REVIEW Food–Drug Interaction: Grapefruit Juice Augments Drug Bioavailabilityfmechanism, Extent and Relevance

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 newly isolated furanocoumarins concentrations of the metaboliteFdehydrofelodipine have reproduced roughly the inhibitory potency of (Bailey et al, 1995; Lundahl et al, 1998). It should be noted grapefruit juice when mixed together, while the that an especially pronounced pharmacokinetic effect has omission of any of the components resulted in decreased been detected among elderly subjects (Dresser et al, 2000). potency, suggesting that all major furanocoumarins Most of these studies reported further decreases in diastolic contribute to the properties of grapefruit juice (Guo blood pressure when felodipine was taken with grapefruit et al, 2000). juice, as well as increase in haemodynamic-related adverse It is likely that no single component is responsible for the effects such as increased heart rate and orthostatic hypoten- interaction in vivo, but probably a combination of the effects sion (Bailey et al, 1991; Lundahl et al, 1997, 1998). Other of many constituents. Their complete identities and relative dihydropyridines exhibiting the interaction to a similar contributions are to be further investigated. extent are nisoldipine (Bailey et al, 1993b; Takanaga et al, 2000) and nicardipine (Uno et al, 2000). A milder but Amounts and timing significant interaction has been detected with nitrendipine, Some of the investigations have been conducted using pranidipine and nimodipine that exhibited bioavailability regular strength grapefruit juice, while others employed increments of 100, 73 and 50%, respectively (Soons et al, double-strength juice, meaning, juice that has been recon- 1991; Fuhr et al, 1998; Hashimoto et al, 1998). However, little stituted using half of the recommended amount of water. or no effect has been detected for nifedipine and amlodipine Another difference in the method of the various studies is (Rashid et al, 1993; Josefsson et al, 1996; Vincent et al, 2000). the ingestion of a single glass vs repeated ingestions. Despite These two dihydropyridines are characterized by a high results that demonstrated higher intensity after repeated bioavailability compared to felodipine, nisoldipine and ingestions (Lilja et al, 2000a), it appears that in most cases, nicardipine, which can explain the lack of the interaction. ingestion of a single glass (250 ml) of regular strength Verapamil and diltiazem are nondihydropyridines calcium grapefruit juice is enough to produce the maximum effect channel antagonists, also extensively metabolized by CYP3A4. (Rau et al, 1997; Kane & Lipsky, 2000). In this fashion, no A significant increase in the bioavailability of verapamil has further changes in the pharmacokinetics of felodipine have been detected in recent studies (Ho et al, 2000; Fuhr et al, 2002), been detected following 14 days of daily intake of grapefruit in contrast to an earlier investigation which observed no effect juice, compared to the effects after the first glass (Lundahl (Zaidenstein et al, 1998). Diltiazem has been found to produce et al, 1998). no interaction with grapefruit juice in a single study (Sigusch Grapefruit juice does not need to be taken simultaneously et al, 1994), and further investigations are needed. with the medication, in order to produce the interaction. The calcium channel antagonists exhibiting the interac- The bioavailability of lovastatin has been reported to be tion have demonstrated altered clinical parameters, includ- doubled, even when taken 12 h after the juice intake (Rogers ing increased adverse effects, when administered with et al, 1999), and the effects of grapefruit juice on felodipine grapefruit juice. Therefore, it is advisable to avoid this have been shown to exist at about 30% of its maximum combination, especially with the more affected agents F even when the drug was taken 24 h after the juice intake felodipine, nisoldipine and nicardipine. (Lundahl et al, 1995). The prolongation of the interaction is consistent with the pharmacological mechanism of the interaction, since biosynthesis of a new enzyme is necessary. CNS modulators Up to 3 days persistence of the juice impact is reported The benzodiazepines are the most important and widely (Takanaga et al, 2000); however, it appears that an interval of used family of sedativeFhypnotics, acting on inhibitory 24 h between ingestion of grapefruit juice and a drug can receptors in the CNS. Few of them are CYP3A4 substrates at a usually prevent a potential clinically relevant interaction certain level, and a potential interaction with grapefruit juice (Lilja et al, 2000b). may cause a deviation from the standard dose, producing an undesired increase in the CNS-depressant effects. A single glass of regular strength grapefruit juice has been shown to Drugs exhibiting the interaction (Table 1) increase by more than 3-fold the AUC of diazepam (Ozdemir Calcium channel antagonists et al, 1998). A similar amount of the juice increased by 50% The calcium channel antagonists are a family of agents that the AUC, as well as the peak concentration of triazolam and are used in the management of hypertension and angina midazolam, two short-acting hypnotics, without affecting pectoris. Numerous studies were performed in order to the elimination half-life (Hukkinen et al, 1995; Kupfersch- investigate the interaction between grapefruit juice and midt et al, 1995). A more recent study has shown that these agents since the interaction was first discovered with repeated consumption of grapefruit juice increases the AUC the dihydropyridine felodipine. These studies showed in- of triazolam by as much as 150% (Lilja et al, 2000a).

