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

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.


INTRODUCTION
Drugs are essential components of medical therapy but concomitant consumption of other substances with drugs can cause unintended and unwanted outcomes which may lead to significant harm in some cases. The risk of drug interactions increases with number of drugs being taken by the patient. For example, the risk of interactions with 6-10 drugs may just be 7 % but with 16-20 drugs, the risk may increase up to 40 % [1]. High risk patients, such as elderly patients taking three or more medications for chronic conditions are more susceptible to suffer from such interactions. Many of such patients also use herbs, fruits, vegetables and other nutrients due to their traditional and folk benefits.
Nutritional status and diet can affect drug action by altering metabolism and function [2].
The global market of fruits and vegetable juices has been forecast to reach 72.29 billion liters by the year 2017 due to their therapeutic potential [3]. About 42.1 % of US population takes dietary supplements and 18.4 % of the population takes these supplements with their medications. Likewise, 73.1 % of Italian cancer patients take their prescribed drugs concomitantly with dietary supplements [4].
The concomitant use of multiple drug regimens along with different herbs and nutrients makes the users more prone to drug-fruit interactions. Such interactions can either lead to loss of therapeutic efficacy of drug or result in drug toxicities e.g. inhibition of metabolism of cilostazol by grapefruit juice leads to purpura [2]. The various mechanisms by which drug interactions can occur are summarized in Figure  1.
Inhibitory effect of grapefruit on cytochrome P 450 was accidentally discovered when grapefruit juice was used to mask the taste of ethanol in assessing the effects of alcohol on felodipine. Cytochrome P 450 is responsible for metabolism of several drugs, steroids and carcinogens. The members of this family are represented as CYP followed by Arabic numeral (family), capital letter (subfamily) and Arabic numeral (gene) e.g. CYP3A4. Six enzymes of this family (CYP1A2, 2C9, 2C19, 2D6, 2E1 and 3A4/5) are responsible for 90 % of oxidation processes [5]. Drug efflux transporters (e.g. p-glycoprotein) and influx transporters (e.g. organic anion transporting polypeptide, OATP), located in human intestine (enterocytes), are present in several fruit juices. OATP is responsible for influx of anionic drugs such as HMG CoA reductase inhibitors, angiotensin receptor blockers (ARBs), several beta blockers and fexofenadine. It has similar classification pattern as cytochrome P 450 i.e. OATP-A and OATP-B in brain and intestine respectively. They are further sub-classified as OATP1A2 and OATP2B1 [6]. Commonly used substrates for CYP450, p-glycoprotein and OATP are given in Table 1.
The current review aims to summarize research studies investigating general or specific interactions between clinically used drugs and fruits/vegetables in humans.

METHOD
In a systematic review, interactions of juices derived from fruits and vegetables with drugs were evaluated using online databases (PubMed, GoogleScholar, ScienceDirect). The search terms used were grapefruit juice, fruit juice-drug interactions, citrus juice drug interactions, drug metabolism, drug food interactions, p-glycoprotein interactions, tropical juice-drug interactions, OATP, cytochrome P 450 drug interactions, vegetable juice drug interactions, pharmacodynamics drug interactions, pharmacokinetics drug interactions, and drug transporters (OATP/p-glycoprotein) were excluded. Figure 2 illustrates the   CYP3A4 fruit juices, fruit juice and fruit juices warnings,. All studies (in vitro and in vivo) demonstrating interactions between drugs and juices from fruits and vegetables involving inhibition of cytochrome P 450 (CYP450), pglycoprotein (p-gp) and organic anion transporting polypeptides (OATPs) were included in the review. The articles included were those published from 1992 to 1013. However, personal communications, conference proceedings, unpublished work, drug interactions that do not involve CYP450 system methodology adopted for the review process.

RESULTS AND DISCUSSION
Findings of literature search ( Sadeque et al [51] has indicated that inhibition of p-glycoprotein causes increases drug delivery towards brain. Inhibition of p-glycoprotein by grapefruit juice may lead to accumulation of loperamide in the brain resulting in respiratory depression. Similarly, the inhibition of OATPs by apple juice increases bioavailability of rosuvastatin resulting in rhabdomyolosis [20,21]. Furthermore, fruit juices inhibit metabolizing enzymes (CYP450, glucuronosyl transferase), drug transporters (OATP, P-gp) and other multiple resistance proteins [MRP]. This in turn increases plasma levels of drugs metabolized by these systems. One widely studied example of such inhibition is grapefruit juice which is reported to inhibit cytochrome P 450 , pglycoprotein and OATP [9,10]. Even a single glass (250 ml) of regular strength grapefruit juice can cause potential inhibition of drug metabolizing enzymes [9,10]. Inhibition of CYP3A4 by grapefruit juice increases the risk of toxicity from calcium channel blockers (tachycardia, hypotension), statins (myopathy, headache, rhabdomyolosis), antihistamines (arrhythmias, prolongation of QT intervals) and immunosuppressant's (renal and hepatic dysfunction) [52]. Although flavonoids (naringenin) and furanocoumarins (bergamottin) in fruits and vegetables have been reported to inhibit CYP450 but their protective effect against cardiovascular diseases and cancer is known [49]. Moreover, there is also potential therapeutic benefit of using active constituents of fruits as they increase drug bioavailability [53]. Concomitant administration of grapefruit juice with cyclosporine is one of the examples of drug sparing effect (reduction of amount of drug being taken with the help of another agent). It reduces repeated dosing of cyclosporine leading to reduction in dose-related side effects and increase patient compliance. Moreover, improvement have been reported in efficacy of antihypertensives and anti-psoriosis therapy by using grapefruit juice as drug sparing agent [53,54].   Few studies have been conducted on tropical fruits and vegetables to elaborate their potential in inhibition of metabolizing enzymes and drug transporters. Tropical fruits are most commonly used in tropical and subtropical countries and screening of these fruits can avoid drug related complications among patients. More studies are required to find out the safety and risk profile of concomitant use of tropical fruits/vegetables with drugs.

CONCLUSION
As a number of drugs are approved by FDA each year, there is less information available about their adverse effects and interactions when the drugs reach the market. It is imperative for physicians and pharmacists to be well aware of interactions of drugs with fruits and vegetables because such interactions can be more complicated than drug-drug interactions. Screening of fruits and vegetables for possible risk of interactions will ensure success of treatment and avoid detrimental effects. Fruits/vegetables containing active components reported to affect metabolizing enzymes or drug transporters must be screened for interactions. It will aid health care professionals during patient counseling. Since it is difficult to create public awareness of the fact that despite offering curative and nutritional benefits, fruit juices can also confer health risk, and therefore, avoidance of concomitant use of fruits/vegetables juices and drugs where required, can be an effective strategy for preventing such interactions.