European Journal of Clinical Nutrition (2004) 58, 1–9 & 2004 Nature Publishing Group All rights reserved 0954-3007/04 $25.00 www.nature.com/ejcn REVIEW Food–drug interaction: grapefruit juice augments drug bioavailabilityFmechanism, extent and relevance A Dahan1* and H Altman2 1Department of Pharmaceutics, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem Israel; and 2Department of Pharmacology, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem Israel More than a decade has passed since it was unintentionally discovered that grapefruit juice interacts with certain drugs. The coadministration of these drugs with grapefruit juice can markedly elevate drug bioavailability, and can alter pharmacokinetic and pharmacodynamic parameters of the drug. The predominant mechanism for this interaction is the inhibition of cytochrome P-450 3A4 in the small intestine, resulting in a significant reduction of drug presystemic metabolism. An additional mechanism is, presumably, the inhibition of P-glycoprotein, a transporter that carries drug from the enterocyte back to the gut lumen, resulting in a further increase in the fraction of drug absorbed. Some calcium channel antagonists, benzodiazepines, HMG-CoA reductase inhibitors and cyclosporine are the most affected drugs. A single exposure to one glass of the juice can usually produce the maximal magnitude of the interaction. The data available so far, concerning this interaction and its clinical implications, are reviewed in this article. It is likely that more information regarding this interaction will accumulate in the future, and awareness of such is necessary for achieving optimal drug therapy. European Journal of Clinical Nutrition (2004) 58, 1–9. doi:10.1038/sj.ejcn.1601736 Keywords: grapefruit; drug interaction; pharmacokinetics; bioavailability; cytochrome P-450 3A4; P-glycoprotein Introduction amounts of ethanol and felodipine resulted in several fold Frequently, during drug therapy, a patient is treated with higher felodipine concentrations than observed in other more than one medicine concurrently in order to treat one investigations of felodipine pharmacokinetics. In addition, or more medical problem. By most accounts, the available lower blood pressure and higher frequencies of adverse information concerning drug influences is valid for each effects were measured compared with felodipine alone drug separately, while concomitant intake of two or more (Bailey et al, 1989). An examination for possible causes failed drugs can alter their influences. Hence, an interaction is said to explain this surprising observation, until, eventually, a to take place when the effects of one drug are changed by the pilot research in a single volunteer was conducted to assess presence of another drug, food, drink or by some environ- the role of the juice (Bailey et al, 1998). Further follow-up mental chemical agent. studies confirmed that grapefruit juice elevated dramatically An investigation was designed 13 y ago to evaluate a felodipine bioavailability and could alter pharmacokinetic possible interaction between ethanol intake and the dihydro- and pharmacodynamic parameters of the drug (Bailey et al, pyridine calcium channel blocker felodipine. Grapefruit 1991). This incidental discovery has led to the publication of juice was used as a flavor supplement in order to mask the numerous articles regarding the interaction between grape- alcohol taste. The concomitant intake of nonintoxicating fruit juice and various drugs, focusing on different aspects: interaction mechanisms, grapefruit juice constituents that are responsible for the interaction, drugs exhibiting the *Correspondence: A Dahan, Department of Pharmaceutics, School of interaction and the clinical relevance. Pharmacy, The Hebrew University of Jerusalem, P.O. Box 12065, Jerusalem 91120, Israel. Guarantor: A Dahan. Mechanisms Contributors: A Dahan, H Altman. Received 12 November 2002; revised 16 December 2002; accepted 5 Cytochrome P-450 (CYP450) is a large family of enzymatic January 2003 proteins that catalyze the oxidation of substrate molecules. Food–drug interaction A Dahan and H Altman 2 Many endogenous compounds, as well as a large number of Multiple drug resistance (MDR) transporters play a major foreign compounds, including drugs, are metabolized in the role in the disposition of many drugs. The most extensively body by CYP450 through this oxidative biotransformation. studied MDR transporter is the P-glycoprotein (P-gp) that The isoenzyme cytochrome P-450 3A4 (CYP3A4) is the reduces the fraction of drug absorbed by carrying the drug predominant CYP form in the human small intestine (Kolars from the enterocyte back to the intestinal lumen (Gottesman et al, 1992), while only a very limited number