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DRUG INTERACTIONS

1390 J Clin Pharmacol 2006;46:1390-1416

Grapefruit is rich in flavonoids, which have been demon-strated to have a preventive influence on many chronicdiseases, such as cancer and cardiovascular disease.However, since the early 1990s, the potential health bene-fits of grapefruit have been overshadowed by the possiblerisk of interactions between drugs and grapefruit andgrapefruit juice. Several drugs interacting with grapefruitare known in different drug classes, such as HMG-CoAreductase inhibitors, calcium antagonists, and immunosu-pressives. Currently known mechanisms of interactioninclude the inhibition of cytochrome P450 as a majormechanism, but potential interactions with P-glycoprotein

and organic anion transporters have also been reported.This review is designed to provide a comprehensive sum-mary of underlying mechanisms of interaction and humanclinical trials performed in the area of grapefruit druginteractions and to point out possible replacements fordrugs with a high potential for interactions.

Keywords: grapefruit; drug interactions; clinical

relevanceJournal of Clinical Pharmacology, 2006;46:1390-1416

2006 the American College of Clinical Pharmacology

Grapefruit-Drug Interactions: Can

Interactions With Drugs Be Avoided?S. U. Mertens-Talcott, I. Zadezensky, W. V. De Castro,

H. Derendorf, and V. Butterweck

History of Grapefruit Drug Interactions

For approximately one and a half decades, a major

focal point in the area of food-drug interactions hasbeen placed on interactions of grapefruit with severaldrugs such as lipid-lowering drugs and calcium chan-nel blockers.1 An initial report regarding grapefruitjuicedrug interactions was published in 1991. Theseinteractions were discovered accidentally in a studyon ethanol drug interactions: grapefruit juice wasused to mask the taste of ethanol in this study. The

bioavailability of the drug felodipine was increasedwhen subjects were consuming grapefruit juice (GFJ)concomitantly with felodipine. This increase wasassociated with a lower dehydrofelodipine/felodip-ine area under the curve (AUC) ratio, decreased dias-tolic blood pressure, and an increased heart rate.2

Since then, several studies have been conducted

investigating the interactions of grapefruit and dif-ferent drugs. Grapefruit juice has been demonstratedto alter the pharmacokinetics of several drugs such

as statins, calcium channel blockers, antibiotics, andothers.2-9 Other fruits, vegetables, and dietary sup-plements also have the potential to cause an adverseinteraction with conventional drugs.10

The reduction of the first-pass metabolismthrough the inhibition of intestinal CYP3A4 seemsto be the major mechanism in the induction of thegrapefruitdrug interaction.11 Hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors and cal-cium channel antagonists are among the affecteddrugs.12 More recently, GFJ has also been foundto inhibit the intestinal P-glycoprotein-mediatedefflux transport of several drugs, increasing theiroral bioavailability.13-16 Other mechanisms of inter-action (eg, altered activity of enzymes other thanCYP3A4) within the CYP450 family17-20 have beenassessed. Several in vitro studies have recentlydemonstrated the potential influence of GFJ andother fruit juices on a number of organic anion-trans-porting polypeptides (OATPs) a group of influxtransporters.21,22

Overall, several human clinical trials demonstratethat grapefruit juice has a potential to interact with

From the Department of Pharmaceutics, Center for Food Drug Interaction

Research and Education, University of Florida, Gainesville. Submitted for

publication April 28, 2006; revised version accepted August 20, 2006.

Address for reprints: V. Butterweck, Department of Pharmaceutics, Center

for Food Drug Interaction Research and Education, JHMHC, POB

110494, Gainesville, FL 32610-0494; e-mail: [email protected].

DOI: 10.1177/0091270006294277

2006 American College of Clinical Pharmacology. All rights reserved. Not for commercial use or unauthorized distribution.by on March 20, 2007http://www.jclinpharm.orgDownloaded from
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GRAPEFRUIT-DRUG INTERACTIONS

DRUG INTERACTIONS 1391

different oral medications when consumed in mod-erate amounts such as 1 to 2 servings.23 Comprehen-sive studies are not available for many drugs. However,the concernthat the concomitant administration of

grapefruit products with certain drugs may causetoxic effects based on increased exposurehas ledto the recommendation to avoid the concomitantconsumption of grapefruit products with drugs ofconcern. Some drugs such as cyclosporine, sirolimus,simvastatin, lovastatin, and felodipine carry a warn-ing label regarding the possibility of an interac-tion.24 For example, a brand-name cyclosporine-basedimmunosuppressant drug carries a label stating,Grapefruit and GFJ affect metabolism, increasing

blood concentrations of cyclosporine, thus shouldbe avoided,24 and a certain nifedipine-based drug islabeled as follows: Co-administration of nifedipine

with GFJ resulted in approximately a 2-fold increasein nifedipine AUC and Cmax with no change in half-life. The increased plasma concentrations are mostlikely due to inhibition of CYP3A4 related first-passmetabolism. Co-administration of nifedipine withGFJ is to be avoided.25 In addition, interactionswith certain medications also have been shown forSeville orange juice, but Seville oranges are usuallynot processed to juice.26,27

