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Nutrition Journal

Open AccesReview

Medicinal importance of grapefruit juice and its interaction withvarious drugs

Jawad Kiani*

and Sardar Z Imam

Address: Medical College, Aga Khan University, Stadium Road, Karachi, Pakistan

Email: Jawad Kiani* - [email protected]; Sardar Z Imam - [email protected]

* Corresponding author Equal contributors

Abstract

Grapefruit juice is consumed widely in today's health conscious world as a protector againstcardiovascular diseases and cancers. It has however, been found to be an inhibitor of the intestinal

cytochrome P 450 3A4 system, which is responsible for the first pass metabolism of many drugs.

The P glycoprotein pump, found in the brush border of the intestinal wall which transports many

of these cytochrome P 450 3A4 substrates, has also been implicated to be inhibited by grapefruit

juice. By inhibiting these enzyme systems, grapefruit juice alters the pharmacokinetics of a variety

of medications, leading to elevation of their serum concentrations. Most notable are its effects onthe calcium channel antagonist and the statin group of drugs. In the case of many drugs, the

increased serum concentration has been found to be associated with increased frequency of dose

dependent adverse effects. In this review, we have discussed the phytochemistry of grapefruit juice,

the various drugs involved in the drug grapefruit juice eraction with their mechanisms of action

and have presented the clinical implications of these interactions.

IntroductionThe grapefruit, thought to be a cross between an orangeand a shaddock, was developed in the West Indies in theearly 1700s and first introduced to Florida in the 1820s.Since the early part of the 20th century, mutant strains of

white grapefruit have appeared with pink to slightly red-dish colour, and have been propagated by citriculturistsinto several strains of grapefruit. The three major types ofgrapefruit that exist today are white, pink/red and ruby/riored varieties. Grapefruit juice combines the sweet andtangy flavour of the orange and shaddock and also pro-

vides up to 69% of the RDA for vitamin C along with asmany as 250 mg of Potassium [1].

However, the wide consumption of grapefruit juice can-not entirely be attributed to its taste, and nutritive value.

In fact, much of the enthusiasm in its use stems from med-ical research that has suggested that grapefruit juicereduces atherosclerotic plaque formation [2] and inhibitsbreast cancer cell proliferation and mammary cell tumor-igenesis [3,4]. Traditionally grapefruit juice has been

found to contain antioxidant, antinitrosaminic, antisep-tic, aperitif, cardiotonic, detoxicant, hypocholesterolemic,sedative and stomachic activities. In the light of its aboveactivities, it has been traditionally indicated throughouttime for anorexia, bacteria, benign prostatic hypertrophy,cancers (breast, colon, prostate, lung, skin and throat),candida, cold, diabetes, dysuria, high cholesterol, infec-tion, insomnia, mycobacterium, mycosis, nervousness,pseudomonas, rheumatism, staphylococcus and yeast.

Published: 30 October 2007

Nutrition Journal2007, 6:33 doi:10.1186/1475-2891-6-33

Received: 27 June 2007Accepted: 30 October 2007

This article is available from: http://www.nutritionj.com/content/6/1/33

2007 Kiani and Imam; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Nutrition Journal2007, 6:33 http://www.nutritionj.com/content/6/1/33


However, as many as fifteen years ago, investigators foundthat grapefruit juice can markedly augment oral drug bio-availability. This was an unexpected observation from aninteraction study between the dihydropyridine calciumchannel antagonist, felodipine, and ethanol in which

grapefruit juice was used as a flavour supplement to maskthe taste of the ethanol [5]. Studies that followed, con-firmed that grapefruit juice significantly increased the oralbioavailability of felodipine [6,7]. Subsequent studiesprobed the constituents of grapefruit juice, its interaction

with various other drugs and the mechanisms of action ofthose interactions. Several grapefruit juice-drug interac-tions were discovered and these remain a potential con-cern especially since the juice and drugs are oftenconsumed together at breakfast. An increasing number ofadverse drug reactions might be avoided on the basis ofknowledge about the interaction of grapefruit juice andrelevant drugs. Therefore, patients need to be educated

about the hazards (and advantages) of grapefruit interac-tion with medication. In recent years, more drugs havebeen investigated for their interaction with grapefruit juiceand new models have been proposed for the mechanismof such interaction. This article presents a simplistic sum-mary of most examples of such interactions and alsoexplores the phytochemistry and possible mechanisms ofaction involved in drug-grapefruit juice interactions inlight of recent studies on this subject.

Mechanism of actionThe mechanism of action of this interaction involves inhi-bition of the CYP 3A4, a member of the cytochrome P 450

(CYP) enzyme system. CYP is a large multigene family ofheme-containing enzymes located in the endoplasmicreticulum of cells throughout the body. It is especiallyconcentrated in the liver and intestinal wall where it isinvolved in oxidative biotransformation of variousendogenous and exogenous substances. CYP 3A isoformsconstitute 70% of CYP enzymes in enterocytes [8,9]. P-glycoprotein (Pgp), a member of the ABC (adenosine tri-phosphate-binding cassette), is another membrane trans-porter located in the apical brush border of enterocytes.Once taken up by the enterocytes, a lipophilic drug maybe metabolized by CYP 3A4 or be pumped back into thelumen by the Pgp. Hence the oral delivery of many drugs

is limited by the actions of CYP 3 A4 or Pgp. Metabolismby the CYP 3A4 will also occur in the liver before the drugfinally enters the systemic circulation. Grapefruit juicecauses inhibition of CYP 3A4 and thus serves to increasethe bioavalability of the drug by decreasing its pre-sys-temic metabolism [10]. This action is in essence, similarto that caused by CYP-inhibiting drugs like itraconazole,ketoconazole and erythromycin [11-13].

