Abstract
The serendipitous discovery that grapefruit juice could dramatically increase the bioavailability of orally administered medications resulted from the findings of a 1989 clinical trial on the pharmacodynamics of felodipine. Grapefruit juice is now estimated to pose a nutrient-drug interaction with more than 85 different medications. The primary mechanism of this interaction is inhibition of cytochrome P450 3A4 (CYP3A4), but grapefruit juice also inhibits organic anion-transporter polypeptides (OATPs). These mechanisms can increase bioavailability, decrease bioavailability, or reduce the metabolic activation of certain medications. Many commonly prescribed drugs interact with grapefruit juice, and these interactions can produce clinically significant effects. Consumption of a single glass of juice is sufficient to alter drug metabolism, and the effect can last as long as 3 days. Practical implications of grapefruit juice-drug interactions are reviewed here.
Introduction
The discovery that grapefruit juice could affect the bioavailability of oral medications came quite by accident. In 1989, David Bailey and his colleagues at the University of Western Ontario designed a study to assess the interaction between ethanol and the calcium channel blocker felodipine (Plendil).1 Following an evening of taste-testing from the home refrigerator, assuming that fruit juice would not affect the outcome, they chose white grapefruit as the most effective vehicle to mask the flavor of ethanol for this study.2 To their surprise, when the medication was taken with nonintoxicating amounts of grapefruit juice-flavored ethanol, Bailey and his colleagues detected felodipine concentrations severalfold higher than previous studies would have predicted. This unexpected finding led to subsequent investigations and a 1991 publication in the Lancet, which reported an almost 3-fold increased bioavailability of felodipine when taken with grapefruit juice.3 Felodipine is the most extensively studied medication related to grapefruit juice-drug interactions, but hundreds of studies and articles have been written on this topic since its initial discovery more than 25 years ago. While grapefruit juice is best known for its ability to increase plasma drug concentrations, more recent research has identified situations where it has the opposite effect. This review summarizes the mechanisms, common medications affected, and practical implications of grapefruit juice-drug interactions to date.
Mechanisms
Felodipine and other related calcium channel blockers undergo considerable first-pass metabolism in the small intestine and liver. These medications are extensively metabolized by cytochrome P450 3A4 (CYP3A4) before they ever reach systemic circulation, resulting in low bioavailability under usual circumstances. The primary mechanism of the grapefruit juice-drug interaction is inhibition of CYP3A4, a mechanism that reduces drug metabolism, resulting in higher amounts of unmetabolized drug in circulation.4 Additional mechanisms of grapefruit juice-drug interactions include inhibition of P-glycoprotein (P-gp) and inhibition of organic anion-transporting polypeptides (OATPs).
Inhibition of CYP3A4
The CYP3A4 enzyme contributes to the metabolism of approximately 50% of all medications.5 Most commonly, CYP3A4 inactivates drugs for elimination, but for some medications (eg, prodrugs) it metabolizes them to more active forms.6 The CYP3A4 enzyme is located in the enterocytes of the small intestine and colon as well as in hepatocytes. Grapefruit juice binds irreversibly to CYP3A4, inactivating it until de novo synthesis returns the enzyme to its previous level. Importantly, grapefruit juice interacts with CYP3A4 only in the small intestine.7 The result is either increased delivery of oral medications to systemic circulation or decreased activation of orally administered prodrugs. Intravenous medications are not affected by grapefruit juice consumption.