Comprehensive conclusions regarding the clinicalsignificance of the observed or predicted grapefruit-drug interactions are still limited; therefore, definitiverecommendations regarding their concomitant admin-istration with GFJ are not available for most drugs inquestion. Most studies investigated acute interactions,and only a few trials assessed the influence of chronicconsumption of grapefruit juice on drug absorptionand metabolism. Moreover, the determination of theclinical relevance of observed interactions in humanintervention trials is impaired by interindividual vari-ability.11 On the other hand, it should be noted thatmany drugs that show an interaction with grapefruitmay be replaced by another drug within the same drugclass without known potential for an interaction.Moreover, the concentrations of polyphenolics with a

known potential for drug interactions vary within agreat range in different grapefruit juices, which in partmay explain the great variability between differentgrapefruit-drug interaction studies.28

The overall attention of scientists, patients, andhealth care professionals currently is focused mainlyon interactions of drugs with grapefruit products.However, other fruits and vegetables and dietarysupplementsmainly St. Johns wort but also greentea and ginsengmay be an additional potentialsource for drug interactions, as recently reviewed.29

Several previous reviews addressed interactions ofgrapefruit and drugs, discussing aspects of involveddrugs and grapefruit components, drug safety, respon-sibilities to the public, and potential solutions.1,30-35

This review is designed to give a comprehensiveupdate on underlying mechanisms, conducted clini-cal trials, and potential replacements for drugs affected

by the consumption of grapefruit.

History of the Grapefruit

Although the vast majority of Citrus varieties aresupposed to have originated in the tropical and sub-troprical regions of Southeast Asia,36,37 the grape-fruit, which receives this denomination because thefruits grow as clusters similar to grapes, is believedto have been generated as an accidental sprout onthe island of Barbados in the Caribbean, where itwas first described as the forbidden fruit of Barbadosin 1750 by Griffith Hughes.38 The first scientificdescription of grapefruit is attributed to the botanist

James Macfadyen in 1837, who named the forbiddenfruit Citrus paradisiMacf.38 Several studies stronglysupport that grapefruit originated from an acciden-tal hybrid between pummelo (Citrus maxima) andsweet orange (Citrus sinensis), which is a hybrid

between pummelo and mandarin.39 Currently, Floridais the worlds largest producer of grapefruit, averag-ing 2 million tons a year, followed by the state of

Texas.

40

POLYPHENOLIC COMPOUNDS INGRAPEFRUIT AND CITRUS WITHPOTENTIAL DRUG INTERACTIONS

Overall, flavonoids and other polyphenolic com-pounds contained in grapefruit have been associatedwith an influence in the prevention of many chronicdiseases, such as several types of cancer and cardio-vascular disease, which has been demonstrated in sev-eral cohort and case control studies.41-44 Specifically,

orange juice, grapefruit juice, and naringin, a majorgrapefruit flavonoid, have been shown to have a ben-eficial effect on the blood lipid profile and antioxidantcapacity in rats.45,46 In a recent clinical consumptiontrial with obese patients, it was demonstrated thatthe consumption of half of a grapefruit 3 times perday before each meal was associated with significantweight loss over a period of 12 weeks compared tothe control group, as well as a significant reductionin 2-hour postglucose insulin concentrations. In thesame study, the consumption of grapefruit juice and



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MERTENS-TALCOTT ET AL

grapefruit extract capsules was associated with sig-nificant weight loss in those subjects with metabolicsyndrome. These data may indicate the beneficial

effects of grapefruit in weight management.47 Manyconsumers have become more aware of the health

benefits of antioxidant, phytochemical-rich fruits,

Figure 1. Chemical structure of polyphenolics in citrus: (A) bergamottin, (B) 67-dihydroxybergamottin, (C) naringenin, (D) naringin,and (E) furanocoumarins-dimer GF-I-1.



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vegetables, and products that contain these com-pounds. In 1997, GFJ was purchased by 21% of allhouseholds as a popular antioxidant breakfast juicepredominantly preferred by the elderly.48

Polyphenolics present the major group of citruscompounds interacting with drugs. Included arehydroxycinnamic acids; flavonoids, such as fla-vanones, flavones, and flavonols; anthocyanins; andcoumarins (see Figure 1 and appendix).49

Interactions between furanocoumarins, bergamot-tin (BG), and 67-dihydroxybergamottin (DHBG), aswell as dimers of furanocoumarins and many drugs,have been demonstrated in many in vitro and invivo studies. Furanocoumarins have been demon-strated to interact with susceptible drugs by differentmechanisms: effects on the activity of the intestinalenzyme CYP3A4 and also the transporters P-gp and

