Enzyme- and Transporter-Mediated Beverage–Drug Interactions: An Update on Fruit Juicesand Green Tea

Guohua An, MD, PhD1, Jatinder Kaur Mukker, PhD2, Hartmut Derendorf, PhD2,and Reginald F. Frye, PharmD, PhD3

AbstractBeverage–drug interactions have remained an active area of research and have been the subject of extensive investigations in the past 2 decades. Theknown mechanisms of clinically relevant beverage–drug interactions include modulation of the activity of cytochrome P450 (CYP) 3A and organicanion-transporting polypeptide (OATP). For CYP3A-mediated beverage–drug interaction, the in vivo CYP3A inhibitory effect is limited to grapefruitjuice (GFJ), which increases the bioavailability of several orally administered drugs that undergo extensive first-pass metabolism via enteric CYP3A. Incontrast, clinically significantOATP-mediated beverage–drug interactions have been observed with not only GFJ but also orange juice, apple juice, and,most recently, green tea. Fruit juices and green tea are all a mixture of a large number of constituents. The investigation of specific constituent(s)responsible for the enzyme and/or transporter inhibition remains an active area of research, and many new findings have been obtained on this subjectin the past several years. This review highlights the multiple mechanisms through which beverages can alter drug disposition and provides an update onthe new findings of beverage–drug interactions, with a focus on fruit juices and green tea.

KeywordsBeverage–drug interaction, Clinical Pharmacology (CPH), Fruit juices, Green tea, OATP, Pharmacokinetics and drug metabolism

As food/beverage and medications are often takentogether, there is a high chance for food/beverage–druginteraction to occur. Food/beverages can influence drugdisposition through multiple mechanisms. For example, ahigh-fat meal can slow gastric emptying and delay drugabsorption. Food/beverages containing high amounts ofmetal ions (eg, milk and yogurt) can reduce thebioavailability of many antibacterial agents (eg, tetracy-cline, fluoroquinolone) through formation of insolublechelates.1,2 Food/beverages rich in dietary fiber canincrease the rate of drug absorption through facilitatinggastric emptying and can decrease the extent of drugabsorption by trapping coadministered drugs in the fibermatrix.3 In addition, food/beverages can also influence thedisposition of coadministered drugs by modulating drug-metabolizing enzymes and/or transporters. The classicexample of enzyme- and transporter-mediated food/beverage–drug interaction is with grapefruit juice(GFJ), a popular breakfast juice purchased by 21% ofall households in the United States. Since the first clinicalreport in 1991,4 it has been well established that GFJ caninterfere with presystemic metabolism of a number oftherapeutic compounds (such as calcium channel block-ers, statins, immunosuppressants, protease inhibitors),5–12

resulting in increased drug exposure and a correspondingincrease in the incidence of adverse drug effects.Recently, GFJ was found to impair the bioactivation ofclopidogrel, a prodrug dependent on CYP2C19- and

CYP3A-mediated bioactivation to an active thiol metab-olite; the interaction results in a decrease in the platelet-inhibitory effect of clopidogrel.13 Additional mechanisticstudies have revealed that GFJ is an irreversible,mechanism-based inhibitor of intestinal CYP3A.14,15

The interaction of CYP3A substrate compounds withother fruit juices, including orange juice and apple juice,has also been investigated, and no interaction has beenobserved.4,16 Although many reports have documentedthe ability of GFJ to significantly increase the exposure ofdrugs that are CYP3A substrates, recent evidence hasshown important interactions between GFJ and severaldrugs that undergo minimal metabolism.17–21 For exam-ple, when taken together with GFJ, the systemic exposure

The Journal of Clinical Pharmacology2015, XX(XX) 1–19© 2015, The American College ofClinical PharmacologyDOI: 10.1002/jcph.563

1Department of Pharmaceutical Sciences and Experimental Therapeu-tics, College of Pharmacy, University of Iowa, Iowa City IA, USA2Department of Pharmaceutics, College of Pharmacy, University ofFlorida, Gainesville FL, USA3Department of Pharmacotherapy and Translational Research, Col-lege of Pharmacy, University of Florida, Gainesville FL, USA

Submitted for publication 12 December 2014; accepted 3 June 2015.

Corresponding Author:Guohua An, MD, PhD, Assistant Professor, Division of Pharmaceuticsand Translational Therapeutics, University of Iowa, 115 S. Grand Ave,Iowa City, IA 52242Email: guohua-an@uiowa.edu

Review

of fexofenadine19 and celiprolol18 were reduced substan-tially. This phenomenon cannot be explained by theknown inhibitory effect of GFJ on CYP3A. These clinicalobservations stimulated further mechanistic studies thatled to the discovery of a new mechanism of GFJ–druginteraction involving inhibition of organic anion-trans-porting polypeptides (OATPs), which are uptake trans-porters known to facilitate the uptake of substratecompounds through the gastrointestinal wall into thebloodstream. Interestingly, in addition to GFJ, severalother fruit juices, including apple juice and orange juice,have also been found to influence the disposition ofvarious drugs that are known to be substrates ofOATPs.17,22–24 In addition to fruit juices, the interactionbetween drugs and green tea, another popular beverageconsumed worldwide and often taken concomitantly withdrugs, started to gain interest because of the recentlyobserved modulatory effect of green tea on transporters,including OATPs.25–27 In 2010, the fruit juice retailmarket in the United States was valued at $16.2 billion. Ithas been estimated that the average American consumesaround 30.3 L of fruit juice every year. In 2012,Americans consumed well over 3.60 billion gallons oftea, with 15% being green tea.28 Considering theextensive consumption of fruit juices and green tea,together with their modulatory effects on drug-metabo-lizing enzymes and transporters, there is potential risk forclinically important interactions between these beverages

with coadministered drugs. GFJ–drug interaction hasbeen extensively studied for more than 2 decades, andmost beverage–drug interaction review articles havemainly focused on this subject.8,29–32 In the past fewyears, reports on the interactions of medications withother beverages, such as orange juice, apple juice, andgreen tea, have accumulated rapidly. In addition, fruitjuices and green tea are all a mixture of a large number ofconstituents. The investigation of the specific constituent-(s) responsible for the enzyme and/or transporterinhibition remains an active area of research, and manynew findings have been obtained on this subject in the pastseveral years (Table 1).33–36 This review covers themultiple mechanisms that have been evaluated forbeverage–drug interaction, including CYP3A, P-glyco-protein, and OATPs and provides an update on newfindings of beverage–drug interactions, with a focus onfruit juices and green tea.

CYP3A-Mediated Beverage–DrugInteractionGrapefruit JuiceGFJ combines the sweet and tangy flavors of the orangeand the pomelo (or shaddock) and provides high amountsof vitamin C and potassium. GFJ carries the AmericanHeart Association’s healthy “heart-check” food mark andis consumed widely as a preventive measure against

Table 1. Effect of the Major Constituents of Fruit Juices and Green Tea on CYP3A, P-gp, and OATP Inhibition

Fruit Juices Major Ingredients

CYP3A Inhibition P-gp Inhibition OATP Inhibition

ReferencesIn VitroEffect

In VivoEffect

In VitroEffect

In VivoEffect

In VitroEffect

In VivoEffect

Naringin þ x þ N/A þþþ þþþ 34, 45, 77, 99, 147Quercetin þ x þ/� N/A þ N/A 34, 78, 79, 104Kaempferol N/A N/A þ/� N/A þ N/A 34, 104

Grapefruitjuice

Bergamottin x N/A þ N/A x N/A 15, 34, 80, 109,147

60 ,70-Dihydroxybergamottin þþþ N/A þ N/A x N/A 15, 34, 80, 109,147

Paradisins þþþ N/A N/A N/A N/A N/A 84, 85Tangeretin x N/A þ N/A N/A N/A 114, 115Nobiletin x N/A þ N/A N/A N/A 114, 115

Orange juice 3,30 ,40 ,5,6,7,8-heptamethoxyflavone(HMF)

x N/A þ N/A N/A N/A 114, 115

Hesperidin N/A N/A N/A N/A þþþ N/A 34Apple juice Phloridzin N/A N/A N/A N/A þ N/A 34

Hesperetin N/A N/A N/A N/A þ N/A 34EC N/A N/A x N/A x N/A 25

Green tea EGC N/A N/A þ N/A x N/A 25, 111, 112ECG N/A N/A þ N/A þ N/A 25, 111, 112EGCG þ N/A þ N/A þ N/A 25, 72, 111, 112,

113

aCoincubation effect. bPreincubation effect. X, no effect;þ, weak effect;þþ, moderate effect;þþþ, strong effect; N/A, information unavailable; EC, epicatechin;EGC, epigallocatechin; ECG, epicatechin gallate; EGCG, epigallocatechin gallate.