European Journal of Clinical Nutrition Food–drug interaction A Dahan and H Altman 4 Table 1 Summary of drug interaction with grapefruit juice

Drug Grapefruit juice influence Potential risk Recommandation

Calcium channel antagonists Felodipine Increased bioavailability Hypotension, tachicardia Avoid combination Nisoldipine Increased bioavailability Hypotension, tachicardia Avoid combination Nicardipine Increased bioavailability Hypotension, tachicardia Avoid combination Nitrendipine Increased bioavailability Hypotension, tachicardia Avoid combination Pranidipine Increased bioavailability Hypotension, tachicardia Avoid combination Nimoldipine Increased bioavailability Hypotension, tachicardia Avoid combination Nifedipine No influence None Amlodipine No influence None Verapamil Increased bioavailability Hypotension, thchicardia Avoid combination Diltiazem No influence None CNS modulators Diazepam Increased bioavailability Increased CNS depression Avoid combination Triazolam Increased bioavailability Increased CNS depression Avoid combination Midazolam Increased bioavailability Increased CNS depression Avoid combination Alprazolam No influence None Carbamazepine Increased bioavailability Increased adverse effects Avoid combination Buspirone Increased bioavailability Increased adverse effects Avoid combination Sertraline Increased bioavailability Increased adverse effects Avoid combination

HMG coA reductase inhibitors Simvastatin Increased bioavailability Rhabdomyolysis, acute renal failure Avoid combination Lovastatin Increased bioavailability Rhabdomyolysis, acute renal failure Avoid combination Atorvastatin Increased bioavailability Rhabdomyolysis, acute renal failure Avoid combination Pravastatin No influence None

Immunosupressants Cyclosporine Increased bioavailability Nephrotoxicity, hypertension, Avoid combination cerebral toxicity

HIV protease inhibitor Saquinavir Increased bioavailability Increased adverse effects Avoid combination

Phosphodiesterase-5 inhibitor sildenafil Increased bioavailability Increased adverse effects Avoid combination

Antihistamines Terfenadine Increased unmetabolised QT prolongation, torsade de pointes Avoid combination drug in plasma

Prokinetics cisapride Increased bioavailability QT prolongation, torsade de pointes Avoid combination

Antiarhythmics Amiodarone Blockage of Metabolite formation Arrhythmias Avoid combination

However, grapefruit juice does not alter the pharmacoki- possessing other risk factors for decreased first pass elimina- netics of alprazolam, even after repeated ingestions, pre- tion such as liver disease and old age. sumably due to its high bioavailability (Yasui et al, 2000). As Another CNS depressant showing an interaction with to the clinical effect, the available data are more ambiguous. grapefruit juice is the anticonvulsant agent carbamazepine. A performance decrease in psychometric tests of human A 40% increase in carbamazepine AUC was observed after subjects undergoing treatment with Midazolam and grape- ingestion of a single glass of the juice (Garg et al, 1998). fruit juice compared to water has been observed in one Grapefruit juice has also been observed to increase pharmacodynamic study (Kupferschmidt et al, 1995). On the substantially the plasma concentration of buspirone, a other hand, in a different study, hardly any increase in the nonbenzodiazepine hypnotic with a very low bioavailability clinical effects of midazolam and triazolam has been due to extensive metabolism by CYP3A4 (Lilja et al, 1998). detected following grapefruit juice intake (Vanakoski et al, Such a dramatic increase could result in toxic levels of 1996). The reported increase in bioavailability of these buspirone. Hence, avoiding this combination should be agents may be clinically significant, especially in patients advised.

European Journal of Clinical Nutrition Food–drug interaction A Dahan and H Altman 5 Sertralin is a serotonin selective reuptake inhibitor that is widely used in the treatment of depression and anxiety disorders, and is metabolized mainly by CYP3A4. A 50% increase in the bioavailability of sertralin when given with grapefruit juice has been reported. These results were consistent with in vitro inhibition of sertralin metabolism (Lee et al, 1999). The clinical relevance of the interaction has not been assessed.