OATP have been demonstrated. However, the CYP3A4-mediated interactions have been confirmed in numer-ous in vitro as well as human clinical trials, whereasthe transporter-mediated drug interactions lack thor-ough investigation in human clinical trials. Overall,single polyphenolic compounds from grapefruit mainlyhave been investigated in the in vitro studies, whereaspredominantly grapefruit juice has been administeredin human clinical trials. This makes a direct com-parison and an assessment of responsible singlepolyphenolic compounds for in vivo interactionsdifficult. Overall, in the in vitro studies, polyphenoliccompounds, including BG, DHBG, furanocoumarindimers, quercetin, and naringenin, have been demon-strated to inhibit cytochrome P450 3A4.50-55 Paineand coworkers56 assessed the kinetics ofreversible andmechanism-based inhibition of CYP3A4 by BG andDHBG with midazolam and testosterone as probes inhuman intestinal microsomes: an increasing number ofhuman intervention studies confirm the contribution ofBG and DHBG to drug interactions with GFJ.17,57-59

Several citrus polyphenolics have been demonstratedto be involved in transporter-mediated drug interac-tion. BG, DHBG, naringin, bergaptol, bergapten, tan-geretin, and nobiletin have been found to inhibit the

transport of P-gp or OATP-mediated drug transportin vitro.22,51,60

The clinical relevance of data obtained from stud-ies with single compounds is questionable becausemost studies were performed in the in vitro systems,limiting the predictability of the effects in vivo.Moreover, concentrations used in some of the invitro studies exceed those expected upon consump-tion of moderate amounts of citrus products in vivo.Overall, in vitro studies with single compoundsdemonstrated that furanocoumarins and their dimers

may primarily be responsible for the interactions ofGFJ with drugs. Most clinical trials have been per-formed using grapefruit juice, which may containfuranocoumarins at varying concentrations.28 A

recent clinical trial using grapefruit juice with andwithout furanocoumarins demonstrated that fura-nocoumarins were mainly responsible for the inves-tigated interaction with felodipine in this study.59 Inthis review, the term grapefruitis used as a generalterm to describe fresh grapefruit and also grapefruitjuice. Among citrus varieties overall, grapefruit, sourorange (Seville), and also limes seem to have a higherpotential among citrus species to interact with drugs,whereas other citrus varieties, such as sweet orange,seem to have an overall low potential to interfere withmedications.57 However, in studies using juicesrather than single compounds, orange juice and apple

juice have also been shown to interact with drugsin a few studies. A recent study in rats demon-strated that orange juice and apple juice decreasedthe oral exposure of fexofenadine, possibly throughthe inhibition of OATP.61 In HeLa cells, orange juiceat 5% strength inhibited the uptake of fexofena-dine in a concentration-dependent manner by anarray of human and rat OATPs,21 and in humanembryonic kidney cells, orange juice inhibited theuptake of estrone-3-sulfate, probably mediated throughOATP-B.22 However, overall, it can be concluded thatorange juice does not have a significant potential indrug interactions.

POSSIBLE MECHANISMS OF INTERACTION

A food-drug interaction may be defined as the alter-ation of absorption, metabolism, or effect of a drug by afood component. The underlying mechanisms can beclassified into the 2 broad categories: pharmacokinet-ics, including alterations in absorption, distribution,metabolism, and excretion, and pharmacodynamics,describing alterations in the drug concentration-effect relationship.62 Citrus components more com-monly affect pharmacokinetics of drugs rather than

pharmacodynamics, which may shift the effect ofthe drug outside of its therapeutic window, possiblyleading either to loss of effects or undesired sideeffects or even toxicity.1 Initially, the liver was assumedto be the major site of grapefruit-drug interactions.However, it has been shown that the interaction onlyoccurs when drugs are administered orally, not intra-venously, which indicates that the interaction may takeplace during the gastrointestinal absorption phase.63,64

In the following sections, the major currently knownmechanism of action including the inhibition of





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enteric CYP3A4 and the more recently describedeffects of grapefruit on the intestinal transporters P-gp and OATP are described.

Cytochrome P450 Family

CYP enzymes are bound to membranes of the endo-plasmatic reticulum and are predominantly expressedin the liver, although they are also present in extra-hepatic tissues such as the gut mucosa. The cytochromeP450 (CYP) enzyme family is the major catalyst ofphase I drug biotransformation reactions. CYP3A4 isthe most abundantly expressed isoform, where thehigh expression levels in the intestinal mucosa andthe broad substrate specificity may contribute to thehigh susceptibility of CYP3A4 for citrus-drug inter-actions.65 Many drugs, for which interactions with

citrus have been demonstrated, are metabolized byCYP3A4. Grapefruit juice can inhibit the activity ofintestinal CYP3A4, which can lead to an interactionwith drugs during their first passage from the intestinallumen into the systemic circulation.66 The alterationof intestinal CYP3A4 by GFJ includes reversible andmechanism-based inhibition as well as destructionof the CYP3A4 protein,23,67 where mRNA levels remainunaltered, indicating an accelerated degradation aftermechanism-based inhibition.68 Moderate consump-tion did not appear to inhibit hepatic CYP3A4 activity.56