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cardiovascular disease. The interaction of GFJ withmedications was discovered essentially by accident in1989 from an interaction study between felodipine, adihydropyridine calcium channel blocker, and ethanol inwhich GFJ was used as a flavor supplement to maskthe taste of the ethanol.37 In that study, Bailey andcoworkers observed that felodipine plasma concentrationsdid not differ between the control group and the ethanolcoadministration group, but felodipine exposure in bothgroups was several-fold higher than values reported inthe literature with the same felodipine dose.37 This dis-crepancy led to a subsequent clinical study conducted in6men to evaluate the role ofGFJ on felodipine disposition.The results showed thatGFJ significantly increased theoralbioavailability of felodipine and tripled the felodipine areaunder the concentration–time curve (AUC) compared withwater.4 The data from this study were published in theLancet in 1991 and represent the first reported clinicalfood/beverage–drug interaction.4 Since then, the GFJ–drug interaction has been investigated extensively, andnumerous clinical studies have documented clinicallyrelevant interactions between GFJ and coadministereddrugs.5,7–9,38–40 For example, GFJ enhanced the AUC ofsaquinavir by 220% compared with water.41 GFJ alsosignificantly increased the exposure of simvastatin.9 In 2studies conducted in healthy volunteers, GFJ augmentedthe cyclosporine AUC to 162% and 143% of that withwater.42,43 GFJ also significantly altered terfenadinepharmacokinetics, resulting in prolongation of repolariza-tion on the electrocardiogram.44 Similar interactions havebeen documented for GFJ and nisoldipine,45 nitrendi-pine,46 lovastatin,5 atorvastatin,47 midazolam,11 cisapr-ide,38 and several others.6,39,48 Several similarities werenoticed in these reports. First, in most cases the drugs onwhich GFJ had a significant effect were typically CYP3Asubstrates with a high first-pass metabolism. Second, forthose drugs on which GFJ had a significant effect, GFJ hadminimal impact on their half-life, indicating that theincreased systemic exposure of coadministered drugs wasmainly caused by inhibition on their first-pass metabolism,resulting in the increase in drug bioavailability. Third,clinically significant GFJ interactions were only observedwhen the drugs were administered orally. No interactionwas observed when the same drug was given byintravenous administration. For example, the effect ofGFJ was evaluated on the disposition of felodipine,49

cyclosporine,42 and midazolam11 after both intravenousand oral administration of these drugs. Significantinteractions were observed when these drugs were takenorally; GFJ had no effect on the pharmacokinetics offelodipine, cyclosporine, and midazolam when they weregiven intravenously.These observations indicated thatGFJmight interact with coadministered drugs through inhibi-tion of intestinal CYP3A, resulting in the reduction of gutwall metabolism and an increase in drug bioavailability.

The direct evidence of intestinal CYP3A inhibitionby GFJ was provided by several in vitro and in vivostudies.14,15 For example, Watkins and coworkers eva-luated the effect of repeated GFJ ingestion on CYP3Aexpression in healthy male volunteers.14 In their study,before and after receiving GFJ, small bowel and colonmucosal biopsies were obtained by upper intestinalendoscopy. The protein concentrations of CYP3A andseveral otherCYP isoforms, includingCYP3A5,CYP1A1,and CYP2D6, were measured.14 In addition, liver CYP3Aactivity was measured with the erythromycin breath test ineach subject. Their results showed that GFJ decreasedenterocyte CYP3A protein concentrations in every sub-ject.14 After receiving GFJ for 6 days, the mean enterocyteCYP3A protein concentration decreased 62%.14 Incontrast, GFJ did not alter liver CYP3A activity, whichis in line with the clinical observations that GFJ has noimpact on the systemic clearance of CYP3A substrates. Inaddition, GFJ did not alter colon levels of CYP3A5, orsmall bowel concentrations of CYP1A1 andCYP2D6.14 Inaddition to measuring the expression of these proteins afterrepeated doses of GFJ, the authors also evaluated the acuteeffect of GFJ, and the preliminary data demonstrated thatintestinal CYP3A protein concentration can be greatlyreduced (decreased by 47%)within 4 hours of consumptionof a single glass of GFJ.14 The authors also examined theeffect of GFJ on CYP3AmRNA expression and found thatthe mean enterocyte CYP3A mRNA concentration wasunchanged after 6 days of GFJ intake.14 Based on theobservation of reduced small bowel CYP3A proteinconcentration with unchanged CYP3AmRNA expression,the possible explanation of the GFJ effect was decreasingCYP3A protein content through a posttranscriptionalmechanism, possibly involving acceleratedCYP3Aproteindegradation via irreversible mechanism-based enzymeinhibition.14

As GFJ can markedly decrease the intestinal CYP3Aprotein content, many researchers anticipated that GFJmay have a prolonged inhibitory effect on CYP3Abecause the return of CYP3A activity is dependent on denovo enzyme synthesis. With this hypothesis, severalclinical studies were conducted to evaluate the duration ofactivity of GFJ.50,51 In one study, the relationship betweentime of intake of GFJ and its effect on felodipinepharmacokinetics was evaluated in 9 healthy subjects.51

Consumption of a single glass of GFJ 0, 1, 4, 10, or 24hours before felodipine administration showed that themagnitude of increase in felodipine exposure wasmaximal with consumption of GFJ 0, 1, or 4 hours beforeits administration.51 The magnitude of GFJ effectdeclined gradually with increasing time interval betweenGFJ and felodipine administration. However significantlyhigher felodipine Cmax was still observed, even when GFJwas consumed 24 hours before felodipine.51 In anotherstudy, the duration of GFJ effect was evaluated on

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nisoldipine pharmacokinetics with similar study design.50

In that study, various time intervals of up to 4 days wereevaluated between GFJ and nisoldipine administration.The results showed that the effect of GFJ decreased in atime-dependent manner and lasted for at least 3 days afterintake.50 Therefore, for those drugs with a narrowtherapeutic window and known to interact with GFJand for elderly people, who are less tolerant of fluctuationin drug exposure, GFJ might need to be avoided for 72hours before taking those medications.

In addition to a prolonged effect, another feature ofGFJ–drug interaction is that the magnitude of thepharmacokinetic interaction is highly variable amongindividuals.8,14,52,53 For example,Watkins and coworkersobserved that the magnitude of the increase in felodipineexposure produced by GFJ varied substantially in 10healthy volunteers, with felodipine Cmax ranging from64% to 597% and AUC from 4% to 368%.14 The sameresearch group also found substantial interindividualdifferences in the concentrations and activities of CYP3Ain small bowel enterocytes. A further relationshipbetween CYP3A content and felodipine exposure wasexamined, and the result revealed that subjects with thehighest content of intestinal CYP3A before GFJadministration tended to have the largest fall in CYP3Acontent and the greatest increase in felodipine plasmaconcentration with GFJ coadministration.14 Therefore,the large variability of GFJ effect observed amongindividuals within each clinical study is dependent oninherent differences in baseline intestinal CYP3A proteincontent. In addition to the large variability of GFJ effectamong individuals within the same study, variable resultswere also obtained when the mean GFJ effect wascompared across different clinical studies. Variability inthe concentrations of GFJ constituents across differentstudies may represent an important factor, because thoseconsituents are known to be dependent on a number offactors, including the type and origin of the grapefruitsused, the manufacturing process, and storage conditions.Another possible factor contributing to the variable resultsacross different clinical studies could be the variation instudy design, such as double-strength versus single-strength GFJ administration. It appears that double-strength GFJ can produce a much greater effect thanregular-strength GFJ. For example, Rogers et al. reportedthat the AUC of lovastatin increased 1.94-fold afterconsumption of regular-strength GFJ.54 In contrast,Kantola et al. found that double-strength GFJ increasedthe AUC of lovastatin about 15.3-fold.5 Similarly, theAUC of simvastatin increased in a much more pro-nounced manner in the presence of double-strength GFJ(16-fold)9 than in the presence of regular-strengthGFJ (3.6-fold).55 In addition to the different strengthsof GFJ used, another variation in study design amongdifferent clinical studies is a single glass of GFJ (acute

exposure) versus repeated GFJ ingestion (extendedexposure). The available reports are inconsistent regard-ing whether repeated GFJ ingestion can cause acumulative inhibitory effect. For example, Culm-Merdeket al. reported that acute and extended exposure to GFJincreased the AUC of triazolam by 51% and 60%,respectively, and the difference was not statisticallysignificant.56 Similarly, Lundahl et al. compared the effectof GFJ on felodipine pharmacokinetics after 1 glass ofGFJ or repeated GFJ ingestion for 14 days, and they foundthat the interaction effect of GFJ was maximal after thefirst glass.57 On the other hand, Lown et al. found that theAUC of felodipine increased about 2.2-fold after the first8-oz glass of GFJ, but 3.1-fold after 5 days of thrice-dailyadministration of GFJ.14 Further investigations areneeded to have a better understanding of whether GFJhas a cumulative CYP3A inhibitory effect.