of other CYP et al, 1996). Grapefruit juice modifies the P-gp transporter isoforms are expressed in this organ (Zhang et al, 1999). The activity. Although few data suggested an activation of main mechanism for enhanced bioavailability of drugs by P-gp efflux by grapefruit juice (Phang et al, 1993; Soldner grapefruit juice is, presumably, the inhibition of CYP3A4 in et al, 1999), most investigators observed an inhibition the small intestine (Edwards et al, 1996; Lown et al, 1997), of the transporter activity (Takanaga et al, 1998; Eagling resulting in a significant reduction of drug presystemic et al, 1999; Wang et al, 2001; Tian et al, 2002). Recently, metabolism. This inhibition was reported in an in vivo the b-blocker talinolol, which is a non-CYP450 substrate, investigation in humans (Schmiedlin Ren et al, 1997). A yet a P-gp substrate, showed an increase in bioavailability decrease of 47% in enterocyte CYP3A4 concentration has when concomitantly taken with grapefruit juice in both been observed 4 h after drinking one glass of grapefruit juice in vitro and in vivo models (Spahn Langguth & Langguth, (Figure 1). Grapefruit juice caused a significant increase in 2001). the bioavailability of drugs exhibiting the interaction, after CYP450 and P-gp share both overlapping tissue distribu- oral dosing. However, after intravenous administration of tion and substrate specificity, thus, the differentiation the same drugsFgrapefruit juice altered neither pharmaco- between the two mechanisms is not definite. Yet, the effects kinetic nor pharmacodynamic parameters (Ducharme et al, of grapefruit juice–drug coadministration are most likely the 1995; Lundahl et al, 1997; Uno et al, 2000). Hence, it result of interaction with CYP3A4, and only to a minor has been concluded that only intestinal CYP3A4 is inhibited extent with the P-gp function. by grapefruit juice, while liver resident CYP3A4 enzymes are not affected. This conclusion is further supported by the finding that the interaction with grapefruit juice markedly elevated the area under the plasma concentra- Constituents tion–time curve (AUC), while no significant change has A number of constituents have been proposed to be been observed in elimination half-life or systemic clearance involved in the interaction between grapefruit juice (Bailey et al, 1991). Owing to a lack in decrease of CYP3A4 and drugs, although much of the data are controversial mRNA following grapefruit juice intake (Lown et al, 1997), it and at this stage it is hard to draw definite conclusions. appears that the mechanism for CYP3A4 inhibition by The flavonoid naringin has been suggested as being grapefruit juice is post transcriptional, possibly through a major component in grapefruit and is not found in other facilitated degradation of the enzyme (Bailey et al, 1998). fruit juices (Kuhnau, 1976; Bailey et al, 1993a). In addition, in studies that were performed on liver microsomes, naringenin, naringin’s aglycon metabolite, showed the ability to inhibit dihydropyridine metabolism in vitro (Miniscalco et al, 1992). However, in vivo studies using isolated naringin have not shown reduced metabolism of CYP3A4 substrates (Bailey et al, 1993b). Also, grapefruit juice itself shows inhibition in vitro under conditions that do not allow the formation of naringenin (Edwards & Bernier, 1996). Thus, naringin and naringenin do not appear to be the sole contributors to the effect. Other flavonoids (quercetin, kaempferol) have also been investigated and found to show inhibitory effects in vitro (Miniscalco et al, 1992) but lack any effect in vivo (Rashid et al, 1993). Another group of compounds that has been detected in grapefruit juice is the furanocoumarins (psoralens) that are known to be mechanism-based inactivators of CYP450, as well as being its substrates (Letteron et al, 1986), and recently have also been shown to inhibit P-gp (Wang et al, 2001). The major furanocoumarin Figure 1 Determination of CYP3A4 concentration by immunoblot present in grapefruit is bergamottin, which demonstrates analysis of endoscopic duodenal biopsies before (Pre) and 4 h after (Post) drinking one glass of grapefruit juice. Villin, an enterocyte a time- and concentration-dependent inactivation protein, served as a control. of CYP enzymes in vitro (He et al, 1998), as well European Journal of Clinical Nutrition Food–drug interaction A Dahan and H Altman 3 0 0 as its metabolite 6 ,7 -dihydroxybergamottin (DHB) creases of up to 300% in AUC and up to 430% in Cmax of (Edwards et al, 1996) and a number of other furanocoumarin felodipine (Bailey et al, 1991; Edgar et al, 1992; Lown et al, derivatives (Ohnishi et al, 2000; Mohri & Uesawa, 2001). 1997; Dresser et al, 2000), as well as increase in the serum DHB, along with four