Several drug classes, such as dihydropyridine cal-cium antagonists and HMG-CoA reductase inhibitors,have been shown to be affected by grapefruit-inducedinhibition of CYP3A4. Grapefruit juice increased theAUC and maximal plasma concentration (Cmax) forthis class of calcium antagonists within a moder-ate range in a single-dose study design (reviewedin Harris et al65). Double-strength GFJ moderatelyincreased the AUC of the HMG-CoA reductaseinhibitors atorvastatin69 and simvastatin.70 This groupalso demonstrated that 1 glass of GFJ caused an increasein plasma triazolam concentrations.71 In a 72-hourstudy, GFJ increased the AUC of simvastatin 3.6-foldand simvastatin acid 3.3-fold. The Cmax of simvas-

tatin and simvastatin acid was increased 3.9-foldand 4.3-fold, respectively, when the GFJ was admin-istered for 3 days and simvastatin on the third day.72

In addition to CYP3A4, other isoforms of the CYPfamilyCYP2C9, CYP2C19, and CYP2D6wereshown to be affected by citrus compounds,73-75 butthe inhibition of CYP enzymes other than CYP3A4does not appear to be of great magnitude and islikely to be of a low clinical significance.65

Paine and coworkers56 investigated the reversibleand mechanism-based inhibition kinetics for grapefruit

compounds and found that DHBG induced a substrate-independent reversible and mechanism-based inhi-

bition on CYP3A4 in human intestinal microsomes.In contrast, BG, being more lipophilic than DHBG,

was a substrate-dependent reversible and substrate-independent mechanism-based inhibitor. Similartrends were found with cDNA-expressed CYP3A4.For BG, the inhibition for testosterone was morepotent than for midazolam, possibly due to thehigher affinity of BG for the testosterone bindingsite. As mechanism-based inhibitors, BG and DHBGare substrates for CYP3A4. In conclusion, both fura-nocoumarins inactivate CYP3A4 by the bindingof the furanoepoxide to the apoprotein.56 Overall,BG and DHBG are described as mechanism-basedinhibitors of CYP3A4 (reviewed in Zhou et al76). Therecovery time of intestinal CYP3A4 was determined

in a human intervention trial after the consumptionof regular-strength GFJ and a single dose of midazo-lam at 2, 26, 50, and 74 hours after administeringthe juice. After 2, 26, 50, and 74 hours, the AUCwas 1.65-, 1.21-, 1.21-, and 1.06-fold increased incomparison to the control, respectively. A recoveryhalf-life of 23 hours was estimated. These resultsimply that a single dose of GFJ may be able to reducethe intestinal presystemic metabolism of orally admin-istered midazolam, with a recovery time of 74 hours.These results are consistent with a mechanism-basedinhibition.18 Although DHBG was shown to be morepotent than BG, coumarin dimers seem to be moreeffective than monomers in the inhibition of CYP3A4.55

In summary, the presented in vitro studies con-firm the inhibitory effects of grapefruit compoundson CYP enzymes, with major effects on CYP3A4,involving both mechanism-based and reversible inhi-

bition. Human intervention trials revealed a greatinterindividual variability, where subjects with thehighest concentrations of CYP3A4 showed the largestreduction. Overall, GFJ does not seem to interact withintravenously administered drugs. The extent of thegrapefruit-drug interaction in the case of CYP3A4seems to depend on individual intestinal enzyme

activity. Subjects with a high activity of CYP3A4 appearto have a higher inhibition by GFJ than subjects witha low initial CYP activity. Consequently, the con-comitant administration of GFJ with a susceptibledrug may cause higher AUC in subjects with a highintestinal CYP3A4 activity, but unexpectedly, thesesubjects tend to have a low AUC after intake of astandard dose of drugs without the administration ofGFJ.66,77 More studies will have to be performed

before sound recommendations for the concomitantintake of citrus with certain drugs can be given.




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P-Glycoprotein

One of the most studied drug transporters is P-glycoprotein (P-gp). P-glycoprotein is a 170-kDa plasma

glycoprotein of the family of adenosine triphosphate(ATP)binding cassette transporters, which is encoded

by the multidrug resistance MDR 1 gene.78,79 P-glyco-protein is expressed constitutively at high levels onthe apical surface of the small intestine, liver, pan-creas, kidney, colon, adrenal glands, and at the blood-

brain barrier and bloodcerebrospinal fluid barriers.79-81

Wacher and coworkers82 reported striking overlapsof substrates and inhibitors between CYP3A4 andP-gp. Therefore, the inhibition of P-gp may also playa role in the effects of GFJ.