In addition to the variations described above, there is adifference between the theoretically predicted risk andclinically relevant and well-documented GFJ–druginteractions. The literature provides generalized theoreti-cally predicted information on different classes of drug–GFJ interactions,58 which may mislead readers to avoidcoadministration of GFJ and drugs whose interactions arenegligible and/or clinically unimportant such as quini-dine, oxycodone, nilotinib, and sunitinib.59

Numerous studies have been conducted to evaluate theCYP3A-mediated GFJ–drug interactions. Detailed lists ofevaluated drugs, including both affected and unaffectedones, have been summarized in a number of excellentreview articles.12,29 In addition, the research center at theUniversity of Florida, Food Drug Interaction Research &Education (http://www.DrugInteractionCenter.org), pro-vides an up-to-date list of drugs that have been evaluated,including the interaction magnitude and sources ofrelevant scientific literature to support clinically docu-mented GFJ interactions.

It should be noted that in addition to the magnitude ofthe increase in the exposure of coadministered drugs,additional factors such as the severity of toxicities of theaffected drug need to be considered as well. For thosedrugs with narrow therapeutic windows and that undergofirst-pass metabolism through intestinal CYP3A, GFJshould be avoided even if the magnitude of interaction onthe pharmacokinetic side is minimal or mild. Several casereports documented drug toxicity that was possiblycaused by a large amount and long-term consumptionof GFJ or grapefruit. For example, Peynaud et al. reportednephrotoxicity of tacrolimus after consumption of a largeamount of marmalade that contained grapefruit (1.5 kgeaten during the preceding 1 week).60 Goldbart et al.reported myelotoxicity of colchicine after consumption ofjuice 1 L/day for the preceding 2 months.61 The limitationof the case reports is that the patients took multiple drugstogether, and there is no information available regarding

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the concentration of the drugwith toxicity. As a result, it isdifficult to conclude that the drug toxicity was trulycaused by the pharmacokinetic interaction between thatdrug and GFJ. For example, Karch reported rhabdomyol-ysis of atorvastatin, and GFJ was anticipated to be theculprit because the patient drank 2–3 glasses of GFJ(extracted from fresh fruit) daily for 2 months.62

However, the concentration of atorvastatin was notmeasured in this case report. On the other hand, resultsfrom a controlled study conducted in 130 patients showedthat there is no clinically significant interaction followingconcomitant administration of atorvastatin and a moder-ate amount of GFJ (300mL daily) for 90 days.47

Other Fruit JuicesAfter the CYP3A-mediated GFJ–drug interaction wasrecognized, the effect of other fruit juices on thedisposition of CYP3A substrates was evaluated in severalclinical studies.31 The interaction between orange juiceand felodipine was evaluated in healthy volunteers, andthe results revealed that orange juice does not affect thepharmacokinetics of felodipine.4 Similarly, results fromanother clinical study showed that apple juice did notsignificantly affect the pharmacokinetics of midazolam,indicating no effect on CYP3A in humans.16 On the otherhand, juice from pomelo grapefruit (Citrus paradisiMacf., G) has been reported to increase the oralbioavailability of felodipine.63 In addition, Seville(sour) orange juice was found to increase the felodipineAUC to the same extent observed with GFJ.64 Asignificant increase in dextromethorphan exposure withSeville (sour) orange juice has also been reported.65 Invitro mechanistic studies indicated that Seville (sour)orange juice decreased intestinal CYP3A protein concen-tration and therefore might inhibit CYP3A by the samemechanism as GFJ.66 Regarding CYP3A-mediated fruitjuice–drug interaction, although both lime juice andblueberry juice demonstrated an inhibitory effect onCYP3A activity in vitro,67,68 both of them showednegative results in vivo when they were evaluated withfelodipine and buspirone, respectively, in 2 independentclinical studies.67,68 However, it should be noted that thelime juice evaluated in vivo was a diluted one (one-quarter strength), and although mean felodipine exposurewas not changed in the presence of dilute lime juice, themagnitude of felodipine increase was correlated with thatobserved with grapefruit juice among individuals(r2¼ 0.95).68 In addition, Kim et al69 evaluated theeffects of various fruit juices on the activity of midazolam10-hydroxylase, a marker of CYP3A, in pooled humanliver microsomes. Their results demonstrated that blackmulberry juice showed the most potent inhibition ofCYP3A (except for grapefruit juice). The inhibitorypotential on human CYP3A was in order GFJ > blackmulberry juice>wild grape juice> pomegranate juice>

black raspberry juice.69 Whether their CYP3A inhibitoryeffect is clinically relevant warrants further in vivoinvestigation.

Green TeaMade from the leaves of Camellia sinensis, green tea isthemost widely consumed beverage in theworld. It can befound in almost 80% of all US households.28 There areseveral types of tea based on the difference in variousdegrees of processing and the level of oxidization. Greentea is not oxidized after leaf harvesting, so it most closelyresemble the chemical composition of the fresh tea leaf.Green tea has become the rawmaterial for extracts used invarious beverages, health foods, and dietary supplements.The effect of green tea on CYP3A activity has beeninvestigated in both in vitro and in vivo studies.70–73

Misakaet al evaluated the effect of green tea extract (GTE)on the activity of CYP3A in vitro using pooled humanintestinal and liver microsomes.71 A noncompetitiveinhibitory effect of GTE on CYP3A was observed, withIC50 of 18.4mg/mL in human intestinal microsomes and13.8mg/mL in human liver microsomes.71 In anotherstudy, GTE from various manufacturers was compared interms of the effect on CYP3A.70 An in vitro study wasconducted in human liver microsomes using quinine asthe CYP3A probe drug. The results showed that the GTEinhibited CYP3A, with the inhibition ranging from 5.6%with Nature’s Resource to 89.9% with Natrol GTE.70 Theeffect on CYP3A varied among different brands of GTE,possibly because of variations in the content of the herbalproduct’s active ingredients. In addition to in vitrostudies, CYP3A-mediated green tea–drug interaction hasalso been evaluated in animal studies.72 For example,following a single oral dose of GTE (400mg/kg) in rats,simvastatin AUC increased 3.4-fold compared with thatin the simvastatin alone group.72 It is worth pointing outthat the GTE–simvastatin interaction observed in rats maynot be easily translated into human because, in general, ratsare not considered as appropriate animalmodels for humanCYP3A4 predictions.74 It has been reported that theinhibition and induction of themajor rat CYP3A isoform inliver (CYP3A1) do not resemble human CYP3A4. So far,no clinically significant interaction between green tea andCYP3A substrates has been observed in clinical studies.For example, 4 weeks of green tea catechin interventiononly resulted in a 20% increase in buspirone exposure,suggesting a small reduction in CYP3A activity.73 Overallthe clinical data on CYP3A-mediated green tea–druginteraction is quite limited.Whether the inhibitory effect ofgreen tea on CYP3A is clinically relevant warrants furtherinvestigation.