The compounds in grapefruit juice responsible for the irreversible inhibition of CYP3A4 are the furanocoumarins (also called psoralens).4 Furanocoumarins are a class of phytochemicals that includes bergamottin and 6’,7’-dihydroxybergamottin. In a study evaluating the individual effects of 5 different furanocoumarins, the omission of any one of the 5 resulted in decreased potency, suggesting that it is the synergistic effect of all naturally occurring furanocoumarins in grapefruit juice that creates the nutrient-drug interaction.8
Inhibition of P-gp
P-glycoprotein (P-gp) is one of the most extensively studied proteins in a class of multiple drug resistance transporters. The P-gp transporter shuttles drugs from enterocytes back into the gut lumen, blocking their absorption. P-glycoprotein is located in the same tissues, has overlapping substrate specificity, and is inhibited by similar compounds as CYP3A4. In vitro studies have demonstrated that the furanocoumarins in grapefruit juice inhibit P-gp. This inhibition allows for greater absorption of oral medications into systemic circulation.9
Inhibition of OATPs
Organic anion-transporter polypeptides (OATPs) constitute a family of transport proteins that enhance intestinal absorption of drugs by shuttling them through enterocytes and into circulation.10 In 2002, Bailey and colleagues (the same researchers who made the initial discovery of grapefruit juice-drug interactions) designed an investigation to assess the effects of grapefruit, orange, and apple juices on the absorption of the antihistamine fexofenadine (Allegra).11 Fexofenadine is not metabolized by cytochrome P450 enzymes, but the investigators expected that P-gp inhibition might increase its bioavailability. Surprisingly, grapefruit juice had the opposite effect: it decreased uptake of fexofenadine by 50% to 90%. In fact, all 3 juices (grapefruit, orange, and apple) markedly reduced the oral bioavailability of fexofenadine when dosed in quantities that would typically be consumed. Studies have determined that this drug-nutrient interaction is mediated by potent and selective inhibition of OATP1A2 and OATP2B1 by naringin in grapefruit juice, hesperidin in orange juice, and multiple components in apple juice.12-13
Common Drugs Affected
A review article published in 2013 reported that grapefruit juice interacts with at least 85 different medications, but the more we learn about drug metabolism, the longer this list becomes.14 Most grapefruit juice-drug interactions result in elevated plasma levels of the involved drug as a result of CYP3A4 inhibition. The opposite effect is seen for prodrugs that rely on CYP3A4 for activation or for drugs that are affected by OATP inhibition. Comprehensive coverage of all drugs affected by grapefruit juice is beyond the scope of this review, but some of the most commonly affected drugs are summarized here.
Potentiated Drug Activity
Cholesterol-lowering statin medications are the most widely prescribed medications known to interact with grapefruit juice. In 1999, randomized trials found that grapefruit juice increased serum concentrations of atorvastatin (Lipitor) by 250% but had no effect on the metabolism of pravastatin (Pravachol).15 A contemporary review reports that a daily glass of grapefruit juice, taken at the same time as the statin, increases blood levels of both simvastatin (Zocor) and lovastatin (Mevacor) by about 260%, while grapefruit juice taken at any time increases levels of atorvastatin by 80%. Surprisingly, this review concludes that the cardiovascular benefits of statin medications outweigh the risks, even when taken with grapefruit juice, and that grapefruit juice need not be avoided. However, cases of rhabdomyolysis have been triggered by regular grapefruit juice consumption in patients taking statin medications.16-17
Medications to treat erectile dysfunction, including sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra), are influenced by grapefruit juice consumption, but to a lesser degree than statins. A randomized crossover trial in 24 adult males found that grapefruit juice increased the bioavailability of sildenafil by 23%—an amount that was considered clinically insignificant.18 However, there was significant variability among the participants, with one subject experiencing a 260% increase in sildenafil concentrations.
Even a single intake of 1 glass (250mL) of grapefruit juice produces a meaningful and lasting inhibition of CYP3A4 and a clinically significant nutrient-drug interaction.
Anxiolytic medications exhibit strong interactions with grapefruit juice. The benzodiazepines alprazolam (Xanax) and triazolam (Halcion) can reach toxic concentrations when dosed with grapefruit juice. A randomized crossover trial in 10 healthy subjects found that grapefruit juice increased plasma concentrations of alprazolam by 150%, an effect that was accompanied by a significant increase in drowsiness.19 In addition, a randomized crossover trial in 10 healthy volunteers found that grapefruit juice dramatically increased serum concentrations of buspirone (Buspar) by 430%.20 This effect was accompanied by a significant increase in the drug’s perceived overall effect.
Antibiotic medications, including erythromycin and clarithromycin, may also be subject to interactions with grapefruit juice. Because clinicians sometimes recommend grapefruit juice to mask the metallic taste of clarithromycin, a randomized trial was designed to investigate any pharmacodynamic interactions. This small study reported that freshly squeezed white grapefruit juice affected neither the absorption of clarithromycin nor its metabolism in any significant way.21 In a study of 6 healthy males, however, the bioavailability of erythromycin was significantly increased by grapefruit consumption.22
Numerous blood pressure medications, including felodipine (Plendil), verapamil (Covera-HS), and losartan (Cozaar) are metabolized by CYP3A4 and therefore can reach elevated plasma concentrations if taken with grapefruit juice.23-24 The antiarrhythmic drugs amiodarone (Cordarone) and dronedarone (Multaq) are affected by grapefruit juice, as are other cardiovascular drugs, including cilostazol (Pletal) and ranolazine (Ranexa).25 Anticonvulsants [carbamazepine (Tegretol)], antipsychotics [pimozide (Orap)], human immunodeficiency virus medications [indinavir (Crixivan), saquinavir (Invirase)], and cancer medications [nilotinib (Tasigna), pazopanib (Votrient)] all interact with grapefruit juice. 26
Reduced Drug Activity
The antihistamine medication fexofenadine (Allegra) was the first medication discovered to exhibit reduced bioavailability when combined with grapefruit juice. The mechanism relies on OATP inhibition by naringin. Other common medications that exhibit this interaction include beta-blocking medications (eg, talinolol, acebutolol, and celiprolol) and levothyroxine.11 If taken with grapefruit juice, the therapeutic effect of these medications will be diminished.
