiqueral S. Ethnopharmacological and chemical characterization of Salvia species used in Valencian traditional herbal preparations. Frontiers in Pharmacology. 2017;8:467. DOI: 10.3389/fphar.2017.00467
  11. 11. Alfano A, Corsuto L, Finamore R, Savarese M, Ferrara F, Falco S, Santabarbara G, De Rosa M, Schiraldi C. Valorization of olive mill wastewater by membrane processes to recover natural antioxidant compounds for cosmeceutical and nutraceutical applications or functional foods. Antioxidants (Basel). 2018;7:E72. DOI: 10.3390/antiox7060072
  12. 12. Benatrehina PA, Pan L, Naman CB, Li J, Kinghorn AD. Usage, biological activity, and safety of selected botanical dietary supplements consumed in the United States. Journal of Traditional and Complementary Medicine. 2018;8:267-277. DOI: 10.1016/j.jtcme.2018.01.006
  13. 13. Maroyi A. Nutraceutical and ethnopharmacological properties of Vangueria infausta subsp. infausta. Molecules. 2018;23:E1089. DOI: 10.3390/molecules23051089
  14. 14. Singh BN. Effects of food on clinical pharmacokinetics. Clinical Pharmacokinetics. 1999;37:213-255. DOI: 10.2165/00003088-199937030-00003
  15. 15. Péter S, Navis G, de Borst MH, von Schacky C, van Orten-Luiten ACB, Zhernakova A, Witkamp RF, Janse A, Weber P, Bakker SJL, Eggersdorfer M. Public health relevance of drug-nutrition interactions. European Journal of Nutrition. 2017;56:23-36. DOI: 10.1007/s00394-017-1510-3
  16. 16. Li ZQ, Tian S, Gu H, Wu ZG, Nyagblordzro M, Feng G, He X. In vitro-in vivo predictive dissolution-permeation-absorption dynamics of highly permeable drug extended-release tablets via drug dissolution/absorption simulating system and pH alteration. AAPS PharmSciTech. 2018;19:1882-1893. DOI: 10.1208/s12249-018-0996-1
  17. 17. Romand S, Schappler J, Veuthey JL, Carrupt PA, Martel S. clEF for rapid pKa determination of small molecules: A proof of concept. European Journal of Pharmaceutical Sciences. 2014;63:14-21. DOI: 10.1016/j.ejps.2014.06.016
  18. 18. Li M, Zhang H, Chen B, Wu Y, Guan L. Prediction of pKa values for neutral and basic drugs based on hybrid artificial intelligence methods. Scientific Reports. 2018;8:3991. DOI: 10.1038/s41598-018-22332-7
  19. 19. Manallack DT, Prankerd RJ, Yuriev E, Oprea TI, Chalmers DK. The significance of acid/base properties in drug discovery. Chemical Society Reviews. 2013;42:485-496. DOI: 10.1039/c2cs35348b
  20. 20. Krishna DR, Klotz U. Extrahepatic metabolism of drugs in humans. Clinical Pharmacokinetics. 1994;26:144-160. DOI: 10.2165/00003088-199426020-00007
  21. 21. Paine MF, Hart HL, Ludington SS, Haining RL, Rettie AE, Zeldin DC. The human intestinal cytochrome P450 “pie”. Drug Metabolism and Disposition. 2006;34:880-886. DOI: 10.1124/dmd.105.008672
  22. 22. Kvist AJ, Kanebratt KP, Walentinsson A, Palmgren H, O’Hara M, Björkbom A, Andersson LC, Ahlqvist M, Andersson TB. Critical differences in drug metabolic properties of human hepatic cellular models, including primary human hepatocytes, stem cell derived hepatocytes, and hepatoma cell lines. Biochemical Pharmacology. 2018;55:124-140. DOI: 10.1016/j.bcp.2018.06.026
