Int J Pharm Pharm Sci, Vol 11, Issue 3, 1-5Review Article


FOOD–DRUG INTERACTION AND THEIR CLINICAL IMPLICATIONS: SELECTED INVESTIGATIONS

M. ABD ELGADIR

Department of Food Science and Human Nutrition, College of Agriculture and Veterinary Medicine, Qassim University, Saudi Arabia
Email: mam.upm@gmail.com

Received: 14 Mar 2018 Revised and Accepted: 22 Jan 2019

ABSTRACT

Food-drug interactions occur as a result of pharmacokinetic or pharmacodynamics mechanisms. Pharmacokinetic mechanisms include what the body does to a drug while Pharmacodynamics mechanisms involve what drugs do to the body. Many types of food have been shown to influence metabolism and the absorption of drugs. Large numbers of drugs are produced and introduced yearly. The interaction between Food and drug may cause negative effects in the nutritional status of the patient as well as safety and efficacy of drug therapy. Due to the possibility of unexpected or poor outcomes, generally, food-drug interactions, in this case, should be avoided. As the good clinical practice, drugs taken by mouth must be absorbed either through the lining of the stomach or the small intestine. Reduction in the absorbance of a drug might be influenced by the presence of food in the digestive tract. The avoidance of such interactions could be possible if the drug is taken 1 hour before or 2 h after eating the food. The effects of several types of food such as milk or milk products, grapefruit and grapefruit juice, bananas, oranges, legumes, fermented meats and pickled fish and some nutrient elements such as calcium, potassium, magnesium, iron, zinc, and vitamin K are highlighted in this paper including their clinical implications.

Keywords: Food-drug interaction, Medication, Clinical implications, Clinical practice

© 2019 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
DOI: http://dx.doi.org/10.22159/ijpps.2019v11i3.25930

INTRODUCTION

Many types of medicines can be useful because of their positive effects in treating and curing many health problems. To ensure that these medicines are safe and effective they must be taken properly. So, medications should have the same predictable effect for all patients, extremely specific in their effects, exhibit linear potency, never be affected by concomitant food or other medications, be totally non-toxic in any dosage and require only a single dose to affect a permanent cure [1]. Some types of food can sometimes have a significant impact on some drugs. Ayo et al. [2], revealed that a drug interaction is a situation in which a substance affects the activity of a drug, i.e. they produce a new effect that neither produces on its own or the effects are increased or decreased. Like drug-drug interaction (3), the interactions may also exist between foods and drugs (food-drug interactions) and could be possible between drugs and herbs (drug-herb interactions). The interactions between food and drugs may inadvertently reduce the absorbance of drug and also may increase the negative effect of the drug. However, due to the physiological response to food intake, particularly the gastric acid secretion, may increase or reduce the bioavailability of certain drugs [4]. Earlier (Schmidt and Dalhoff [5], reported that these may occur due to the lack of knowledge about the active ingredients that involved in the relevant substances. Several types of research have been dedicated with the objectives of investigating the effects of certain food-drug interaction systems [6-17]. The aim of the present was to investigate and highlight the effect of food-drug systems and their various clinical implications.

General food/some food components-drug interaction

Some specific types of foods can have unique influences on drug interaction and disposition. Within the gastrointestinal tract, an oral administration of a drug concurrent with meal alters may influence the rate or extent of drug absorption as well as the physicochemical conditions of the drug. Davit and Conner [18], claimed that a change in the rate of drug absorption is less clinically significant than a change in the extent of the drug absorption because due to the influences in bioavailability of both drug and meal. According to FDA [19], tested a meal contains about 800 to 1,000 kcal, with about 50% of calories as fat (eg, two strips of bacon, two eggs fried in butter, two slices of buttered toast, whole milk and brown potatoes and concluded that that such a meal will create the greatest perturbation on gastrointestinal physiology and be reflected in a meal’s influence on drug bioavailability. Therefore, it is very important to test meal conditions used in any conducted study before making a clinical recommendation. Using data generated invitro studies can clearly predict food effects and drug disposition using the Biopharmaceutics Classification System [19-23]. Boullata et al. [9], suggested that based on drug solubility and intestinal permeability some drugs have low solubility but high permeability and are expected to have an enhanced extent of absorption when administered with food. On the other hand, some other specific foods have impaired the absorption of drugs with poor permeability when examined in several clinical studies.