Candidate Constituents for CYP3A InhibitionIn addition to vitamin C and potassium, the majorconstituents in GFJ are the flavonoids, with naringin the

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most abundant. Naringin is responsible for the bitter tasteof GFJ and has been found to be present in GFJ atconcentrations up to 1200mg/mL.75 In addition tonaringin, other flavonoids, such as quercetin andkaempferol, are also present in GFJ in trace amounts.Although naringin is prevalent in GFJ, it is absent fromorange juice. As orange juice does not affect CYP3A,people initially suspected that naringin might be theingredient in GFJ causing CYP3A inhibition. However,commercially available pure naringin administered in thesame amount as found inGFJ produced little change in thepharmacokinetics of nisoldipine or felodipine, indicatingthat naringin is not the main contributor to CYP3A-mediated GFJ–drug interactions.45,76 Quercetin, anotherflavonoid present in GFJ and many other juices, wasfound to have an inhibitory effect on CYP3A in vitro.77

However, a clinical study conducted in 8 healthyvolunteers showed that after an oral dose of 400mgquercetin, nifedipine exposure was not changed, indicat-ing that quercetin may not be responsible for interactionsas well.78 As flavonoids present in GFJ failed to explainthe in vivo CYP3A-mediated GFJ–drug interaction,further investigation was conducted to evaluate otherconstituents of GFJ. In addition to flavonoids, GFJ alsocontains furanocoumarins, including 60,70-dihydroxyber-gamottin and bergamottin. The effect of 60,70-dihydrox-ybergamottin on CYP3A has been evaluated in several invitro studies.15,79 Edwards et al. found that 60,70-dihydroxybergamottin has a potent inhibitory effect onCYP3A, and the addition of 60,70-dihydroxybergamottinto orange juice decreased CYP3A activity to valuescomparable to those observed with GFJ.79 Studiesconducted by Watkins and coworkers using recombinantCYP3A revealed that 60,70-dihydroxybergamottin is amechanism-based inhibitor and caused time- and concen-tration-dependent inactivation of CYP3A.15 This findingsupports the idea that loss of intestinal CYP3A producedby GFJ in vivo may result from accelerated degradationof the enzyme. Based on these in vitro investigations,60,70-dihydroxybergamottin is considered an activeingredient in GFJ on CYP3A inhibition. In addition to60,70-dihydroxybergamottin, bergamottin, another majorfuranocoumarin present in GFJ, was also evaluatedclinically, and the data indicated that bergamottin wasalso active.80–82 In addition to 60,70-dihydroxybergamot-tin and bergamottin, dimers of the furanocoumarins, alsoknown as paradisins, have also demonstrated a potentCYP3A inhibitory effect in several in vitro studies.83,84

To confirm whether furanocoumarins are the maincontributors of the in vivo CYP3A-mediated GFJ–druginteractions, several studies compared the effect ofmodified GFJ (furanocoumarins were removed) withthe original GFJ. The results showed that furanocou-marin-free GFJ failed to alter the disposition of felodipineand cyclosporine, 2 drugs known to interact with

unmodified GFJ.85,86 With the role of furanocoumarinsin CYP3A-mediated GFJ–drug interactions confirmed,efforts have been taken recently to remove furanocou-marins from GFJ based on the chemical, physical, andgenetic approaches.85,87,88 For example, it has beenreported that furanocoumarins can be removed bychemical extraction and reconstitution,85 degraded byheat,87 or inactivated by ultraviolet radiation (Figure 1).88

In addition, Gmitter and coworkers used geneticmodification to develop GFJ cultivars with low or freeof furanocoumarins (Figure 2).89

Other than GFJ, only a few other fruit juices, such asSeville (sour) orange juice and pomelo grapefruit juicehave been reported to have significant in vivo interactionwith CYP3A substrates. Similar to GFJ, Seville (sour)orange juice and pomelo grapefruit juice also containfuranocoumarins.63,64 Therefore, furanocoumarins maybe the active ingredients in Seville (sour) orange juice andpomelo grapefruit juice responsible for the observed invivo interactions.

P-gp-Mediated Beverage–DrugInteractionP-glycoprotein (P-gp) is one of the most importantmembers of the ATP-binding cassette transporter super-family, and it has been extensively studied since it wasdiscovered by Ling and coworkers in 1976.90,91 P-gp wasinitially discovered in cancer cells and represents animportant mechanism of multidrug resistance.92 Furtherinvestigation on localization of P-gp revealed that P-gp isnot confined to tumor cells; it is also expressed in a numberof normal human tissues, including intestine, liver,kidneys, and brain and has been found to play a pivotalrole in drug absorption, distribution, and elimination.93,94

Various clinically important compounds, including anti-cancer drugs, HIVprotease inhibitors, immunosuppressiveagents, H2-receptor antagonists, and antibiotics, havebeen reported to be substrates of P-gp.94 Similar toCYP3A, P-gp is also highly expressed in the enterocytes ofthe intestine and hepatocytes of the liver, where it activelypumps various xenobiotics back into the gastrointestinaltract, thereby preventing absorption into systemic circula-tion. CYP3A and P-gp have been found to have substantialoverlap in substrates and modulators and are believed toplay a concerted role in drug disposition.95,96 Theinvestigation of the interplay between intestinal CYP3Aand P-gp remains an active area of research.

Grapefruit JuiceBecause many CYP3A modulators are also found to haveamodulatory effect on P-gp, the potent inhibitory effect ofGFJ on intestinal CYP3A led many research groups toevaluate the effect of GFJ on P-gp.97–102 Takanaga et al.investigated the effect of GFJ extracts on the transport of

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vinblastine, a well-known P-gp substrate, across Caco-2cells. They observed enhanced uptake and apical-to-basolateral transport of vinblastine in the presence of GFJextracts, indicating an inhibitory role of GFJ on P-gp.98

Similarly, Butterweck and coworkers reported that thebasolateral-to-apical directional transport of talinolol, anonmetabolized P-gp substrate, was selectively inhibitedbyGFJ and its components.100 Benet’s group, on the otherhand, reported contradictory findings when they evaluat-ed the effect of GFJ with a range of concentrations(0.05%, 0.5%, and 5%) on the transport of vinblastine

across MDCK/MDR cell monolayers.99 They observed asignificant increase in the basolateral-to-apical transportof vinblastine in the presence of GFJ, indicating a possiblestimulation role of GFJ on P-gp.99 In addition, theyfound that GFJ activated the efflux of vinblastinein a concentration-dependent manner. Interestingly,Mitsunaga et al. found mixed results in a study evaluatingthe effect of citrus bioflavonoids on vincristine transportacross MBEC4 (mouse brain capillary endothelial)cells.103 In the concentration range of 10–50mM,quercetin and kaempferol (both present in GFJ) showed

Figure 1. (A) Nifedipine plasma concentration–time curves after intraduodenal administration of nifedipine 30 minutes after preadministered saline,GFJ, and 6-hour ultraviolet-irradiatedGFJ. (B) Concentration of bergamottin and 60,70-dihydroxybergamottin (6,7-DHB) inGFJ after 6-hour ultravioletirradiation. A and B adapted from Uesawa Y, Mohri K. Biol Pharm Bull, 2006;29:1286–1289.

Figure 2. Concentration of 6,7-DHB, bergamottin, and paradisin C in the diploid hybrids. The 3 furanocoumarins (FCs) in half of them wereundetectable or extremely low. This figure is adapted from Chen C et al. J. Amer Soc Hort Sci. 2011;136:358–363.

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concentration-dependent biphasic modulation of vincris-tine uptake by activating P-gp at low concentrations(10mM) and inhibiting P-gp at high concentrations(50mM).103 A potential explanation for these disparateresults is that different research groups used differentexperimental conditions. The concentrations of GFJtested in Benet’s group were low, and the stimulatoryeffect of GFJ on P-gp observed at those low GFJconcentrations appears to be in line with the phenomenonof biphasic modulation of flavonoids on P-gp reported byMitsunaga et al.103 In addition to P-gp activity, the effectof GFJ on P-gp expression was also investigated byseveral research groups, and conflicting results wereobtained, ranging from decreasing P-gp level to no effect,to increasing P-gp level.14,104,105 For example, Watkinsand coworkers found that consumption of GFJ for 6 daysdid not affect intestinal P-gp protein content in 10 healthyvolunteers.14 Romiti et al. evaluated the effect of GFJ onthe expression of P-gp in human tubular cell line HK-2,and they observed a dose-dependent decrease in both P-gpprotein level and mRNA level in the presence of GFJ.104

However, Panchagnula et al. found that chronic adminis-tration of GFJ led to increased levels of P-gp expression inrat everted ileum sac.105 It should be noted that amongabove 3 studies, only Watkins’s group evaluated the invivo effect of GFJ on intestinal P-gp expression inhumans, and the remaining 2 studies were performedeither in vitro in a kidney cell line or in vivo in rat. Inaddition to in vitro investigations, several preclinical andclinical studies were conducted to evaluate the effect ofGFJ on the disposition of drugs that are P-gp substrateswith minimal CYP3A-mediated metabolism.101,106,107

One clinical study investigated the interaction betweenGFJ and digoxin, a well-known P-gp substrate undergo-ing little metabolism. The results demonstrated that GFJdid not alter the bioavailability of digoxin.106 However, asdigoxin has high oral bioavailability (70%–80%),whether it is an appropriate P-gp probe drug to beevaluated in vivo is questionable. Another study evaluat-ed the effect of GFJ on the disposition of talinolol in rats,another nonmetabolized P-gp substrate, and found that inthe presence of GFJ, the exposure of talinolol wasdoubled.107 The clinical significance of P-gp-mediatedGFJ–drug interactions remains to be elucidated.