  23. 23. Sevior DK, Pelkonen O, Ahokas JT. Hepatocytes: The powerhouse of biotransformation. The International Journal of Biochemistry & Cell Biology. 2012;44:257-261. DOI: 10.1016/j.biocel.2011.11.011
  24. 24. Alqahtani S, Bukhari I, Albassam A, Alenazi M. An update on the potential role of intestinal first-pass metabolism for the prediction of drug–drug interactions: The role of PBPK modeling. Expert Opinion on Drug Metabolism & Toxicology. 2018;14:625-634. DOI: 10.1080/17425255.2018.1482277
  25. 25. Malik MY, Jaiswal S, Sharma A, Shukla M, Lal J. Role of enterohepatic recirculation in drug disposition: Cooperation and complications. Drug Metabolism Reviews. 2016;48:281-327. DOI: 10.3109/03602532.2016.1157600
  26. 26. Stockmann C, Constance JE, Roberts JK, Olson J, Doby EH, Ampofo K, Stiers J, Spigarelli MG, Sherwin CM. Pharmacokinetics and pharmacodynamics of antifungals in children and their clinical implications. Clinical Pharmacokinetics. 2014;53:429-454. DOI: 10.1007/s40262-014-0139-0
  27. 27. Turnheim K. When drug therapy gets old: Pharmacokinetics and pharmacodynamics in the elderly. Experimental Gerontology. 2003;38:843-853
  28. 28. Koren G, Pariente G. Pregnancy—Associated changes in pharmacokinetics and their clinical implications. Pharmaceutical Research. 2018;35:61. DIO: 10.1007/s11095-018-2352-2
  29. 29. Brewer L, Williams D. Clinically relevant drug–drug and drug–food interactions. Pharmaceutical Medicine. 2013;27(1):9-23. DOI: 10.1007/s40290-013-0008-4
  30. 30. Klingenberg M. Pigments of rat liver microsomes. Archives of Biochemistry and Biophysics. 1958;75(2):376-386. DOI: 10.1016/0003-9861(58)90436-3
  31. 31. Ioannides C, Lewis DF. Cytochromes P450 in the bioactivation of chemicals. Current Topics in Medicinal Chemistry. 2004;4:1767-1788
  32. 32. Brewer CT, Chen T. PXR variants: The impact on drug metabolism and therapeutic responses. Acta Pharmaceutica Sinica B. 2016;6:441-449. DOI: 10.1016/j.apsb.2016.07.002
  33. 33. Eagling VA, Back DJ, Barry MG. Differential inhibition of cytochrome P450 isoforms by the protease inhibitors, ritonavir, saquinavir and indinavir. British Journal of Clinical Pharmacology. 1997;44(2):190-194
  34. 34. Restrepo JG, Garcia-Martín E, Martínez C, Agúndez JA. Polymorphic drug metabolism in anaesthesia. Current Drug Metabolism. 2009;10:236-246. DOI: 10.2174/138920009787846305
  35. 35. Nelson DR. Cytochrome P450 nomenclature, 2004. Methods in Molecular Biology. 2006;320:1-10. DOI: 10.1385/1-59259-998-2:1
  36. 36. Ding X, Kaminsky LS. Human extrahepatic cytochromes P450: Function in xenobiotic metabolism and tissue-selective chemical toxicity in the respiratory and gastrointestinal tracts. Annual Review of Pharmacology and Toxicology. 2003;43:149-173. DOI: 10.1146/annurev.pharmtox.43.100901.140251
  37. 37. Tompkins LM, Wallace AD. Mechanisms of cytochrome P450 induction. Journal of Biochemical and Molecular Toxicology. 2007;21:176-181
  38. 38. Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacology & Therapeutics. 2013;138:103-141. DOI: 10.1016/j.pharmthera.2012.12.007