Interaction of some vegetables with drugs

Some vegetables (broccoli, Brussels sprouts, kale, parsley, spinach, and others) had a high content of vitamin K. Earlier, Holt [24] was reported that making sudden changes in the amounts eaten or eating large quantities of these vegetables interferes with the safety and effectiveness of warfarin therapy. Great decrease in warfarin activity might be resulted from eating charbroiled food. However, Zikria [25], revealed that eating cooked onions may increase warfarin activity. On the other hand, it was reported that soy foods had both an increase and decrease effect on warfarin activity [25], but the author found that the combination of cranberry juice and warfarin administration appeared to be associated with an elevated international normalized ratio without bleeding in an elderly patient.

Fruit juice-drug interaction

Several juices were found to have an interaction with medication by metabolizing and altering transporters enzymes to a wider degree than initially described [26, 27]. Naringin, an ingredient in most citrus fruits has been shown to reduce aliskiren uptake [28]. Grapefruit juice was the first identified, but based on flavonoid and furanocoumarin content other juices have also been shown to interact with medication [29, 30]. It was found that furanocoumarins had significant inhibition on intestinal isoenzymes and can also interfere with transporters, thereby increasing oral drug bioavailability. Grapefruit juice was found to have a significant effect on Aliskiren which is recognized as a direct renin inhibitor indicated for the treatment of hypertension. A clinical study conducted on 11 healthy volunteers administered using 200 ml single-strength of grapefruit juice (three times daily for five days) and 150 mg of aliskiren on day 3 showed that relative to water, grapefruit juice significantly reduced mean aliskiren by 61% [31]. A study with 28 healthy volunteers receiving 300 mg aliskiren and either water or grapefruit juice (300 ml) revealed a decrease of 38% by of the drug in the presence of grapefruit juice [28]. This decrease in the absorption of the drug was in a good agreement with the previous studies by several authors [30, 33-36]. However, some clinical studies with certain β-blockers, fexofenadine, and fluoroquinolones have demonstrated that orange juice can reduce systemic exposure by up to 83% [39-42]. Tapaninen et al. [31] investigated the effect of orange juice on aliskiren. In a randomized study, 12 healthy volunteers ingested 200 ml of orange juice, water or apple juice for a frequency of three times daily for a period of five days. On day 3, the volunteers ingested a single dose of 150 of aliskiren. The result showed that orange juice reduced aliskiren geometric mean by 62% relative to water while having no effect on elimination half-life. Apple juice was also investigated on drug metabolism in vitro and in human volunteers [26]. The evidence exists that apple juice inhibits organic anion transporting polypeptides activity which recognized as proteins that facilitate uptake of a number of endogenous compounds such as hormones and bile acids [41]. Apple juice intake on fexofenadine was evaluated in a randomized crossover study of 14 healthy volunteers [42]. Midazolam (5 mg) and fexofenadine (60 mg) with 300 ml of either normal-strength apple juice or water were orally taken. It was found that apple juice decreased fexofenadine mean 79% compared to water but it did not show significant effects on midazolam, indicating that apple juice had minimal effect on midazolam activity. Some other dedicated studies have shown the same effect of apple juice on fexofenadine [43-47].

Green tea-drug interaction

Green tea (GT) is well known among the most worldwide consumed beverages. It is obtained from the non-fermented leaves of the Camellia sinensis plant. It has promising health beneficial effects and it is considered as one of the most important nutraceuticals that used as new treatment approaches for oral cancer [48]. The polyphenols of GT (GTP), particularly catechin (−) epigallocatechin-3-gallate (EGCG), which has about 50–80% of the total catechins in GT, is reported to have an antioxidant effect [49]. It was investigated and reported that the anti-carcinogenic effect of tea catechins with EGCG being the most active.