Other Fruit JuicesIn addition to GFJ, the effect of several other fruit juiceson P-gp has also been investigated. For example, althoughorange juice does not affect CYP3A activity or expres-sion, a 50% ethyl acetate extract of orange juicewas foundto significantly decrease the efflux ratio of vinblastine andsaquinavir in Caco-2 cells, indicating an inhibitory effectof orange juice extract on P-gp.108 Seville (sour) orangejuice has been suggested to selectively inhibit intestinalCYP3A without affecting P-gp based on the observations

that it increases the exposure of felodipine but not that ofcyclosporine.66 Xu et al. evaluated the effects of severalcitrus fruit juices on the transport of digoxin in Caco-2 cellmonolayers and showed that the apical-to-basolateraldigoxin efflux was enhanced 50% by fruit juice in theorder of lemon juice > lime juice > pomelo juice >GFJ.109 Most investigations of P-gp-mediated interactionbetween drugs and fruit juices (other than GFJ) have beenmainly conducted in vitro. Thus, the in vivo effect of fruitjuices on P-gp remains unclear and warrants furtherevaluation.

Green TeaThe modulatory effects of green tea catechins on P-gphave been observed in many independent studies.27,110–112 For example, Qian et al. evaluated the effect ofepigallocatechin gallate (EGCG), the most abundantcatechin in green tea, on P-gp activity.112 A 3-dimensional model of the carboxyl-terminal nucleotide-binding domain (NBD2) form of P-gp was built byhomology modeling. The structural model of the complexindicated that EGCG was tightly bound to the ATP-binding site of NBD2. In addition, results of the in vitrouptake study showed that EGCG inhibited P-gp andincreased the intracellular accumulation of doxorubicin indrug-resistant KB-A1 cells.112 The authors also con-ducted an in vivo study using nude mice bearingdoxorubicin-resistant P388 leukemia and found thatEGCG could enhance the efficacy of doxorubicin andincreased the doxorubicin concentration in the resistanttumors.112 Jodoin et al. reported that green tea catechins,at the concentration of 30mg/mL, inhibited the photo-labeling of P-gp by 75% and increased by 3-fold theaccumulation of rhodamine-123 in themultidrug-resistantCHRC5 cell line.111 Moreover, the modulation of P-gptransport by green tea catechins was found to be areversible process. Among the catechins tested, EGCG,epicatechin gallate (ECG), and catechin gallate were allfound to have inhibitory effects on P-gp.111 Similarly,another study evaluated the effects of individual green teacatechins and found that several catechins inhibit P-gp,with a potency rank order of EGCG> ECG> EGC.110 Incontrast, epicatechin (EC) did not have any effect on P-gp.Although the inhibitory effect of green tea catechins on P-gp has been demonstrated in several in vitro and in vivoanimal studies, the clinical relevance of the interactionbetween green tea catechins and P-gp substrates isunknown and remains to be elucidated.

Candidate Constituents for P-gp InhibitionIn addition to fruit juices or fruit juice extract, theindividual constituents have also been studied to identifythe candidate active ingredients for P-gp modulation.113

Naringin is a major constituent in GFJ that has beenreported to reduce the apical efflux of vinblastine at the

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concentration present in GFJ and increase steady-stateuptake from the apical side to 124%.98 However, theeffect of naringin is modest and may not account forthe effect observed with GFJ. Bergamottin and 60,70-dihydroxybergamottin, the major furanocoumarins pres-ent in GFJ, have also been evaluated, and both ingredientswere found to decrease the efflux ratio of vinblastine andsaquinavir in bidirectional transport studies conducted inCaco-2 cell monolayers, indicating an inhibitory effecton P-gp.108 In addition, quercetin and kaempferol, bothpresent in GFJ, were found to have a biphasic effect onP-gp in vitro, and both function as stimulators at lowconcentrations and inhibitors at high concentrations.103

On the other hand, Kim et al. evaluated the in vivo effectof quercetin on the pharmacokinetics of fexofenadine inhealthy volunteers, and they found that short-term use ofquercetin elevated the plasma concentrations of fexofe-nadine (60% increase in fexofenadine AUC), probably bythe inhibition of P-gp-mediated efflux in humans.114 Inaddition to constituents of GFJ, components from orangejuice have also been evaluated regarding their modulatoryeffect on P-gp. The polymethoxylated flavones in orangejuice, including 3,30,40,5,6,7,8,-heptamethoxyflavone(HMF), 40,5,6,7,8,-pentamethoxyflavone (tangeretin),and 30,40,5,6,7,8,-hexamethoxyflavone (nobiletin) werefound to increase the steady-state uptake of vinblastine inCaco-2 cells in a concentration-dependentmanner.115 Theorder of potency of these compounds on P-gp inhibition ata concentration of 50mM was tangeretin > HMF >nobiletin.115 Butterweck and coworkers also evaluatedthe effect of polymethoxylated flavones from citrus onP-gp using talinolol as a probe substrate. They foundthat polymethoxylated flavones significantly decreasedtalinolol transport from the basolateral to the apical side,with tangeretin being the most potent, followed bynobiletin, HMF, and sinensetin.102 In contrast, none ofthese polymethoxylated flavones inhibited CYP3A.115 Inaddition, it has been reported that the P-gp inhibitoryeffect of GFJ components, including bergamottin and60,70-dihydroxybergamottin, were considerably weakerthan those polymethoxylated flavones in orange juice.113

Regarding green tea, the information related to itscandidate active ingredients on Pgp is discussed in theGreen Tea section above.

OATP-Mediated Beverage–DrugInteractionOATPs belong to the family of membrane solute carrier(SLC) transporters and have been found to facilitate thesodium-independent influx of both endogenous andexogenous compounds.116,117 Opposite to the functionof P-gp and other efflux transporters, which pump thedrugs out of cells, OATPs facilitate the translocation ofdrugs into cells and therefore are considered uptake

transporters.116 OATPs are encoded by solute carrierorganic anion-transporting (SLCO) genes and up to now11 humanOATP transporters have been identified, amongwhich OATP1A2, OATP1B1, OATP1B3, and OATP2B1have been well characterized.118 These 4 OATPs haveconsiderable overlap in their substrate spectrum, and theytransport various compounds from different classes,including angiotensin II receptor blockers, angiotensin-converting enzyme inhibitors, antihistamines, statins,antibiotics, and beta-adrenergic blocking agents.117,119–121 Although both lipid-soluble drugs and water-solubledrugs can be transported by OATPs, intestinal OATPsusually play a bigger role in the absorption of hydrophilicdrugs than do lipophilic drugs, as the latter can alsoundergo other pathways (such as passive diffusion) forabsorption and consequently will not be influenced asdramatically as the hydrophilic drugs when the intestinalOATPs are inhibited. The expression of OATP1B1 andOATP1B3 is confined to the liver, and these 2 transportershave been reported to play an important role in hepaticuptake of xenobiotics across the sinusoidal membranefrom blood.120–123 In contrast to the tissue-specificexpression of OATP1B1 and OATP1B3, OATP2B1 islocalized in several tissues, including liver, smallintestine, spleen, and placenta.118,124–126 OATP2B1 isexpressed in significant amounts on the apical membraneof small intestinal epithelial cells,126,127 thereby facilitat-ing the transfer of its substrates from the intestine to thebloodstream. Similar to OATP2B1, OATP1A2 is alsoexpressed in several tissues, including brain, testis, andprostate.120,128 The function of OATP1A2 in the intestinehas been debated in the literature because of thecontroversial reports on its expression in the intestine.127

Some studies reported no OATP1A2 detection, whereasother groups identified relatively low SLCO1A2 mRNAexpression in the intestine.118,127

Grapefruit JuiceThe modulatory effect of GFJ on OATPs was discoveredunexpectedly from several clinical studies in which theoriginal aim was to evaluate the role of GFJ in thedisposition of drugs that are substrates of P-gp. As GFJhas demonstrated the inhibitory effect on P-gp in many invitro studies, several research groups conducted furtherclinical studies to test the hypothesis that GFJ wouldenhance the oral bioavailability of nonmetabolized P-gpsubstrates in vivo. However, 2 independent clinicalstudies, one conducted by Parker et al. and another byBecquemont et al., showed that in the presence of GFJ, thechange in the pharmacokinetics of digoxin, a P-gpsubstrate undergoing minimal metabolism, was rathermodest.106,129 One potential explanation for this negativeresult is the intrinsically high oral bioavailability ofdigoxin, which makes the interpretation difficult. Thisstimulated a search for more suitable P-gp probe drugs to