HMG-CoA reductase inhibitors The statins are an important class of cholesterol lowering medications that act by competitive inhibition of 3-hydroxy-3- methylglutaryl coenzyme A (HMG-CoA) reductase. Statins undergo metabolism through CYP3A4 to various degrees. Simvastatin and lovastatin are inactive lactones that undergo hydrolysis by esterases to form the active simvastatin acid and lovastatin acid, respectively. Inhibition of simvastatin metabolism by naringenin was demonstrated in vitro (Ubeaud et al, 1999). After drinking 200 ml double-strength grapefruit juice three times a day for 3 days, the concomitant intake caused a 16-fold increase in the AUC of simvastatin, and a seven-fold increase in the AUC of simvastatin acid (Lilja et al,1998).The same regimen of grapefruit juice caused a 15-fold increase in the AUC of lovastatin, and a five-fold increase in the AUC of lovastatin acid (Figure 2) (Kantola et al, 1998). Although a large amount of grapefruit juice has been used, these data can indicate that a regular amount of the juice can alter the pharmacokinetic parameters of simvastatin and lovastatin. This trend is further supported by double AUC values for lovastatin and lova-statin acid after drinking one glass of Figure 2 Serum concentrations of lovastatin and lovastatin acid regular strength grapefruit juice in the morning for three after a single oral dose of 80 mg lovastatin, after ingestion of large consecutivedaysfollowedbyadoseofthemedicineatthe amounts of grapefruit juice (K) or water (J). third evening (Rogers et al, 1999). The AUC value of atorvastatin showed a 2.5-fold increase after drinking double- sporine microemulsion formulation as well (Bistrup et al, strength grapefruit juice 3 times a day for 3 days (Lilja et al, 2001). Elevated cyclosporine concentrations were reported 1999). Grapefruit juice has no effect on pravastatin (Lilja et al, in healthy subjects (Yee et al, 1995) and in transplant 1999), apparently since it is metabolized only to a limited patients (Min et al, 1996). In pediatric renal transplant extent by CYP3A4 (Jacobsen et al, 1999). It would be wise to patients, concomitant grapefruit juice administration altered avoid the combination of this class of medications with cyclosporine AUC, Cmax and elimination parameters as well grapefruit juice, especially in view of the fact that the (Brunner et al, 2000). Grapefruit juice had no effect after concomitant intake of statins with CYP3A4 inhibitors pro- intravenous administration of the drug (Ducharme et al, duced adverse effects such as rhabdomyolysis and acute renal 1995). Cyclosporine has a narrow therapeutic index, and failure (Williams & Feely, 2002). many side effects such as nephrotoxicity, hypertension and cerebral toxicity. Therefore, it seems necessary to advise patients treated with cyclosporine not to consume grapefruit Cyclosporine juice during therapy. Cyclosporine is a powerful immunosuppressive agent used extensively in transplantation to prevent rejection of transplanted organs. Cyclosporine is extensively meta- Saquinavir bolized by CYP3A4 in the gut wall of the small intestine Saquinavir is a protease inhibitor, used in the treatment of and in the liver (Kolars et al, 1991). It is also a high affinity P- human immunodeficiency virus infection. It has poor oral gp substrate (Lown et al, 1997). An increase of more than bioavailability because of extensive intestinal metabolism, 60% in cyclosporine AUC was reported following grapefruit mediated by CYP3A4 (Fitzsimmons & Collins, 1997). The juice ingestion (Ducharme et al, 1995; Ioannides Demos et al, oral bioavailability of saquinavir increased by a factor of two 1997). This alteration has been observed with the cyclo- following ingestion of 400 ml grapefruit juice, without