Initial studies indicated that GFJ had no influenceon the activity of P-gp: it was found that 8 oz of GFJ

(3 times per day for 6 days) did not alter P-gp con-centrations in healthy volunteers.68 These findingswere confirmed in an in vitro study in Caco-2 coloncarcinoma cells, where compounds from grapefruitwere not found to modulate P-gp.51 In 1999, it wasreported that GFJ increased P-gp-mediated transportin MDCK-MDR1 cells.83 Controversially, in laterfindings, these results were attributed to an equipment-generated artifact by the authors.84 Takanaga andcoworkers85 were the first to demonstrate the inhibi-tion of P-gp by GFJ in Caco-2 cells with vinblastineas a probe. Because vinblastine also is a substrateof CYP3A4, the conclusion regarding the inhibitionof P-gp is limited. In a study investigating GFJ andphenolic compounds from oranges, such as tan-geretin, nobiletin, and heptamethoxyflavone, whichhave been demonstrated not to alter CYP3A4 activ-ity, it was shown that the net influx of vincristineinto human myelogenous leukemia cells was increasedconclusively through the inhibition of P-gp.86 Furtherin vitro studies with different probes (talinolol,digoxin, vinblastine) corroborate the findings thatGFJ inhibits the efflux of P-gp substrates.87-89 In addi-tion to GFJ, orange juice and pummelo juice seemto inhibit the activity of P-gp in vitro.89 Overall,

flavones from orange juice have been shown to bemore potent than compounds from grapefruit in theinhibition of P-gp.85

Few human clinical trials confirmed the possibilityof P-gp being involved in GFJ-drug interactions. Aclinical intervention study conducted by Edwards andcoworkers90 indicated that GFJ may interact with P-gpactivity. In this study, AUC and peak concentration ofcyclosporine were increased by GFJ. Seville orangejuice did not have an influence on cyclosporine, but itreduced enterocyte concentrations of CYP3A4. DHBG

did not inhibit P-gp in vitro. These data imply thatthe inhibition of P-gp activity by other compoundsin GFJ may be responsible for the increased bioavail-ability of cyclosporine, but cyclosporine also is a

substrate for CYP3A4, which may have signifi-cantly contributed to the increased bioavailability ofcyclosporine in this study. In a randomized 3-waycrossover intervention study in which healthy vol-unteers were administered felodipine as a probewith Seville orange juice, diluted GFJ (normalized toan equivalent total concentration of BG and DHBG),and sweet orange juice, the AUC of felodipine wasincreased by Seville orange juice and GFJ. AlthoughSeville orange juice and GFJ probably interact withfelodipine through the inactivation of intestinalCYP3A4, there was no apparent interaction betweenSeville orange juice and cyclosporine, which indi-

cated that grapefruit may cause interactions alsothrough the inhibition of intestinal glycoprotein.84

Conversely, the pharmacokinetics of known P-gpsubstrates were not altered by GFJ in several clinicalstudies, which were designed to investigate the effectof GFJ on the bioavailability of digoxin, amlodipine,and indinavir26,91,92potentially due to other unknownmechanisms and factors, such as strength of theadministered juices and length of consumption rele-vant for the interactions.93

Overall, grapefruit and other citrus may interactwith several drugs through the combined inhibitionof CYP3A4 with other mechanisms. The magnitudeof interactions may strongly depend on variationsin the polyphenolic profile of the GFJs and studydesign.94,95 The clinical significance of P-gp-relatedinteractions between drugs and GFJ will have to beclarified in further clinical studies.

Organic Anion-Transporting Polypeptides

The family of OATPs consists of membrane carriersthat mediate the transport of anionic molecules. Morerecently, the transport of nonanionic molecules has

been observed. Organic anion-transporting polypep-

tides can be found in the small intestine on luminalmembranes of enterocytes and in the liver as media-tors of drug uptake.96,97 OATP-A is predominantlylocated in the brain, and OATP-B has been found onthe membranes of intestinal epithelial cells.98,99 Theinhibition of drug uptake mediated by OATP mayalter the plasma concentration of drugs serving asOATP substrates.

Grapefruit juice and orange juice have been found toreduce the uptake of fexofenadine and celiprolol, bothsubstrates for P-gp and OATP, but not CYP3A4.21,100-103





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In the observed interaction, the bioavailability wasdecreasedif P-gp had played a major role, the

bioavailability would have been increased instead.This observation led to the conclusion that a mech-

anism other than P-gp was involved. Several in vitrostudies were designed to verify this observation, butonly few clinical trials have been performed to estab-lish the clinical significance of this mechanism.