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have better evaluation of P-gp-mediated GFJ–druginteractions. Fexofenadine, an antihistamine drug, andceliprolol, a selective b1-adrenergic receptor-blockingagent, were considered suitable P-gp probe drugs. Bothdrugs are substrates of P-gp, and their metabolism isnegligible in humans, meaning that the GFJ effect onCYP3A would not confound the results. In addition, P-gpinhibitors (eg, itraconazole, ritonavir) have been reportedto increase the exposures of fexofenadine and celiprolol,suggesting that P-gp plays an important role in theirabsorption.18,130–132 More importantly, both compoundshave relatively low bioavailability (�30%), which meansthat the interaction would not be masked if GFJ trulyaffects P-gp. However, when the effect of GFJ on thedisposition of fexofenadine and celiprolol were evaluatedseparately in healthy volunteers by 2 independentresearch groups (one by Lilja et al. and another byDresser et al),18,19 similar results were obtained: oppositeto what they expected, that the exposure of these 2 drugswould increase with GFJ ingestion, the exposures of bothfexofenadine and celiprolol were significantly decreased.Dresser et al. found that the AUC and Cmax offexofenadine in the GFJ coingestion group were reducedto about to 33% and 38%, respectively, of the valuesobtained in the control group.19 Similarly, Lilja et al.reported that during the GFJ phase, the AUC and Cmax ofceliprolol were substantially reduced to about 13% and5%, respectively, of the respective placebo phasevalues.18 Consistent with these observations, GFJ waslater found by Schwrz et al. to also be able to decrease theplasma concentrations of talinolol.133 As these phenome-na cannot be explained by the known inhibitory effect ofGFJ on P-gp (or CYP3A), the researchers conductingthese studies anticipated that these interactions might bemediated by a novel and potentially clinically importantmechanism. Further investigations revealed that thesecompounds are substrates of OATPs, an uptake trans-porter family that can enhance the bioavailability ofsubstrate compounds through facilitating their uptakefrom the intestine. Among the OATP members, initiallyOATP1A2 was proposed by Kim and coworkers as thekey intestinal uptake transporter for the GFJ–fexofena-dine interaction.19,134 They screened OATP uptaketransporters and found that only OATP1A2 can effective-ly transport fexofenadine.134 The same research groupalso examined the expression of a panel of uptaketransporters using human duodenal biopsy samples anddetected the mRNA expression of OATP1A2. Recently,Nozawa et al. reported that fexofenadine, along withseveral other drugs, is transported by OATP2B1 at bothneutral and acidic pH.135 The role of OATP2B1 infexofenadine absorption was further confirmed by an invivo clinical study. It has been reported that there is asingle nucleotide polymorphism in human OATP2B1,which causes a change in function (c.1457C>T,

S486F),136 Imanaga et al. investigated the effect of theSLCO2B1 c.1457C>T polymorphism on fexofenadinepharmacokinetics and found that when fexofenadine wasadministered with water, subjects with the c[1457C>T]allele showed a significant decrease in fexofenadine AUCwith no change in half-life, indicating an important role ofOATP2B1 in fexofenadine absorption.16 Considering thehigh expression of OATP2B1 in the intestine and itsimportant role in the uptake of fexofenadine and otherOATP substrates, OATP2B1 may play a bigger role thanOATP1A2 in OATP-mediated GFJ–drug interactions.The contribution of OATP1A2 to in vivoOATP-mediatedGFJ–drug interactions warrants further investigation.

Interactions between GFJ and CYP3A substrates areknown to occur via irreversible mechanism-basedinhibition, leading to a prolonged effect of GFJ onCYP3A inhibition.14,15 Regarding duration of activity ofGFJ on OATP, Kim and colleagues reported thatconsumption of GFJ concomitantly or 2 hours beforefexofenadine administration was associated with reducedoral fexofenadine plasma concentrations, whereas fex-ofenadine exposure was not affected when GFJ was taken4 hours before drug administration.134 Recently, Tanakaet al. compared the inhibitory duration of GFJ onceliprolol (an OATP substrate) and midazolam (aCYP3A substrate) in healthy volunteers, and their resultsalso indicated that GFJ inhibition on OATP appears todissipate over a shorter period than has been observedwith CYP3A inhibition.137 In addition to the inhibitoryduration of GFJ on OATP, the effect of GFJ volume onOATP inhibition was also evaluated.138 Bailey andcoworkers conducted a randomized 4-way crossoverstudy in which GFJ or water at normal (300-mL) or high(1200-mL) volume was ingested concomitantly with120mg fexofenadine in 12 healthy volunteers.138 Theirresults revealed that the 300- and 1200-mL volumes ofGFJ diminished the mean exposure of fexofenadine to58% and 36%, respectively, of those observed withequivalent volumes of water.138 As a 4-fold higher GFJvolume only reduced fexofenadine AUC moderatelymore, a commonly consumed volume (300mL) of GFJappeared to be near the upper portion of the volume–response curve and already produced a clinicallysignificant magnitude of OATP inhibition. To date,many clinical studies have been carried out to evaluateOATP-mediated GFJ–drug interactions. Lists of evaluat-ed drugs, including both affected and unaffected ones,have been summarized in a number of excellent reviewarticles.20,21

Other Fruit JuicesIn contrast to CYP3A-mediated fruit juice–drug inter-actions, in which orange juice and apple juice do not showin vivo CYP3A inhibitory effects, clinically significantOATP-mediated fruit juice–drug interactions were

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observed not only with GFJ, but also with orange juiceand apple juice (Figure 3).16,19 Dresser et al. examined theeffect of GFJ, orange juice, and apple juice on thedisposition of fexofenadine in healthy volunteers, andtheir results revealed that all these 3 fruit juices markedlydecreased fexofenadine exposure, with the reduction inplasma concentration of fexofenadine being the largest inthe case of coadministration with apple juice, followed byorange juice and GFJ.19 This indicated that apple juice hasa more potent in vivo inhibitory effect on OATP2B1 thando orange juice and GFJ. Tamai and coworkers recentlyconducted an in vitro uptake study in Xenopus oocytesexpressing OATP2B1 and evaluated the inhibitory effectof GFJ, orange juice, and apple juice on the uptake ofestrone-3-sulfate, a typical OATP2B1 probe drug.34 Theyfound that coincubation with apple juice had a weakerinhibitory effect on OATP2B1, with the inhibitionpotency order of GFJ > orange juice > apple juice.34

The same trend was also obtained by another researchgroup using estrone-3-sulfate and glibenclamide asOATP2B1 probe drugs.17 Because there is an in vitroand in vivo disconnect regarding the potency of differentfruit juices on OATP2B1 inhibition, further investigationwas conducted. A recent in vitro study evaluated thecoincubation effect as before, but also evaluated the effectof preincubation with fruit juices, including GFJ, orangejuice, and apple juice, on OATP2B1-mediated drug

transport.33 The results showed that when OATP2B1-expressing Xenopus oocytes were preincubated for 15minutes with different fruit juices, apple juice induced aremarkable decrease in OATP-mediated uptake ofestrone-3-sulfate and fexofenadine. A similar but lesspotent effect was observed with orange juice, whereasGFJ did not exhibit the preincubation effect.33 Apple juicehad the most potent preincubation effect at 15 minutes,and its inhibitory action lasted for at least 240 minutes.33

Because the order of potency of preincubation effect onOATP2B1 among these 3 fruit juices is consistent withthe order of potency of the OATP2B1 inhibitory effectobserved in vivo, the preincubation effect may play abigger role than the coincubation effect for apple juice andorange juice for interactions with OATP2B1. In addition,the in vitro observation that GFJ has no preincubationeffect is consistent with the clinical phenomenon that GFJinhibition on OATP dissipates over a shorter period.Based on the long-lasting inhibitory effect of apple juiceand orange juice on OATP2B1 observed in vitro, it isreasonable to speculate that these 2 fruit juices may have aprolonged effect on OATP2B1-mediated drug absorptionin humans. Recently, Akamine et al. evaluated the effectof onetime apple juice ingestion on fexofenadinepharmacokinetics in healthy subjects, and they foundthat onetime ingestion of apple juice significantlydecreased the AUC for (R)- and (S)-fexofenadine by

Figure 3. Schematic representation of clinically relevant enzyme- and transporter-mediated beverage–drug interaction. The left column representsintestinal metabolism of a drug that undergoes extensive first-pass metabolism by enteric CYP3A in (A) the absence and (B) the presence of grapefruitjuice (GFJ); the right column represents intestinal influx transport of a nonmetabolized OATP substrate in (C) the absence and (D) the presence ofbeverages (GFJ, orange juice [OJ], apple juice [AJ], and green tea [GT]).