European Journal of Clinical Nutrition Food–drug interaction A Dahan and H Altman 6 affecting elimination parameters, and with no effect after elevated terfenadine plasma concentrations (Benton et al, intravenous administration of the drug (Kupferschmidt et al, 1996; Clifford et al, 1997). One glass of regular strength 1998). Inhibition of saquinavir metabolism in vitro by grapefruit juice was enough to produce maximum effect on grapefruit juice components has also demonstrated (Eagling terfenadine pharmacokinetics (Rau et al, 1997). As for cardiac et al, 1999). Until further investigations, this combination effects, repeated consumptions of grapefruit juice simulta- should be avoided. Other protease inhibitors have high neously to 60 mg terfenadine twice a day for a week resulted bioavailability, thus, interaction with grapefruit juice is in a significant increase in QT interval (Benton et al, 1996; unlikely to occur. Honig et al, 1996). A 29-y-old man who had been taking terfenadine twice daily for more than a year, collapsed and died on a day on Sildenafil which he had consumed two glasses of grapefruit juice. His Sildenafil citrate is used for the oral treatment of erectile postmortem plasma terfenadine concentration was 35 ng/ dysfunction. It acts by enhancing the ability of nitric oxide ml, and the death was attributed by the coroner to to inhibit phosphodiesterase type 5. Sildenafil undergoes terfenadine toxicity. The man was not taking erythromycin, extensive metabolism through CYP3A4 (Hyland et al, 2001). ketoconazole, or any other drug known to affect terfenadine The ingestion of 250 ml grapefruit juice 1 h before and metabolism (Spence, 1997). Thus, it seems necessary to avoid concomitantly with sildenafil increased the oral bio- concomitant consumption of grapefruit juice and terfena- availability of sildenafil by 23% (Jetter et al, 2002). One case dine.

report indicated a 42% increase in Cmax but no change in AUC value for 100 mg of sildenafil taken with grapefruit juice (Lee & Min, 2001). Consequently, sildenafil pharmaco- Amiodarone kinetics becomes less predictable with grapefruit juice, and it Amiodarone is a class III antiarrythmic agent. Its major is advisable to avoid this combination. metabolite, N-desethylamiodarone (N-DEA) has been shown to contribute the antiarrythmic effect, possibly to a greater extent than the parent drug (Talajic et al, 1987; Zhou et al, Cizapride 1998). Formation of N-DEA is mediated by CYP3A4 (Fabre Cizapride, a prokinetic agent, has been used for the et al, 1993). A measure of 300 ml grapefruit juice simulta- treatment of a number of gastrointestinal disorders. CYP3A4 neously, 3 and 9 h after amiodarone dose, caused a complete is the primary mode of elimination of cisapride (Bohets et al, inhibition of N-DEA formation (Libersa et al, 2000). The 2000). In two different studies, 250 ml of grapefruit juice clinical implications of this finding are still unclear and need ingested concomitantly with a 10 mg dose of cizapride further investigation. caused a 50% increase in the bioavailability of cizapride (Gross et al, 1999; Offman et al, 2001). In another study, high doses of grapefruit juice were used and similar outcomes Conclusions have been reported (Kivisto et al, 1999). Serious cardiac It is likely that more information regarding this interaction, adverse effects, such as tachycardia, palpitations, QT pro- including more drugs exhibiting the interaction, will longation and torsade de pointes, have been associated with accumulate in the future. It can be anticipated, based on high plasma concentrations of cizapride, including 80 deaths the analogous mechanism, that grapefruit juice will demon- (Michalets & Williams, 2000). It appears that a clinically strate, at least partially, similar interactions that occur with significant outcome may arise from the combination of erythromycin, ketoconazole and other macrolide antibiotics cizapride and grapefruit juice, and avoidance of this and azole antifungal agents. It is important to notice that the combination is recommended. whole fruit can cause the same outcomes as does the juice (Bailey et al, 2000). The vast majority of the investigations regarding this Terfenadine interaction are characterized by a wide variability of the

Terfenadine is a second generation, nonsedative, selective H1 results among patients within each study, as well as receptor antagonist used in the treatment of many allergic variability between studies. The different kinds of juice used conditions. Terfenadine undergoes nearly complete pre- by different investigators might be a contributor for this. systemic elimination by CYP3A4 to such a broad extent There might be differences in the ability to inhibit the and rapid kinetics that normally terfenadine cannot be enzyme, between fresh and processed juice, as well as detected in plasma. The antihistaminic activity in vivo has between hand-squeezed vs machine-squeezed, where the been attributed to its carboxilic metabolites (Yun et al, 1993). machine squeezing can produce a better extraction of the High levels of unmetabolized terfenadine are associated with active components. There is no uniformity in the concen- significant cardiotoxicity such as QT prolongation and trations of the different constituents between different torsade de pointes (Woosley et al, 1993). Administration of manufacturers, and even between different batches (Fukuda grapefruit juice concurrently with terfenadine significantly et al, 2000). Hence, the argument that a patient whose

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