Prodrugs that are activated by CYP3A4 metabolism may also demonstrate reduced activity when taken with grapefruit juice. The antiplatelet agent clopidogrel (Plavix) is a good example. When 14 healthy volunteers drank grapefruit juice for 3 days and then took clopidogrel, plasma concentrations of clopidogrel’s active metabolite only reached 13% of that in the control group.27 The reduced concentration was accompanied by a marked decrease in the platelet-inhibitory effect of the drug. Other drugs that rely on CYP3A4 for activation include losartan (Cozaar), codeine, and tamoxifen. Studies have not directly assessed the interaction, but grapefruit juice could, theoretically, reduce the efficacy of these drugs.6
Practical Implications
Case reports confirm that grapefruit juice-drug interactions can create clinically relevant and serious side effects.15 As CYP3A4 inhibition increases drug bioavailability, toxicity becomes a real concern. Drugs that are most likely to reach toxic levels are those that undergo extensive metabolism by CYP3A4 in the small intestine. Reports of adverse events from grapefruit juice interaction include hypotension with cardiovascular agents, sedation with anxiolytic agents, nephrotoxicity with immunosuppressant agents, and respiratory depression with pain medications.15
Even a single intake of 1 glass (250mL) of grapefruit juice produces a meaningful and lasting inhibition of CYP3A4 and a clinically significant nutrient-drug interaction.28 In fact, when subjects continued to drink grapefruit juice for 14 days, they experienced no further effect beyond the effect of a single glass. In addition, the compounds responsible for the nutrient-drug interaction (ie, bergamottin and naringin) are also present in sufficient quantities in whole grapefruit to produce a clinical effect.29 Any recommendation to avoid grapefruit juice intake should, therefore, also include a recommendation to avoid the whole fruit.
The duration of grapefruit juice’s effect on drug metabolism varies among studies. Because its primary mechanism of effect involves irreversible CYP3A4 enzyme inhibition, the effect of drinking a single glass of grapefruit juice can last for more than 3 days.30 However, in a study evaluating the interaction between grapefruit juice and simvastatin, the effect became negligible after just 24 hours.31 For interactions that involve OATP inhibition, the duration of effect is much shorter.32 In the studies that showed grapefruit juice mitigated the therapeutic effect of fexofenadine, the duration of effect was between 2 and 4 hours.11
It might be proposed that regular and consistent intake of grapefruit juice could decrease the drug dosage required for a therapeutic effect, particularly when the interaction involves CYP3A4 inhibition. Unfortunately, studies suggest that this is not only impractical but also dangerous. People exhibit a range of biochemical individuality, such that enzymatic activity of CYP3A4 varies from person to person in an unpredictable way.33 In addition, the amount of active grapefruit constituents varies from juice to juice and thus glass to glass.34
In some situations, it is safe to recommend substitution of another type of fruit juice. Orange juice does not inhibit CYP3A4 the way that grapefruit does.3 Pomegranate juice does not either.35 When the interaction involves OATP inhibition, however, all juices tested (ie, grapefruit, orange, and apple) created a significant decrease in drug availability.
Conclusion
Grapefruit juice-drug interactions are numerous and can create clinically significant effects. Since the fortuitous discovery of this interaction in 1989, numerous clinical trials and case studies have been published. The effect of grapefruit juice on drug metabolism is a particular concern for the elderly and those who take multiple medications or change medications frequently.
A variety of online resources are available to evaluate nutrient-drug interactions. These include Integrative Therapeutics’ Healthnotes® Interactions Checker and the Drug Interactions Checker accessed through Drugs.com. If there is any question about a potential interaction, check the package insert or prescribing information for details on drug metabolism. If the drug is metabolized by CYP3A4, there is a chance for a grapefruit juice-drug interaction.