Table 1: Selected food-drug interaction and their clinical implication*

Food Medicine Type of effect Clinical implications
Milk or milk products Ciprofloxacin(Cipro) Levofloxacin (Levaquin) Calcium in milk bind with these drugs inhibiting absorption of the drugs as well as calcium Administer 2 h before or 2 h after milk or milk products
Grapefruit and grapefruit juice

Beta-adrenergic antagonists

Labetalol Metoproplol

Propranolol (Inderal)

 Increased absorption by decreased first-pass metabolism; can slow heart rate and lower blood pressure

Avoid grapefruit or grapefruit

juice 2 h before or 1 hour

after administration of the drug
Bananas, oranges, legumes, and meats

Diuretics, potassium-sparing; Amiloride(Midamor) Spironolactone (Aldactone)

Triamterene (Dyrenium)

 Prevents kidneys from excreting potassium causing toxicity, slow heart rate, palpitations, and possibly cardiac arrest Limit potassium-rich foods, such as bananas, oranges, and green leafy vegetables, and salt substitutes that contain potassium.
Foods that raise blood sugar, such as sweets and refined flour

Antidiabetic drugs, Sulfonylureas Chlorpropamide

Glipizide (Glucotrol)

 Reduces control of blood sugar Vitamin B12 deficiency and irreversible nerve damage Avoid foods containing simple sugars and refined flour
Aged cheeses, fava beans, yeast extracts, Monomine oxidase; inhibitors; Isocarboxazid Phenelzine (Nardil), Tranylcypromine Potentially fatal spike in blood pressure Avoid foods and beverages containing tyramine or tryptophan while taking medications and for 2 w after stopping this drug.
High-fiber products, such as bran, pectin, bulk laxatives Cardiac glycosides Decreases absorption of the drug Administer before 1 hour or 4 h after ingestion of high fiber food products
Regular meal or snack Anti-tuberculosis; Rifampin (Rifadin, Rimactance). Delays or decreases absorption of the drug Administer 1 hour before or 2 h after meal or snack
Dietary fiber and Fatty foods

Simvastatin (Zocor) Lovastatin (Mevacor) Lovastatin (Mevacor)

Atorvastatin (Lipitor)

 Decrease absorption of the drugs; cause headage and stomachage and muscle breakdown Give with low-fiber foods or 1 hour after administration of drugs
Grapefruit juice Drugs that prolong repolarization Amiodarone (Cordarone, Pacerone Significantly enhanced toxicity Give on an empty stomach, 1 hour before or 2 h after meal or snack
Fermented meats, pickled fish Inhibitors; monomine oxidase Potentially affect fatal spike in blood pressure Avoid these foods after taking drugs for 2 w.
Soybean formulas Thyroid supplements Decreases absorption; increases fecal elimination Avoid soybean formulas and Limit foods high in iodine, such as rutabaga, soybeans, or turnips.
High-carbohydrate meals Respiratory medications May cause nausea, vomiting, headache, irritability Avoid high-carbohydrate meals or supplements and when necessary 2 h after dose
High-fat meals

Bronchodilators

theophylline

 Decreases absorption of the drug; May cause nausea, vomiting, headache, irritability Avoid high-fat meals or supplements and when necessary hold enteral nutrition 1 hour before medication.

There are numerous investigations and reports in this regards [51-53]. GT was found to have high concentrations of catechins, including epigallocatechin (EGC), epicatechin (EC) and epicatechin gallate (ECG). Zaveri [53] studied the activity of predominant catechin extensively for health benefits on OATP1A2 (organic anion transporting polypeptide 1A2) and OATP1A2 (organic anion transporting polypeptide 2A1) and OATP2B1 have in vitro. He reported that both EGCand ECG at 100 μM inhibited OATP2B1-mediated estrone-3-sulfate uptake by ~70%. This finding agreed with that revealed by Roth et al. [54] and Fuchikami et al. [55]. However, ECG showed higher potency than EGCG (IC50 of 36 vs. 100 μM) [52]. Moreover, they reported that ECG at 100 μM also inhibited OATP1A2-mediated estrone-3-sulfate uptake by ~75% but ECG again showed higher potency than (IC50 of 10 vs. 55 μM). The consumption of a cup of GT (e. g., 240–300 ml) or two cups of GT will result in inhibition of OATP activity due to high concentrations of ECG in intestinal line.