  39. 39. Fanni D, Ambul R, Gerosa C, Nemolato S, Castagnola M, Van Eyken P, Faa G, Fanos V. Cytochrome P450 genetic polymorphism in neonatal drug metabolism: Role and practical consequences towards a new drug culture in neonatology. International Journal of Immunopathology and Pharmacology. 2014;27:5-13. DOI: 10.1177/039463201402700102
  40. 40. Sychev DA, Ashraf GM, Svistunov AA, Maksimov ML, Tarasov VV, Chubarev VN, Otdelenov VA, Denisenko NP, Barreto GE, Aliev G. The cytochrome P450 isoenzyme and some new opportunities for the prediction of negative drug interaction in vivo. Drug Design, Development and Therapy. 2018;12:1147-1156. DOI: 10.2147/DDDT.S149069
  41. 41. Misra A, Chanotiya CS, Gupta MM, Dwivedi UN, Shasany AK. Characterization of cytochrome P450 monooxygenases isolated from trichome enriched fraction of Artemisia annua L. leaf. Gene. 2012;510:193-201. DOI: 10.1016/j.gene.2012.09.015
  42. 42. Shen Q, Chen YF, Wang T, Wu SY, Lu X, Zhang L, Zhang FY, Jiang WM, Wang GF, Tang KX. Overexpression of the cytochrome P450 monooxygenase (cyp71av1) and cytochrome P450 reductase (cpr) genes increased artemisinin content in Artemisia annua (Asteraceae). Genetics and Molecular Research. 2012;11:3298-3309. DOI: 10.4238/2012
  43. 43. Huang Y, Jiang B, Nuntanakorn P, Kennelly EJ, Shord S, Lawal TO, Mahady GB. Fukinolic acid derivatives and triterpene glycosides from black cohosh inhibit CYP isozymes, but are not cytotoxic to Hep-G2 cells in vitro. Current Drug Safety. 2010;5:118-124
  44. 44. Savai J, Varghese A, Pandita N, Chintamaneni M. Investigation of CYP3A4 and CYP2D6 interactions of Withania somnifera and Centella asiatica in human liver microsomes. Phytotherapy Research. 2015;29:785-790. DOI: 10.1002/ptr.5308
  45. 45. Pan Y, Abd-Rashid BA, Ismail Z, Ismail R, Mak JW, Pook PC, Er HM, Ong CE. In vitro modulatory effects on three major human cytochrome P450 enzymes by multiple active constituents and extracts of Centella asiatica. Journal of Ethnopharmacology. 2010;130:275-283. DOI: 10.1016/j.jep.2010.05.002
  46. 46. Hsieh YW, Huang CY, Yang SY, Peng YH, Yu CP, Chao PD, Hou YC. Oral intake of curcumin markedly activated CYP 3A4: In vivo and ex-vivo studies. Scientific Reports. 2014;4:6587. DOI: 10.1038/srep06587
  47. 47. Chen Y, Liu WH, Chen BL, Fan L, Han Y, Wang G, Hu DL, Tan ZR, Zhou G, Cao S, Zhou HH. Plant polyphenol curcumin signifcantly affects CYPIA2 and CYP2A6 activity in healthy, male Chinese volunteers. Annals of Pharmacotherapy. 2010;44:1038-1045. DOI: 10.1345/aph.1M533
  48. 48. Wang Z, Sun W, Huang CK, Wang L, Xia MM, Cui X, Hu GX, Wang ZS. Inhibitory effects of curcumin on activity of cytochrome P450 2C9 enzyme in human and 2C11 in rat liver microsomes. Drug Development and Industrial Pharmacy. 2015;41:613-616. DOI: 10.3109/03639045.2014.886697
  49. 49. Modarai M, Gertsch J, Suter A, Heinrich M, Kortenkamp A. Cytochrome P450 inhibitory action of Echinacea preparations differs widely and co-varies with alkylamide content. The Journal of Pharmacy and Pharmacology. 2007;59:567-573. DOI: 10.1211/jpp.59.4.0012
  50. 50. Gorski JC, Huang SM, Pinto A, Hamman MA, Hilligoss JK, Zaheer NA, Desai M, Miller M, Hall SD. The effect of echinacea (Echinacea purpurea root) on cytochrome P450 activity in vivo. Clinical Pharmacology and Therapeutics. 2004;75:89-100. DOI: 10.1016/j.clpt.2003.09.013