Grapefruit juice and orange juice were found todecrease OATP-A-mediated fexofenadine uptake intoHeLa cells, and apparently, this inhibition of OATP-A was more potent than the inhibition of P-gp. Ina corresponding human trial, the same authorsdetermined that GFJ and orange juice decreased the

bioavailability of fexofenadine in healthy volunteers.21

The authors discussed that the apparent decreasedbioavailability of fexofenadine in humans may have

been caused indirectly by an increased drug intakewhen the drug was administered with water, due tothe lower osmolarity of water. Therefore, a nonpolarfraction of GFJ was tested in a clinical trial. Thisnonpolar fraction also significantly reduced the

bioavailability of fexofenadine, confirming the ini-tial hypothesis. In 2 corresponding clinical inter-vention trials, the oral pharmacokinetics of 50 mgtalinolol were determined acute and after 6 daysof repeated grapefruit juice ingestion (900 mL/d)in 24 healthy volunteers. Results demonstratedthat the acute and chronic consumption of grape-fruit juice decreased the talinolol area under theserum concentration-time curve (AUC), peak serumdrug concentration (Cmax), and urinary excretionvalues by approximately 45% to 65% compared towater. However, renal clearance, elimination half-life, or time to reach Cmax (tmax); MDR1 messengerribonucleic acid; and P-glycoprotein levels in duo-denal biopsy specimens were not affected by thegrapefruit juice. Conclusively, grapefruit juice seemedto inhibit an intestinal uptake process compared toP-glycoprotein, where intestinal P-glycoprotein expres-sion was not altered.104

Grapefruit juice, orange juice, BG, DHBG, quercetin,

naringin, naringenin, and tangeretin significantlyinhibited OATP-B-mediated drug transport in vitro.22

In a study with rats, orange juice decreased the oralbioavailability of fexofenadine to a lesser extent thanthat observed in humans.61 The clinical relevance ofthis study does not appear to be high because fex-ofenadine mainly is a substrate for OATP-A, whichin humans predominantly occurs in the brain, whereasOATP-B occurs in the intestines. In general, it should

be considered that genetic differences between speciesmay contribute to differences in the susceptibility tograpefruit-induced inhibition involving OATP.

In summary, OATPs appear to play an importantrole in the influx for a number of drugs into entero-cytes and hepatocytes. The inhibition of OATP activ-ity has been demonstrated for orange and GFJ in the in

vitro experiments. The clinical relevance of this mech-anism remains to be investigated in further humanintervention trials. The OATP-mediated GFJ-druginteractions may be of clinical relevance for drugssuch as itraconazole, fexofenadine, and talinolol.

CLASSES OF DRUGS INTERACTINGWITH GRAPEFRUIT JUICE

Below, major drug classes for which grapefruit inter-actions have been reported are comprehensivelydescribed and summarized. Previously, several clin-

ical trials and underlying mechanisms on grapefruit-drug interactions have been summarized, in whichdrugs were classified into 3 groups (increase, decrease,or no change in Cmax and AUC, respectively).

105 It isdifficult to predict the clinical significance of phar-macokinetic drug interactions, specifically for drugswhere side effects cannot be quantified. A recenteffort in the United States involving the Food andDrug Administration (FDA) and the PharmaceuticalResearch and Manufacturers of America (PhRMA)has the goal to establish some general guidelines tohelp drug companies, prescribers, and patients inter-pret the clinical significance of drug interactions.106

These guidelines are based on clinical experiencewith several well-defined drug interactions, mainlyincluding the inhibition of CYP3A4. For this inter-action mechanism, benzodiazepine midazolam wasshown to be a reproducible probe allowing quantita-tive determination of the interaction potential of anenzyme inhibitor. For midazolam, the extent of inter-action can be measured in the form of an increase inthe AUC. Recently, it was suggested that less than 2-fold changes of midazolam AUC should be classifiedas weak, which was observed after midazolam coad-ministration with ranitidine, low volumes of GFJ,

roxithromycin, fentanyl, or azithromycin.106

AUCchanges ranging from 2- to 5-fold were classified asmoderate, which occurs after midazolam coad-ministration with erythromycin, diltiazem, flucona-zole, verapamil, large volumes of GFJ, and cimetidine.A strong interaction was marked by changes exceed-ing a 5-fold increase in midazolam AUC. Examplesinclude ketoconazole, itraconazole, and mibefradil.According to the current knowledge, strong drug inter-actions are considered clinically significant. Somedrugs for which strong interactions have been shownare carrying a warning label.



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Where applicable, the clinical relevance of GFJinteractions described in this review was assessedaccording to the PhRMA classification.106 Below, cur-rently available scientific reports of human clinical

trials are summarized. In vitro studies or studies inanimal models are listed where no human clinicaldata are available. An overview is given in the appen-dix. A detailed overview and scientific summaries ofthe presented human clinical trials can be found onthe Web pages of the Center for Food Drug Interactionat the University of Florida (www.druginteraction-center.org). Several nonscientific online databasesalso provide information regarding grapefruit-druginteractions. However, close attention should be paidto the source of reports and the scientific basis ofthe presentation because much anecdotal, sensa-tionalized, and nonscientific information may be

presented.

Antiallergics

Interaction studies are reported for the antiallergicdrugs terfenadine,107-110 desloratadine,111 and fexofe-nadine.111 Concomitantly consumed GFJ did not alterthe mean exposure for desloratadine, whereas forfexofenadine, it was decreased. Three studies showedincreased exposure to terfenadine coadministeredwith GFJ.107-109 Overall, the effects of GFJ on this drugclass do not appear to be of high clinical relevance.