An et al 11

49% and 59%, respectively.139 This suggests that theOATP2B1 inhibition effect does not require repeatedingestion or a large volume of apple juice. Therelationship between time of intake of apple and orangejuices and their effect on OATP2B1-mediated drugdisposition has not yet been evaluated in vivo. In addition,the exact mechanism of the preincubation effect of appleand orange juices on OATP2B1 remains unclear andrepresents another interesting topic that warrants furtherinvestigation.

In addition to fexofenadine, apple juice and orangejuice have also been reported to substantially reduce thesystemic exposures of many other OATP2B1sub-strates.22–24 For example, orange juice and apple juicemarkedly reduced aliskiren peak plasma concentrationsby 80% and 85%, respectively, and aliskiren AUC by62% and 65%, respectively, in 12 healthy volunteers;there was no effect on aliskiren elimination half-life orrenal clearance.22 Jeon et al. reported that apple juicegreatly reduced atenolol exposures in healthy volunteers,and the effect was volume dependent: the 600- and 1200-mL volumes of apple juice diminished atenolol AUC to42.0% and 18.5%, respectively, of that observed withwater.24 In 1 clinical study that was conducted to evaluatethe effect of orange juice on celiprolol disposition,celiprolol Cmax and AUC were decreased by 89% and83%, respectively, when celiprolol was taken togetherwith orange juice.23

Although GFJ, orange juice, and apple juice adminis-tration has significantly reduced the systemic exposure ofmany OATP substrates, including fexofenadine, talinolol,celiprolol,18,23 and atenolol,24 an effect was not shown forseveral other drugs known to be transported by OATP.For example, GFJ did not affect the disposition ofpravastatin and pitavastatin, although both are substratesof OATP2B1.7,140–142 One explanation for these negativeinteractions is that OATP may not play a major role intheir absorption. Another possible explanation is that theeffect of fruit juices on OATP is substrate- and inhibitordependent. One potential mechanism for this substrate-and modulator-specific effect is the presence of multiplebinding sites in the OATP2B1 protein that show distinctfunctionality.35,119 Tamai and colleagues found thatOATP2B1 showed biphasic kinetics with high-affinityand low-affinity sites in transporting estrone-3-sulfate,and the uptake was pH dependent.35 The Km values were0.1 and 29.9mM, and the Vmax values were 14.1 and 995fmol/min per oocyte for the high-affinity and low-affinitysites, respectively.35 They also evaluated the effect of 12compounds on estrone-3-sulfate uptake, and the resultsrevealed that 4 compounds were inhibitors for bothaffinity sites, 4 compounds only inhibited the high-affinitysite, 2 compounds only inhibited the low-affinity site, and2 compounds had no effect on either site.35 Theseresults indicated that there are at least 2 active sites on

OATP2B1 that differ in substrate and inhibitor selectivity.Accordingly, the OATP2B1-mediated fruit juice–druginteraction would occur only when fruit juices and drugsshare the samebinding site onOATP2B1.Further evidencesupporting the multiple-binding-site hypothesis wasprovided byTamai’s group.36 In their study, they evaluatedGFJ–drug interactions using OATP2B1-expressing Xen-opus oocytes with 2 model drugs: fexofenadine, whichinteracts clinically with GFJ, and pravastatin, which doesnot. Both pravastatin and fexofenadine exhibited biphasicsaturation kinetics, indicating the presence of multiplebinding sites on OATP2B1.36 In addition, their resultsshowed that GFJ strongly inhibited fexofenadine uptakemediated by the low-affinity site, but not pravastatin uptakeby the low-affinity site. On the other hand, the uptake ofpravastatin but not fexofenadine at the high-affinity sitewas strongly inhibited byGFJ.36 As both fexofenadine andpravastatin at clinically relevant concentrations are mainlytransported via the low-affinity site on OATP2B1, onlyfexofenadine is likely to interact with GFJ onOATP2B1 attherapeutic concentrations. These data further support theconcept of substrate dependence in OATP2B1-mediatedfruit juice–drug interactions. This is important because thepresence of multiple binding sites on OATP2B1 may atleast partly explain observed differences in interactionsbased on binding-site affinities for substrate compounds.Regarding the effect of orange juice on OATP, anotherpotential mechanism is the pH-lowering effect of orangejuice. The uptake of OATP2B1 has been reported to be pHdependent. Kobayashi et al. reported that uptake of [3H]estrone-3-sulfate and [14C]pravastatin by OATP2B1 at pH5.5 was significantly higher than that at pH 7.4.126

Koitabashi reported that orange juice increased thebioavailability of pravastatin in both rats and healthyhuman subjects.143 This may be because of the pH-lowering effect of orange juice, which subsequentlyincreased OATP-mediated uptake of pravastatin.

Green TeaThe interaction between green tea catechins and OATPshas also been investigated.25 Roth et al. measured theuptake of the model substrate estrone-3-sulfate by cellsexpressing OATP1A2, OATP1B1, OATP1B3, orOATP2B1 in the absence and presence of the 4 mostabundant catechins found in green tea, namely, EC, ECG,epigallocatechin (EGC), and EGCG.25 They found thatEC and EGC did not significantly affect estrone-3-sulfateuptake by any of the 4 cell lines, indicating that they do nothave a modulatory effect on the tested OATPs. Onthe other hand, ECG and EGCG significantly inhibitedthe uptake of estrone-3-sulfate uptake mediated byOATP1A2, OATP1B1, and OATP2B1.25 In addition,the authors observed the substrate-dependent effect ofECG and EGCG on OATP1B3-mediated uptake. Theseresults indicated that 2 of the major flavonols present in

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green tea have a substantial effect on the function ofOATPs expressed in the intestine and liver, which canpotentially alter the disposition of coadministered OATPsubstrate compounds. Interestingly, ECG and EGCGwere not only found to be modulators but also substratesof OATP, and both of them are transported by OATP1A2and OATP1B3.25 In addition, the authors reported that theIC50 values of ECG and EGCG on OATP2B1 inhibitionwere estimated to be 35.9 and 101mM, respectively.25

Notably, the average concentration of ECG and EGCG inbrewed green tea is reported to be 450mM (ie, 19.7mg/100mL) and 430mM (ie, 77.8mg/100mL), respectively,with the maximal concentration of each catechin in thelow millimolar range. Therefore, drinking a few cups oftea would result in the intestinal concentration of ECGand EGCG in the same range of their IC50 values,considering a gastric fluid volume of 100 to 500mL on anempty stomach. Thus, the OATP-mediated green tea–drug interaction has the potential to be clinicallyimportant. The effect of green tea on the disposition ofOATP substrates has been evaluated in humans. In aclinical trial conducted in Japan by Misaka and cow-orkers,144 10 healthy volunteers received a single oraldose of nadolol with green tea or water after repeatedconsumption of green tea with exceptionally highcatechin content (700mL/day) or water for 14 days. Asshown in Figure 4, they found that green tea markedlydecreased the Cmax and AUC of nadolol by 85.3% and85%, respectively.144 In addition, the effects of nadolol on

systolic blood pressure were significantly reduced bygreen tea. As nadolol undergoes minimal metabolism andhas been reported to be an OATP1A2 substrate, theauthors suggested that the interaction may be caused bythe inhibitory effect of green tea catechins on OATP1A2.It should be noted that the green tea–type beverage used inthis study is classed as “Food for SpecifiedHealth Use” bythe Ministry of Health, Labour, and Welfare of Japan. Itcontains an exceptionally high total catechin content(�540mg/bottle), and the catechin concentration is 2 to 5times higher than that of typical bottled green tea sold inJapan145 and 6 to 50 times higher than that of typical bottledgreen tea in the United States. Further investigations,including studies that reflect actual green tea consumptionpatterns, are warranted to provide additional insight forassessing the potential risks associated with consuminggreen tea along with taking selected medications.

Candidate Ingredients for OATP InhibitionThe candidate active components in GFJ, orange juice,and apple juice responsible for OATP-mediated druginteractions have been evaluated recently in a number ofin vitro and clinical studies.33,34,146 Naringin, the mostabundant flavonoid present in GFJ, demonstrated a potentin vitro inhibitory effect on OATP1A2, with an IC50

value of 3.6mM.146 Recently, naringin was alsofound to have a potent inhibitory effect on OATP2B1(IC50¼ 4.63mM).34 Consistent with the potent inhibitoryeffect observed in vitro, Bailey et al. found that an

Figure 4. Plasma concentrations of nadolol (circles) and systolic blood pressure (triangles) after oral administration of 30mg nadolol with 700mL ofgreen tea or water following pretreatment with green tea or water for 14 days in 10 healthy volunteers. Adapted fromMisaka et al. Clin Pharmacol Ther.2014;95:432–438.

