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Effect of Fruit/Vegetable-Drug Interactions on CYP450, OATP and P-Glycoprotein: a Systematic Review

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Effect of Fruit/Vegetable-Drug Interactions on CYP450, OATP and P-Glycoprotein: a Systematic Review Mallhi et al Tropical Journal of Pharmaceutical Research October 2015; 14(10): 1927-1935 ISSN: 1596-5996 (print); 1596-9827 (electronic) © Pharmacotherapy Group, Faculty of Pharmacy, University of Benin, Benin City, 300001 Nigeria. All rights reserved. Available online at http://www.tjpr.org http://dx.doi.org/10.4314/tjpr.v14i10.27 Original Research Article Effect of Fruit/Vegetable-Drug Interactions on CYP450, OATP and p-Glycoprotein: A Systematic Review Tauqeer Hussain Mallhi1*, Azmi Sarriff1, Azreen Syazril Adnan2, Yusra Habib Khan1, Muhammad Imran Qadir4, Azhar Amir Hamzah3 and Amer Hayat Khan1 1Discipline of Clinical Pharmacy, School of Pharmaceutical Sciences, University Sains Malaysia, Penang 11800, 2Chronic Kidney Disease Resource Centre, School of Medical Sciences, Health Campus, University Sains Malaysia, 3Urology Unit, Department of Surgery, Hospital University Sains Malaysia, Kelantan 16150, Malaysia, 4Institute of Molecular Biology & Biotechnology, Bahauddin Zakariya University, Multan, Pakistan *For correspondence: Email: [email protected]; Tel: +60105644191 Received: 2 August 2014 Revised accepted: 23 July 2015 Abstract Purpose: To review the concomitant use of certain drugs with fruit/vegetable juices that may lead to drug-juice interactions resulting in medication-related problems. Method: In this systematic review, online databases (PubMed, Google Scholar and Science Direct) were searched for information on juices derived from fruits and vegetables that are reported to have inhibitory effects on cytochrome P450, p-glycoprotein and organic anion transporting polypeptides (OATPs). Results: Fruits can inhibit CYP1A1, CYP1A2, CYP1A4, CYP3A1, CYP3A4, CYP2C6, CYP2C9, CYP2E1 and drug transporters (P-glycoprotein, OATP). On the other hand CYP1A1, CYP1A2, CYP2A2, CYP3A1, CYP1B1, CYP2B1, CYP2B2, CYP2C1, CYP2C6, CYP2E1 can be inhibited by some vegetables. Antihypertensives, antidiabetics, statins, analgesics and antipsychotics were the most common drugs interacting with fruits and vegetables. The inhibition of their metabolism by fruits and vegetables can cause serious toxic effects, e.g., hypertension, poor glycemic control, rhabdomyolosis and drug overdose-related toxic effects. Overall, active components of fruits and vegetables can interact with many drugs leading to adverse effects. Conclusion: Screening of fruits/vegetables for possible risk of interaction, and patient counseling are some effective strategies for preventing such interactions for optimal patient care. Keywords: Fruits and vegetables, Cytochrome P450, Drug interactions, p-Glycoprotein, Organic anion transporting polypeptides Tropical Journal of Pharmaceutical Research is indexed by Science Citation Index (SciSearch), Scopus, International Pharmaceutical Abstract, Chemical Abstracts, Embase, Index Copernicus, EBSCO, African Index Medicus, JournalSeek, Journal Citation Reports/Science Edition, Directory of Open Access Journals (DOAJ), African Journal Online, Bioline International, Open-J-Gate and Pharmacy Abstracts INTRODUCTION of interactions with 6-10 drugs may just be 7 % but with 16-20 drugs, the risk may increase up to Drugs are essential components of medical 40 % [1]. High risk patients, such as elderly therapy but concomitant consumption of other patients taking three or more medications for substances with drugs can cause unintended chronic conditions are more susceptible to suffer and unwanted outcomes which may lead to from such interactions. Many of such patients significant harm in some cases. The risk of drug also use herbs, fruits, vegetables and other interactions increases with number of drugs nutrients due to their traditional and folk benefits. being taken by the patient. For example, the risk Trop J Pharm Res, October 2015; 14(10): 1927 Mallhi et al Nutritional status and diet can affect drug action transporters (e.g. p-glycoprotein) and influx by altering metabolism and function [2]. transporters (e.g. organic anion transporting polypeptide, OATP), located in human intestine The global market of fruits and vegetable juices (enterocytes), are present in several fruit juices. has been forecast to reach 72.29 billion liters by OATP is responsible for influx of anionic drugs the year 2017 due to their therapeutic potential such as HMG CoA reductase inhibitors, [3]. About 42.1 % of US population takes dietary angiotensin receptor blockers (ARBs), several supplements and 18.4 % of the population takes beta blockers and fexofenadine. It has similar these supplements with their medications. classification pattern as cytochrome P450 i.e. Likewise, 73.1 % of Italian cancer patients take OATP-A