Table 2: Selected nutrient-drug interaction and their clinical implication*

Nutrient in food Medicine Type of effect Clinical implications
Calcium Ciprofloxacin (Cipro) Calcium binds with these drugs inhibiting absorption of the drugs Hold enteral feeding 1 hour before and 2 h after administration of the drug.
Potassium Diuretics, thiazide; Chlorthalidone (Hygroton) Causes loss of potassium and magnesium; can cause rapid heart rate and arrhythmias Administer potassium/magnesium supplement or foods such as apricots, bananas, cantaloupe, dairy foods, dried beans, lentils, oranges, and tomatoes.
Magnesium Quinolones Magnesium binds with this drugs inhibiting absorption of the drugs Avoid meals contain magnesium and magnesium supplement
Vitamin D supplements Gastrointestinal Medications Calcium toxicity and kidney failure Avoid milk; milk products and calcium supplement
Aluminum Levofloxacin (Levaquin) Aluminum binds with this drugs inhibiting absorption of the drugs Avoid meals contain aluminum and aluminum supplement
Iiron Norfloxacin (Noroxin) Iron binds with this drugs inhibiting absorption of the drugs Avoid meals contain iron and iron supplement
Zinc Ofloxacin (Floxin Zinc binds with this drugs inhibiting absorption of the drugs Avoid meals contain zinc and zinc supplement
Vitamin B12 Proton-pump inhibitors Vitamin B12 deficiency if used long term Avoid foods rich in Vitamin B12
Meals that high in pyridoxine (B6) Antiparkinson drugs Decreases absorption of the drug, increases symptoms Limit foods rich in pyridoxine such as chicken, fish, liver, and kidney.
Vitamin K Medications affecting the blood and blood-forming organs anticoagulant such as warfarin (Coumadin) increases chance of blood clots Limit foods high in vitamin K such as broccoli, spinach, kale, and turnip greens.
High-dose itamin K Medications affecting the blood and blood-forming organs anticoagulant such as Prolongs clotting time and increases the risk of bleeding Avoid foods rich or foods, such as leafy green vegetables, antagonize action; soy proteins; high doses of vitamin E (400 IU)
High-potassium supplements Potassium toxicity can slow heart rate and possibly cause cardiac arrest Avoid excessive potassium intake including salt substitutes that contain potassium.
Iodine Metformin (Glucophage) Decreases absorption; increases fecal elimination Limit foods high in iodine, such as brussels sprouts, cabbage, rutabaga, soy beans.

*Harrington and Gonzales, 2004) [50]

CONCLUSION

Food-drug interaction is considered a critical issue and most studies in this regard are conducted to evaluate appropriate dosing, formulation of new drug candidates and intake timing. Commonly consumed foods could have inhibition effect on drug or either increase/decrease the absorption of certain drugs. Foods should be tested comprehensively before taking certain drugs to avoid the possibility of interaction with the drug. Therefore patients are advised to tell their doctors and pharmacists about their food intake and dietary supplements so that serious interactions between foods and drugs can be avoided. Carefully following the clinical implications in this article is highly suggested and recommended.

ACKNOWLEDGMENT

This work was supported by Department of Food Science and Human Nutrition, College of Agriculture and Veterinary Medicine, Qassim University, Saudi Arabia.

ABBREVIATIONS

FDA (US Food and Drug Administration), GT (green tea), GTP (green tea polyphenols), EGCG (epigallocatechin-3-gallate), OATP1A2 (organic anion transporting polypeptide 1A2), OATP2B1 (organic anion transporting polypeptide 2A1), IC50 (the concentration of an inhibitor where the response (or binding) is reduced by half).