  51. 51. Yu JS, Choi MS, Park JS, Rehman SU, Nakamura K, Yoo HH. Inhibitory effects of Garcinia cambogia extract on CYP2B6 enzyme activity. Planta Medica. 2017;83:895-900. DOI: 10.1055/s-0043-104934
  52. 52. Xiao W, Li S, Wang S, Ho CT. Chemistry and bioactivity of Gardenia jasminoides. Journal of Food and Drug Analysis. 2017;25:43-61. DOI: 10.1016/j.jfda.2016.11.005
  53. 53. Gao LN, Zhang Y, Cui YL, Yan K. Evaluation of genipin on human cytochrome P450 isoenzymes and P-glycoprotein in vitro. Fitoterapia. 2014;98:130-136. DOI: 10.1016/j.fitote.2014.07.018
  54. 54. Zhou XW, Ma Z, Geng T, Wang ZZ, Ding G, Yu-an B, Xiao W. Evaluation of in vitro inhibition and induction of cytochrome P450 activities by hydrolyzed ginkgolides. Journal of Ethnopharmacology. 2014;158(Pt A):132-139. DOI: 10.1016/j.jep.2014.10.023
  55. 55. Lau AJ, Chang TK. Inhibition of human CYP2B6-catalyzed bupropion hydroxylation by Ginkgo biloba extract: Effect of terpene trilactones and flavonols. Drug Metabolism and Disposition. 2009;37:1931-1937. DOI: 10.1124/dmd.109.028118
  56. 56. Deng Y, Bi HC, Zhao LZ, He F, Liu YQ, Yu JJ, Ou ZM, Ding L, Chen X, Huang ZY, Huang M, Zhou SF. Induction of cytochrome P450s by terpene trilactones and flavonoids of the Ginkgo biloba extract EGb 761 in rats. Xenobiotica. 2008;38:465-481. DOI: 10.1080/00498250701883233
  57. 57. Xiao J, Chen D, Lin XX, Peng SF, Xiao MF, Huang WH, Wang YC, Peng JB, Zhang W, Ouyang DS, Chen Y. Screening of drug metabolizing enzymes for the ginsenoside compound K in vitro: An efficient anti-cancer substance originating from Panax ginseng. PLoS One. 2016;11:e0147183. DOI: 10.1371/journal.pone.0147183
  58. 58. Misaka S, Miyazaki N, Fukushima T, Yamada S, Kimura J. Effects of green tea extract and (−)-epigallocatechin-3-gallate on pharmacokinetics of nadolol in rats. Phytomedicine. 2013;20:1247-1250. DOI: 10.1016/j.phymed.2013.07.003
  59. 59. Albassam AA, Markowitz JS. An appraisal of drug-drug interactions with green tea (Camellia sinensis). Planta Medica. 2017;83:496-508. DOI: 10.1055/s-0043-100934
  60. 60. Satoh T, Fujisawa H, Nakamura A, Takahashi N, Watanabe K. Inhibitory effects of eight green tea catechins on cytochrome P450 1A2, 2C9, 2D6, and 3A4 activities. Journal of Pharmacy & Pharmaceutical Sciences. 2016;19:188-197. DOI: 10.18433/J3MS5C
  61. 61. Niu L, Ding L, Lu C, Zuo F, Yao K, Xu S, Li W, Yang D, Xu X. Flavokawain A inhibits cytochrome P450 in in vitro metabolic and inhibitory investigations. Journal of Ethnopharmacology. 2016;191:350-359. DOI: 10.1016/j.jep.2016.06.039
  62. 62. Li Y, Mei H, Wu Q, Zhang S, Fang JL, Shi L, Guo L. Methysticin and 7,8-dihydromethysticin are two major kavalactones in Kava extract to induce CYP1A1. Toxicological Sciences. 2011;124:388-399. DOI: 10.1093/toxsci/kfr235
  63. 63. Gurley BJ, Gardner SF, Hubbard MA, Williams DK, Gentry WB, Khan IA, Shah A. In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes. Clinical Pharmacology and Therapeutics. 2005;77:415-426. DOI: 10.1016/j.clpt.2005.01.009