and OATP-B in brain and intestine their prescribed drugs concomitantly with dietary respectively. They are further sub-classified as supplements [4]. OATP1A2 and OATP2B1 [6]. Commonly used substrates for CYP450, p-glycoprotein and OATP The concomitant use of multiple drug regimens are given in Table 1. along with different herbs and nutrients makes the users more prone to drug-fruit interactions. The current review aims to summarize research Such interactions can either lead to loss of studies investigating general or specific therapeutic efficacy of drug or result in drug interactions between clinically used drugs and toxicities e.g. inhibition of metabolism of fruits/vegetables in humans. cilostazol by grapefruit juice leads to purpura [2]. The various mechanisms by which drug METHOD interactions can occur are summarized in Figure 1. In a systematic review, interactions of juices derived from fruits and vegetables with drugs Inhibitory effect of grapefruit on cytochrome P450 were evaluated using online databases was accidentally discovered when grapefruit (PubMed, GoogleScholar, ScienceDirect). The juice was used to mask the taste of ethanol in search terms used were grapefruit juice, fruit assessing the effects of alcohol on felodipine. juice-drug interactions, citrus juice drug Cytochrome P is responsible for metabolism of interactions, drug metabolism, drug food 450 interactions, p-glycoprotein interactions, tropical several drugs, steroids and carcinogens. The juice-drug interactions, OATP, cytochrome P members of this family are represented as CYP 450 drug interactions, vegetable juice drug followed by Arabic numeral (family), capital letter interactions, pharmacodynamics drug (subfamily) and Arabic numeral (gene) e.g. interactions, pharmacokinetics drug interactions, CYP3A4. Six enzymes of this family (CYP1A2, and drug transporters (OATP/p-glycoprotein) 2C9, 2C19, 2D6, 2E1 and 3A4/5) are responsible were excluded. Figure 2 illustrates the for 90 % of oxidation processes [5]. Drug efflux Figure 1: Types of drug interactions, GIT: Gastrointestinal tract, FPM: First pass metabolism, OATP: Organic anion transporting polypeptide Trop J Pharm Res, October 2015; 14(10): 1928 Mallhi et al Table 1: Commonly used substrates for cytochrome P450, p-glycoprotein and OATP [7,8] CYP1A2 CYP2B6 CYP2C19 CYP2C9 Propranolol, Buproproion, Amitriptyline, Citalopram, Celecoxib, Diclofenac, Fluoxetine, Naproxen, Cyclophosphamide Cyclophosphamide, Fluvastatin Ondansetron, Diazepam, Indomethacin, Glipizide, Ibuprofen, Naproxen, Theophylline, PPIs, Phenobarbitone, Phenytoin, Piroxicam, Verapamil Progesterone, Propranolol, Rosiglitazone, ARBs, Warfarin Tolbutamide, Warfarin CYP3A4/ CYP3A5/ CYP2D6 CYP2E1 p-Glycoprotein Substrates CYP3A7 Amitriptyline, Acetaminophen, Macrolides, calcium channel Vinblastine, vincristine, Nortriptyline, Enflurane, Ethanol, blockers, statins, beta doxorubicin, dexamethasone, Ondansetron Halothane, Isoflurane, blockers, anti HIV drugs, morphine, digoxin, loperamide, Paroxetine, Theophylline benzodiazepine, cisapride, cimetidine Phenacetin, dextromethorphan, Lidocaine, estradiol, hydrocortisone, OATP Substrates Metoclopramide, lidocaine, progesterone, Cephalosporins, anticancer, lipid Tamoxifen, quinidine, quinine, lowering drugs, HIV protease Venlafaxine, tamoxifen, vincristine inhibitors, ARBs, enalapril, Beta blockers valsartan, fexofenadine ARBs: angiotensin receptor blockers, PPIs: proton pump inhibitors, OATP: Organic anion transporting polypeptide. Figure 2: Flow chart of review process CYP3A4 fruit juices, fruit juice and fruit juices in the review. The articles included were those warnings,. All studies (in vitro and in vivo) published from 1992 to 1013. However, personal demonstrating interactions between drugs and communications, conference proceedings, un- juices from fruits and vegetables involving published work, drug interactions that do not inhibition of cytochrome P450 (CYP450), p- involve CYP450 system methodology adopted glycoprotein (p-gp) and organic anion for the review process. transporting polypeptides (OATPs) were included Trop J Pharm Res, October 2015; 14(10): 1929 Mallhi et al RESULTS AND DISCUSSION Sadeque et al [51] has indicated that inhibition of p-glycoprotein causes increases drug delivery Findings of literature search (Table 2) showed towards brain. Inhibition of p-glycoprotein by that CYP1A1, CYP1A2, CYP1A4, CYP3A1, grapefruit juice may lead to accumulation of CYP3A4, CYP2C6, CYP2C9 and CYP2E1 are loperamide in the brain resulting in respiratory more commonly inhibited metabolizing enzymes depression. Similarly, the inhibition of OATPs by by fruits and their juices. On the other hand apple juice increases bioavailability of CYP1A1, CYP1A2, CYP2A2, CYP3A1, CYP1B1, rosuvastatin resulting in rhabdomyolosis [20,21]. CYP2B1, CYP2B2, CYP2C1, CYP2C6, CYP2E1 Furthermore, fruit juices inhibit
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