Antibiotics

Interaction studies were performed with clar-ithromycin,112 erythromycin,113 and telithromycin.114

Overall, the clinical relevance of the reported inter-actions with antibiotics appears to be low.

Anticoagulants

Inconsistent data were derived from studies performed

with coumarins. The percentage of 7-hydroxycoumarinexcreted in urine was found to be decreased,115butin a second study, the appearance of the metabolitewas delayed, whereas the recovery in urine wasunchanged.116 The delay in appearance of the metabo-lite was confirmed in a third study.117 No interactionswith warfarin have been confirmed.118 Currently, noclinically relevant interactions have been confirmedfor this drug class. More extensive clinical studiesare necessary to assess the overall effect of GFJ onthis drug class.

Antimalaria Drugs

Grapefruit juice was found to increase the exposureof artemether119,120 and halofantrine.121 However, brady-

cardia or changes in the QTc interval were notreported for artemether when administered with GFJ.No changes in pharmacokinetic parameters wereobserved when quinidine74,122 or quinine123 was coad-ministered with GFJ. However, quinidine was reportedto have a QTc interval prolongation at 1 hour afterdrug administration. According to the classificationof Bjornsson et al,106 the interactions of quinidine andquinine would be considered weak and unlikely to beclinically relevant, but the observed interaction withhalofantrine can be considered clinically relevant.

Antiparasitic Drugs

A moderate and weak interaction is reported foralbendazole124 and praziquantel,125 respectively.Therefore, a concomitant consumption should only

be considered after a cautious risk and benefit assess-ment. An interaction of GFJ with praziquantel seemsunlikely to be clinically relevant, but a moderateinteraction was observed for albendazole.

Sedative-Hypnotics

No changes in pharmacokinetic parameters were

observed when alprazolam was administered con-comitantly with GFJ126 in a single-dose experiment.With midazolam,7,18,127,128 triazolam,71,128-131 andquazepam,130 minor exposure increases were observedwhen administered concomitantly with GFJ. In a recentclinical trial with triazolam, the acute and extendedexposure to GFJ produced a significant inhibition ofenteric, but not hepatic, CYP3A4 and also causedsignificant pharmacodynamic effects.131 A clinicallyrelevant interaction has also been observed for bus-pirone132 and diazepam.133 More human interventiontrials will have to be conducted to investigate theextent of interactions for this drug class.

Calcium Channel Blockers

Amlodipine,91,134 diltiazem,135,136 nimodipine,137

nifedipine,2,138,139 pranidipine,140 and verapamil141-143

were shown to interact weakly with GFJ. However,only for amlodipine, diltiazem, nimodipine, andverapamil were no changes reported in pharmaco-dynamic parameters (heart rate and blood pressure).No pharmacodynamic alterations were reported for





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nifedipine and GFJ. Felodipine,17,58,63,68,84,91,141-150

nicardipine,151 nisoldipine,152,153 nitrendipine,3 andmanidipine154 moderately interacted with GFJ. Changesin pharmacodynamic parameters were reported after

GFJ was administered with felodipine. Overall, prod-ucts containing felodipine, nicardipine, nisoldipine,and nitrendipine should only be consumed with GFJafter a cautious risk and benefit assessment.

HIV Protease Inhibitors

Amprenavir155 and indinavir26,156 did not inducechanges in pharmacokinetic parameters when admin-istered concomitantly with GFJ. The AUC of saquinavirwas increased by GFJ.9,157 However, overall, thereported interactions can be considered weak andare unlikely to be clinically relevant.

HMG-CoA Reductase Inhibitors

Increased exposures were reported for atorvas-tatin,69,158,159 lovastatin,160,161 and simvastatin72,132,162butnot for pravastatin69,158 and pitavastatin.159 Atorvastatinexhibited a moderate interaction with GFJ regardingthe overall exposure. Lovastatin and simvastatin exhib-ited a strong interaction. Pravastatin or pitavastatincould be chosen as an alternative drug if clinicallyrecommendable and if patients want to ensure a lackof interaction. Overall, the changes in pharmacoki-

netics (AUC) of statins by far exceeded the extent ofpharmacodynamic changes.

Hormones

Grapefruit juice did not affect 17-beta estradiol163 orprednisone164 pharmacokinetics. AUCs were weaklyelevated for ethinylestradiol165 and methylpred-nisolone.166 A decreased morning cortisol plasmaconcentration was found after methylprednisoloneadministration with GFJ. The absorption of levothy-roxine was mildly decreased after repeated consump-tion of grapefruit juice, but here the authors conclude

a low clinical relevance.167 Anecdotal reports thatgrapefruit juice may cause contraceptives to lose theireffect could not be confirmed by scientific studies.