AUTHORS CONTRIBUTIONS

All the author have contributed equally

CONFLICT OF INTERESTS

No conflict of interest is declared

REFERENCES

  1. Frankel EH. Basic concepts. In: Handbook of food-drug interactions. McCabe BJ, Frankel EH, Wolfe JJ. (Eds.) CRC Press: Boca Raton; 2003. p. 2.

  2. Ayo JA, Agu H, Madaki I. Food and drug interactions: its side effects. Nutr Food Sci 2005;35:243–52.

  3. Jith PK, Kumar A, Joy AC. A prospective study of drug-drug interactions and adverse drug reactions among stroke patients in a tertiary care hospital. Asian J Pharm Clin Res 2016;9:100–4.

  4. Hansten PD. Appendix II: important interactions and their mechanisms. In: Katzung BG. Editor. 09th edn. Basic and Clinical Pharmacology, McGraw hill, Boston; 2004. p. 1110.

  5. Schmidt LE, Dalhoff K. Food-drug interactions. Drugs 2002;62:1481–502.

  6. Lin L, Wang M, Tsai T. Food-drug interaction of (−)-epigallocatechin-3-gallate on the pharmacokinetics of irinotecan and the metabolite SN-38. Chem Biol Interact 2008;174:177–82.

  7. Uwai Y, Ozeki Y, Isaka T, Honjo H, Iwamoto K. Inhibitory effect of caffeic acid on human organic anion transporters hOAT1 and hOAT3: a novel candidate for food-drug interaction. Drug Metabol Pharm 2011;5:486–93.

  8. Bushra R, Aslam N, Khan AY. Food-drug interactions. Oman Med J 2011;26:77–83.

  9. Boullata JI, Pharm DR, Hudson LM. Drug-nutrient interactions: a broad view with implications for practice. J Acad Nutr Diet 2012;112:506–17.

  10. Egashira K, Sasaki H, Higuchi S, Ieiri I. Food-drug interaction of tacrolimus with pomelo, ginger, and turmeric juice in rats. Drug Metabol Pharm 2012;27:242–7.

  11. Won CS, Nicholas H Oberlies, Mary F Paine. Mechanisms underlying food-drug interactions: inhibition of intestinal metabolism and transport. Pharm Ther 2012;136:186–201.

  12. De Boer A, Florence Van Hunsel, Aalt Bast. Adverse food-drug interactions. Regul Toxicol Pharm 2015;73:859–65.

  13. Mouly S, Lloret Linares C, Sellier P, Sene D, Bergmann J. Is the clinical relevance of drug-food and drug-herb interactions limited to grapefruit juice and Saint-John’s Worth? Pharm Res 2017;118:82–92.

  14. Di Minno A, Frigerio B, Spadarella G, Ravani A, Sansaro D, Amato M, Kitzmiller JP, et al. Old and new oral anticoagulants: food, herbal medicines and drug interactions. Blood Rev 2017;31:193–203.

  15. Pasko P, Rodacki T, Domagała Rodacka, Palimonka RK, Marcinkowska M, Owczarek D. Second generation H1-antihistamines interaction with food and alcohol-a systematic review. Biomed Pharm 2017;93:27–39.

  16. Wang N, Zhu C, Zhang X, Zhai X, Lu Y. Food-drug interactions involving multiple mechanisms: a case study with an effect of capsaicin on the pharmacokinetics of irinotecan and its main metabolites in rat. J Funct Foods 2018;40:292–8.

  17. Ashak R, Kousalya K, Senthil NB, Valentina P. An outlook on the mechanisms of drug interactions with other drugs, fruits, herbs and their preventive measures. Asian J Pharm Clin Res 2016;9:10–8.

  18. Davit BM, Conner DP. Food effects on drug bioavailability. In: Krishna R, Yu L. eds. Biopharmaceutics applications in drug development. New York, NY: Springer; 2008. p. 317–35.