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aqueous solution of naringin at the same concentration inGFJ (1200mM) significantly reduced the exposure offexofenadine in healthyvolunteers, indicating that naringinis a major active ingredient in GFJ for OATP inhibition.146

As in the above study naringin was responsible for abouthalf the reduction in the fexofenadine AUC compared withthat seen with GFJ, other ingredient(s) in addition tonaringin may also be responsible for the OATP inhibitionby GFJ on fexofenadine absorption. In addition toflavonoids, furanocoumarins in GFJ, including bergamot-tin and 60,70-dihydroxybergamottin, have also beenevaluated, and no inhibitory effect on OATP wasobserved.34,146 Recently Tamai’s group screened a panelof ingredients in GFJ, orange juice, and apple juice toevaluate their effect on OATP.34 They reported that 8major flavonoids (naringin, naringenin, hesperidin, hes-peretin, phloridzin, phloretin, quercetin, and kaempferol)contained in the juices inhibited OATP2B1-mediatedestrone-3-sulfate uptake with IC50 values of 4.63, 49.2,1.92, 67.6, 23.2, 1.31, 9.47, and 21.3mM, respectively.34

Based on the potency of OATP2B1 inhibition and typicalamounts found in fruits juices, naringin and hesperidin arereported to be the major OATP2B1 inhibitors in GFJ andorange juice, respectively, whereas a combination ofmultiple components appears to be responsible forOATP2B1 inhibition by apple juice.34 It should be notedthat theseflavonoidswere all evaluated under coincubationconditions. As noted earlier, apple juice has a weakinhibitory effect on OATP2B1 in vitro under coincubationconditions, but it demonstrated a long-lasting inhibitoryeffect under preincubation conditions.33 The specificingredient(s) responsible for the long-lasting inhibitoryeffect of apple juice on OATP2B1 are unknown and war-rant further investigation. Regarding green tea, the infor-mation related to its candidate active ingredients on OATPinhibition is provided in the Green Tea ection above.

Beverage–Drug Interactions Mediatedby Other Enzymes/TransportersThe primary focus of beverage–drug interaction researchhas been on CYP3A, P-gp, and OATP. There is limitedinformation on beverage–drug interactions mediated byother enzymes and transporters. GFJ has been reported toinhibit the phase II enzyme sulfotransferase (SULT) 1A1and SULT 1A3.147 In addition, drugs that are substrates ofesterase enzymes were affected in vitro by GFJ.148 Theclinically relevant beverage–drug interactions mediatedby intestinal OATP stimulated research on the effect offruit juices on other intestinal uptake transporters. Forexample, Minmura et al. evaluated the in vitro effect ofatenolol on human organic cation transporter 1 (OCT1),an uptake transporter expressed at the brush bordermembrane of enterocytes. They reported that OCT1-mediated atenolol transport can be inhibited by various

flavonoids, including those that are contained in fruitjuices.149 Similarly, Staub et al. investigated the effect offruit juices on peptide transporter 1 (PEPT1), an importantuptake transporter that is also expressed in the apical sideof intestine, with glycylsarcosine and cefadroxil beingused as the substrates.150 They found that PEPT1-mediated drug uptake was decreased when they werecoincubated with fruit juices, but the in vitro effect onPEPT1 was less than that on OATP.150 We recentlyreported that ingredients in fruit juices, especially those inorange juice, have potent inhibitory effect on the effluxtransporter breast cancer resistance protein (BCRP).151

Among the 14 ingredients screened, 4 ingredients in GFJ(ie, bergamottin, 60,70-dihydroxybergamottin, quercetin,and kaempferol), 2 ingredients in orange juice (tangeretinand nobiletin), and 1 ingredient in apple juice (ie,hesperetin) greatly inhibited BCRP-mediated dasatinibefflux at a concentration of 50mM (P < .001).151 Furtherconcentration-dependent studies revealed that bergamot-tin, 60,70-dihydroxybergamottin, tangeretin, and nobiletinare potent BCRP inhibitors, with IC50 values of 3.19, 5.2,1.19, and 1.04mM, respectively.151 It should be noted thatthe information in this section is from in vitro experi-ments. The potential effect of beverage on these enzymes/transporters in humans has not been established, andfurther in vivo and clinical investigations are warranted.

Conclusion and Future DirectionsSince the initial finding in 1989 that GFJ significantlyincreased felodipine blood concentrations, beverage–drug interaction remains an area of active research and hasreceived extensive investigations in the past 2 decades.The known mechanisms for clinically relevant beverage–drug interactions include CYP3A and OATP (Figure 3).For CYP3A-mediated beverage–drug interactions, the invivo CYP3A inhibitory effect is limited to a few fruitjuices, including GFJ, Seville (sour) orange juice, andpomelo grapefruit juice. It should be noted that, althoughnumerous CYP3A substrates have been evaluated, astrong degree of interaction (ie, AUC ratio� 5) with GFJonly occurs with a fairly small number of drugs.12 This isnot surprising, as GFJ only has an inhibitory effect onenteric CYP3A. As a result, significant CYP3A-mediatedGFJ–drug interaction only occurs when a CYP3Asubstrate is orally administered and undergoes extensivefirst-pass metabolism via enteric CYP3A. It should benoted that the magnitude of pharmacokinetic interactionshould not be the only factor to evaluate the potential riskof GFJ–drug interaction. For those drugs with a narrowtherapeutic window (such as tacrolimus) known tointeract with GFJ and for elderly people, who are lesstolerant of the fluctuation in drug exposure, GFJ should beavoided even if the magnitude of interaction on thepharmacokinetic side is minimal or mild. In addition,

14 The Journal of Clinical Pharmacology / Vol XX No XX 2015

purity and amount of the constituents in these beveragesmay be variable and inconsistent, which representpotential confounding factors in interpreting the data inthese studies and in applying it clinically. The furano-coumarins in GFJ are responsible for the clinicallysignificant CYP3A inhibition. Several methods, includingfiltration, heating, and UV radiation, have been developedto remove the furanocoumarins in GFJ. Recently, GFJcultivars with extremely low levels or free of furanocou-marins have been developed through genetic modifica-tion, which may have the potential to be adapted for large-scale production. Although CYP3A-mediated beverage–drug interactions are limited to GFJ, clinically significantOATP-mediated beverage–drug interaction have beenobserved with not only GFJ, but also orange juice, applejuice, and, most recently, green tea. In contrast to CYP3A,OATP inhibition by beverages appears to be competitiveand short-lived. In addition, the extent of the interaction isinfluenced by the volume of the juice/beverage consumed.This suggests that the magnitude of the interaction couldbe minimized by reduced consumption or be avoided byseparating drug administration from beverage ingestion.

Among the clinical studies that demonstrated clinicallysignificant beverage–drug interactions, many of thesewere carried out in conditions in which subjects receiveddouble-strength and/or unrealistically large quantities ofbeverages, neither of which represents typical consumerusage. As a result, the effect of beverages observed maynot realistically reflect the real magnitude of interaction inthe way in which patients ordinarily take medication. Anexample is the green tea study, in which a product withexceptionally high total catechin content was found tomarkedly decrease nadolol exposure in healthy volunteers(Figure 4). As the catechin concentration ingested in thatstudy was 2 to 5 times higher than that of typical bottledgreen tea in Japan and 6 to 50 times higher than that oftypical bottled green tea in the United States, it is difficultto translate the applicability of the findings to a real-worldsetting. Further investigations, including studies thatreflect actual fruit juice/green tea consumption patterns,are warranted to provide additional insight into assessingthe potential risks associated with consuming thesebeverages. As clinically relevant beverage–drug inter-actions only occur in a fairly small number of CYP3Aand/or OATP substrates and most of the interaction areonly modest, complete avoidance of these beverages isunwarranted for the majority of patients. However, asnoted earlier, for patients who take narrow therapeuticrange substrates, grapefruit juice should be avoidedbecause the variability of the effect cannot be predictedand the effect is profound for some narrow therapeuticrange drugs such as tacrolimus. Furthermore, in thosecases in which clinically relevant beverage–drug inter-actions are possible, therapeutic alternatives are usuallyavailable to avoid the interaction.

Declaration of Conflicting Interests

H.D. is a Clinical Research Advisor for the Florida Departmentof Citrus, Bartow, FL.

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