Immunosuppressants

Eleven out of a total of 13 studies reported increasedcyclosporine exposure.64,90,168-176 Conversely, 2 stud-ies reported no GFJ-induced change in AUC.164,177

Overall, the clinical significance of interactions isassumed to be low.

Antitumor Drugs

Few studies have been performed with human subjectsfor this drug class. The mean AUC of etoposide was

increased when administered concomitantly withGFJ.178 However, the report does not state the statis-tical significance of the reported data. To developrecommendations for this drug class, further researchwill have to be conducted. Currently, the clinical sig-nificance of interactions with GFJ appears to be low.

Over-the-Counter Drugs

Contradicting results were reported when caffeinewas administered with GFJ. Whereas no changes inAUC, blood pressure, and heart rate were reported

by Maish and coworkers,179 a second study foundincreased AUC and half-life, without an assessmentof pharmacodynamic parameters.180 Overall, no clin-ically significant interactions of an over-the-counterdrug with GFJ have been reported.

Beta-Blockers

AUC and Cmax of celiprolol decreased by 95%, whenadministered concomitantly with GFJ,100 but heartrate and blood pressure remained unchanged. It isconclusive that observed interactions are clinicallyrelevant. The plasma concentrations of acebutolol181

were slightly decreased by grapefruit juice. Furtherstudies in humans will have to be conducted toderive reliable conclusions. Currently, clinically sig-nificant interactions appear to be unlikely.

Antiarrhythmics

Coadministration of amiodarone182 with regular-strength GFJ resulted in a significant but weakincrease in AUC and Cmax, but a decrease in the alter-ation on the PR and QTc interval was observed.These data imply that not only pharmacokineticdata should be considered when determining the

extent of the significance of a given GFJ-drug inter-action. Overall, the changes in pharmacodynamicparameters should be taken into account when pre-scribing this drug to patients who wish to consumeGFJ.

Other Drugs

Grapefruit juice has shown to increase the exposureof carbamazepine,183 cisapride,77,184-186 fluvoxamine,187

losartan,188 methadone,189 scopolamine,190 sertraline,191



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and repaglinide.192 However, only the interaction ofGFJ and carbamazepine and cisapride appears to beclinically relevant. No alteration in exposure wasobserved for clozapine,193,194 theophylline195 and

haloperidol,196 omeprazole,197 and phenytoin.198 Con-tradicting results were reported for itraconazole,199-201

digoxin,92,202 and sildenafil.203,204 Overall, the clinicalrelevance for this drug class appears to be minor.

CONCLUSIONS

Grapefruit juice has been shown to interact withseveral orally administered medications. In most cases,the expected interactions will be minor and of littleclinical relevance. However, the overall observationthat a single serving of GFJ can induce a long-lastingincrease in oral bioavailability of some drugs, whichmay lead to a potential drug toxicity, does call forcaution. For those patients who wish to consumeGFJ while taking a certain medication, potentialalternatives may be available for several of the drugs.Conceptually, drugs with a strong interaction could

be substituted by drugs within the same class thatexhibit a weak or no interaction. Where toxicity can

be expected, GFJ should be avoided during the periodof drug treatment. In addition, the replacement withnoninteracting drugs is limited by their therapeuticinterchangeability and is dependent on a physiciansrecommendation and safety assessment. In this con-

text, it should be considered that for patients whoregularly consumed GFJ before the dose of their med-ication was adjusted and continue with a constantconsumption of GFJ during their medication, a poten-tial toxicity appears relatively unlikely.11

There are situations when toxicity is more likelyto occur:

1. For patients taking unusually high doses of a sus-ceptible drug who then consume GFJ for the firsttime, GFJ may lead to a sudden decrease of intesti-nal CYP3A4 activity.

2. In patients with severe liver disease, the exposure tothe drug would be expected to be higher, with theintestines being the major site of metabolism. Alsoin these patients, a sudden decrease in CYP activityin the intestines may lead to an increase of drugconcentration.

3. Patients susceptible to toxic effects from drugs arelikely to exhibit a drug toxicity when the bioavail-ability is increased.11

FUTURE DIRECTIVES

Overall, patients treated with drugs that have showna significant potential for grapefruit-drug interactionneed to the counseled regarding a concomitant use.Care must be taken to avoid careless prescription ofsusceptible drugs. A potential change to an alterna-tive drug without known interactions may be con-sidered. However, overcautious overreaction leadingto complete avoidance of citrus products seemunreasonable, especially because these contain sig-nificant amounts of antioxidant phytochemicalswith significant health benefits.

Further research is needed extending across moredrugs for grapefruit, citrus fruits other than grape-

fruit, and other food products in general. Furtherclinical research will have to be conducted to con-clusively determine the mechanisms and clinicalrelevance of these interactions.

Financial disclosure: This research was partially supported bya grant from the US Department of Agriculture.



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APPENDIX

Antiallergics

ModerateInteraction(AUCIncrease>2-2-2-2-2-

jugo toronja 1

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