  19. FDA. US Food and Drug Administration. Guidance for industry: Food-effect bioavailability and fed equivalence studies. Food Drug Administration: Rockville, MD, December; 2002. Available from: http://www.fda.gov/downloads/Drugs/Guidance Compliance Regulatory Information Guidances/ucm070241.pdf. [Last accessed on 25 Jan 2018].

  20. Amidon GL, Lennern Ås H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutics drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res 1995;12:413–20.

  21. Wu CY, Benet LZ. Predicting drug disposition via application of BCS: Transport/absorption/elimination interplay and development of a biopharmaceutics drug disposition classification system. Pharm Res 2005;22:11–23.

  22. Yang Y, Faustino PJ, Volpe DA, Ellison CD, Lyon RC, Yu LX. Biopharmaceutics classification of selected–blockers: solubility and permeability class membership. Mol Pharm 2007;4:608–14.

  23. Custodio JM, Wu CY, Benet LZ. Predicting drug disposition, absorption/elimination/transporter interplay and the role of food on drug absorption. Adv Drug Delivery Rev 2008;60:717–33.

  24. Holt GA. Food and drug interactions. Chicago. Precept Press; 1998. p. 293.

  25. Zikria J, Goldman R, Ansell J. Cranberry juice and warfarin: when bad publicity trumps science. Am J Med 2010;123:384–92.

  26. Dresser GK, Bailey DG, Leake BF, Schwarz UI, Dawson PA, Freeman DJ, et al. Fruit juices inhibit organic anion transporting polypeptide-mediated drug uptake to decrease the oral availability of fexofenadine. Clin Pharmacol Ther 2002;71:11–20.

  27. Bailey DG, Dresser GK, Bend JR. Bergamottin, lime juice and red wine as inhibitors of CYP3A4 activity: Comparison with grapefruit juice. Clin Pharmacol Ther 2003;73:529–37.

  28. Rebello S, Zhao S, Hariry S, Dahlke M, Alexander N, Vapurcuyan A, et al. Intestinal OATP1A2 inhibition as a potential mechanism for the effect of grapefruit juice on aliskiren pharmacokinetics in healthy subjects. Eur J Clin Pharmacol 2012;68:697–708.

  29. Greenblatt DJ. Analysis of drug interactions involving fruit beverages and organic anion–transporting polypeptides. J Clin Pharmacol 2009;49:1403–7.

  30. Komperda KE. Potential interaction between pomegranate juice and warfarin. sPharmacotherapy 2009;29:1002–6.

  31. Tapaninen T, Neuvonen PJ, Niemi M. Grapefruit juice greatly reduces the plasma concentrations of the OATP2B1 and CYP3A4 substrate aliskiren. Clin Pharmacol Ther 2010;88:339–42.

  32. Ho PC, Saville DJ, Coville PF, Wanwimolruk S. Content of CYP3A4 inhibitors, naringin, naringenin and bergapten in grapefruit and grapefruit juice products. Pharm Acta Helv 2000;74:379–85.

  33. Ross SA, Ziska DS, Zhao K, ElSohly MA. Variance of common flavonoids by brand of grapefruit juice. Fitoterapia 2000;71:154–61.

  34. De Castro WV, Mertens Talcott S, Rubner A, Butterweck V, Derendorf H. Variation of flavonoids and furanocoumarins in grapefruit juices: a potential source of variability in grapefruit juice–drug interaction studies. J Agric Food Chem 2006;54:249–55.

  35. Wanwimolruk S, Marquez PV. Variations in the content of active ingredients causing drug interactions in grapefruit juice products sold in california. Drug Metabol Drug Interact 2006;21:233–43.

  36. Brill S, Zimmermann C, Berger K, Drewe J, Gutmann H. In vitro interactions with repeated grapefruit juice administration-to peel or not to peel? Planta Med 2009;75:332–35.

  37. Neuhofel AL, Wilton JH, Victory JM, Hejmanowsk LG, Amsden GW. Lack of bioequivalence of ciprofloxacin when administered with calcium-fortified orange juice: a new twist on an old interaction. J Clin Pharmacol 2002;42:461–6.