  64. 64. Mathews JM, Etheridge AS, Black SR. Inhibition of human cytochrome P450 activities by kava extract and kavalactones. Drug Metabolism and Disposition. 2002;30:1153-1157
  65. 65. Nowack R. Review article: Cytochrome P450 enzyme, and transport protein mediated herb–drug interactions in renal transplant patients: Grapefruit juice, St John’s wort—And beyond! Nephrology (Carlton). 2008;13:337-347. DOI: 10.1111/j.1440-1797.2008.00940.x
  66. 66. Gurley BJ, Gardner SF, Hubbard MA, Williams DK, Gentry WB, Cui Y, Ang CY. Clinical assessment of effects of botanical supplementation on cytochrome P450 phenotypes in the elderly: St John’s wort, garlic oil, Panax ginseng and Ginkgo biloba. Drugs & Aging. 2005;22:525-539
  67. 67. Soleymani S, Bahramsoltani R, Rahimi R, Abdollahi M. Clinical risks of St John’s wort (Hypericum perforatum) co-administration. Expert Opinion on Drug Metabolism & Toxicology. 2017;13:1047-1062. DOI: 10.1080/17425255.2017.1378342
  68. 68. Hakooz N, Hamdan I. Effects of dietary broccoli on human in vivo caffeine metabolism: A pilot study on a group of Jordanian volunteers. Current Drug Metabolism. 2007;8:9-15. DOI: 10.2174/138920007779315080
  69. 69. Vanduchova A, Tomankova V, Anzenbacher P, Anzenbacherova E. Influence of sulforaphane metabolites on activities of human drug-metabolizing cytochrome P450 and determination of sulforaphane in human liver cells. Journal of Medicinal Food. 2016;19:1141-1146
  70. 70. Hanley MJ, Cancalon P, Widmer WW, Greenblatt DJ. The effect of grapefruit juice on drug disposition. Expert Opinion on Drug Metabolism & Toxicology. 2011;7:267-286. DOI: 10.1517/17425255.2011.553189
  71. 71. Chen M, Zhou SY, Fabriaga E, Zhang PH, Zhou Q. Food-drug interactions precipitated by fruit juices other than grapefruit juice: An update review. Journal of Food and Drug Analysis. 2018;26:S61-S71. DOI: 10.1016/j.jfda.2018.01.009
  72. 72. Singh B, Singh JP, Kaur A, Singh N. Phenolic compounds as beneficial phytochemicals in pomegranate (Punica granatum L.) peel: A review. Food Chemistry. 2018;261:75-86. DOI: 10.1016/j.foodchem.2018.04.039
  73. 73. Molden E, Spigset O. Fruit and berries—Interactions with drugs. Tidsskrift for den Norske Lægeforening. 2007;127:3218-3220
  74. 74. Zhang JW, Liu Y, Cheng J, Li W, Ma H, Liu HT, Sun J, Wang LM, He YQ, Wang Y, Wang ZT, Yang L. Inhibition of human liver cytochrome P450 by star fruit juice. Journal of Pharmacy & Pharmaceutical Sciences. 2007;10:496-503
  75. 75. Hosoi S, Shimizu E, Arimori K, Okumura M, Hidaka M, Yamada M, Sakushima A. Analysis of CYP3A inhibitory components of star fruit (Averrhoa carambola L.) using liquid chromatography-mass spectrometry. Journal of Natural Medicines. 2008;62:345-348. DOI: 10.1007/s11418-008-0239-y
  76. 76. Hidaka M, Fujita K, Ogikubo T, Yamasaki K, Iwakiri T, Okumura M, Kodama H, Arimori K. Potent inhibition by star fruit of human cytochrome P450 3A (CYP3A) activity. Drug Metabolism and Disposition. 2004;32:581-583. DOI: 10.1124/dmd.32.6.581

Written By

Xóchitl S. Ramírez-Gómez, Sandra N. Jiménez-García, Vicente Beltrán Campos, Esmeralda Rodríguez Miranda, Gabriel Herrera Pérez and Rafael Vargas-Bernal

Submitted: 11 April 2018 Reviewed: 05 July 2018 Published: 05 November 2018