  38. Wallace AW, Victory JM, Amsden GW. Lack of bioequivalence when levofloxacin and calcium-fortified orange juice are coadministered to healthy volunteers. J Clin Pharmacol 2003;43:539–44.

  39. Lilja JJ, Juntti Patinen L, Neuvonen PJ. Orange juice substantially reduces the bioavailability of the beta-adrenergic–blocking agent celiprolol. Clin Pharmacol Ther 2004a;75:184–90.

  40. Lilja JJ, Juntti Patinen L, Neuvonen PJ. Effects of regular consumption of grapefruit juice on the pharmacokinetics of simvastatin. Br J Clin Pharmacol 2004b;58:56–60.

  41. Hagenbuch B, Gui C. Xenobiotic transporters of the human organic anion transporting polypeptides (OATP) family. Xenobiotica 2008;38:778–801.

  42. Imanaga J, Kotegawa T, Imai H, Tsutsumi K, Yoshizato T, Ohyama T, et al. The effects of the SLCO2B1 c.1457C>T polymorphism and apple juice on the pharmacokinetics of fexofenadine and midazolam in humans. Pharm Genom 2011;21:84–93.

  43. Mougey EB, Feng H, Castro M, Irvin CG, Lima JJ. Absorption of montelukast is transporter-mediated: a common variant of OATP2B1 is associated with reduced plasma concentrations and poor response. Pharm Genom 2009;19:129–38.

  44. Ieiri I, Doi Y, Maeda K, Sasaki T, Kimura M, Hirota T, et al. Microdosing clinical study: pharmacokinetic, pharmacogenomic (SLCO2B1), and interaction (grapefruit juice) profiles of celiprolol following the oral microdose and therapeutic dose. J Clin Pharmacol 2011;52:1078–89.

  45. Ming X, Knight BM, Thakker DR. Vectorial transport of fexofenadine across caco–2 cells: involvement of apical uptake and basolateral efflux transporters. Mol Pharm 2011;8:1677–86.

  46. Glaeser H, Bailey DG, Dresser GK, Gregor JC, Schwarz UI, McGrath JS, et al. Intestinal drug transporter expression and the impact of grapefruit juice in humans. Clin Pharmacol Ther 2007;81:362–70.

  47. Mandery K, Bujok K, Schmidt I, Keiser M, Siegmund W, Balk B, et al. Influence of the flavonoids apigenin, kaempferol, and quercetin on the function of organic anion transporting polypeptides 1A2 and 2B1. Biochem Pharmacol 2010; 80:1746–53.

  48. Zlotogorski A, Dayan A, Dayan D, Chaushu G, Salo T, Vered M. Nutraceuticals as new treatment approaches for oral cancer: II. Green tea extracts and resveratrol. Oral Oncol 2013;49:502–6.

  49. Shahidi F, Ambigaipalan P. Phenolics and polyphenolics in foods, beverages and spices: antioxidant activity and health effects-a review. J Funct Foods 2015;18:820–97.

  50. Harrington L, Cris Gonzales C. Food and drug interactions in critically ill adults. Crit Care Nurs Clin North Am 2004; 16:501–8.

  51. Min KJ, Kwon TK. Anticancer effects and molecular mechanisms of epigallocatechin–3–gallate. Int Med Res 2014;3:16–24.

  52. Shirakami Y, Shimizu M, Moriwaki H. Cancer chemoprevention with green tea catechins: from bench to bed. Curr Drug Targets 2012;13:1842–57.

  53. Zaveri NT. Green tea and its polyphenolic catechins: medicinal uses in cancer and noncancer applications. Life Sci 2006; 78:2073–80.

  54. Roth M, Timmermann BN, Hagenbuch B. Interactions of green tea catechins with organic anion–transporting polypeptides. Drug Metab Dispos 2011;39:920–6.

  55. Fuchikami H, Satoh H, Tsujimoto M, Ohdo S, Ohtani H, Sawada Y. Effects of herbal extracts on the function of human organic anion–transporting polypeptide OATP–B. Drug Metab Dispos 2006;34:577–82.