Grapefruit juice causes quick and irreversible sustainedinhibition of the CYP system, possibly by greatly acceler-

ating the degradation of these enzymes while also reduc-ing translation from its mRNA. However, the process oftranscription of mRNA from the cell DNA is not affected.Overall, grapefruit juice reduces the levels of CYP 3A4 inthe cells by as much as 47% within four hours of ingestion

of grapefruit juice with the resultant increased bioavaila-bility being maintained for as long as 24 hours, by whichtime 30% of its effect is still detectable [14-17]. It has beenobserved that decreased content of CYP3A4 was not asso-ciated with increased CYP3A4 mRNA, probably indicatingthe absence of a feedback mechanism for CYP3A4 expres-sion. Restoration of CYP3A4 activity would thereforerequire denovo synthesis or enterocyte replacement,accounting for the prolonged duration of the actions ofgrapefruit juice [18].

Grapefruit juice shows a high variability of the magnitudeof effect among individuals. This variability is dependent

upon inherent differences in enteric CYP3A4 proteinexpression such that individuals with highest baselineCYP3A4 have the highest proportional increase [19,20].However, the effects of grapefruit juice are predominantlyon the intestinal CYP rather than hepatic CYP. This isshown by the fact that most of the drugs that are involvedin interaction with grapefruit juice undergo their primarymetabolism at the intestinal level and in usual quantity,grapefruit juice does not affect the pharmacokinetics ofthese drugs when they are administered intravenously.Furthermore, while it increases the area under the plasmaconcentration-time curve (AUC), it has no significanteffect on the half life of the drugs [10,21-23].

In contrast to the clear inhibitory effects of grapefruit juiceon CYP 3A4, the effects of grapefruit juice on Pgp are con-troversial, ranging from activation to inhibition. Earlierresults have shown grapefruit juice to cause activation ofPgp in vitro [24]. Any such activation in vivo will mean agreater efflux of the drug back into the lumen, therebydecreasing the oral bioavailability of that drug and at leastpartially, if not completely offsetting the effects producedby the inhibition of CYP system of enzymes. This is takenas an explanation for the less-than-expected increase inthe bioavailability of drugs that are established substratesof Pgp [24]. However, grapefruit juice does not change the

absorption of digoxin, a prototypical P-glycoprotein sub-strate, likely because it has high inherent oral bioavailabil-ity [17,25]. However, recent studies have demonstratedthe inhibition of Pgp by grapefruit juice both by its down-regulation and inhibition of function [26,27]. For exam-ple, grapefruit juice increases the bioavailability ofcyclosporine. This effect is thought to be primarily thoughPgp inhibition (instead of CYP3A4 inhibition) sinceorange juice mediated reduction in enterocyte CYP3A4concentrations did not produce a similar increase in bio-availability [17]. In fact, grapefruit juice has also shown
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inhibition of multidrug resistant protein 2 (MRP2), anefflux protein closely related to Pgp in terms of its expres-sion and function [26].

Yet, in spite of all what is known, the mechanism of action

of grapefruit juice-drug interaction requires further inves-tigation. Investigators still need to determine for certaintyany in vivo effect of grapefruit juice on Pgp. One study[28] has also reported the action of grapefruit juice inde-pendent of its actions on Pgp and CYP 3A4. This alsorequires further investigation. Similarly, grapefruit andeven orange juice have also recently been shown to bepotent in vitro inhibitors of a number of organic anion-transporting polypeptides (OATPs) that are involved inapical-to-basal transport of drugs in the small intestine[17,18,25,29]. They were also found to decrease theabsorption of the non-metabolized OATP substrate, fex-ofenadine hence pointing towards inhibition of intestinal

uptake transporters by fruit juices to decrease drug bioa-vailability. This newly proposed mechanism of action andits effect vis a vis various medications also demands fur-ther investigation [25,29].

Assessment of the in vitro CYP inhibition potential forthese natural products has important implications for pre-dicting the likelihood of natural product-drug interac-tions if these products are taken concomitantly. Thesusceptibility of CYP3A4 to modulation by food constitu-ents may be related to its high level of expression in theintestine, as well as its broad substrate specificity.Reported ethnic differences in the activity of this enzyme

may be partly due to dietary factors. Food-drug interac-tions involving CYP1A2, CYP2E1, glucuronosyltrans-ferases and glutathione S-transferases have also beendocumented, although most of these interactions aremodest in magnitude and clinically relevant only fordrugs that have a narrow therapeutic range. Recently,interactions involving drug transporters, including P-glyc-oprotein and the organic anion transporting polypeptide,have also been identified. Hence a lot of food varietieshave the potential to require dosage adjustment to main-tain drug concentrations within their therapeutic win-dows, especially with drugs that have a high first passdegradation [30]. Further research is needed to determine

the scope, magnitude and clinical importance of foodeffects on drug metabolism and transport.

Relevant phytochemistryAnother area in which the search for definite answers con-tinues, is the quest to find the active constituents of grape-fruit juice that are responsible for its actions on CYPenzyme systems and Pgp. The components of grapefruitjuice that are responsible for clinical drug interactionshave yet to be fully determined but the compoundsthought to be responsible for this action include flavo-

noid glycosides (narirutin, naringin, naringinen, querce-tin, kaemferol, hesperidin, neohesperidin, didymin, andponcirin) [8,31-34], furanocoumarins (6',7'-dihydroxy-bergamottin, bergamottin) and sesquiterpen (nootka-tone)[8,22,32,35,36].

Flavanoids exist in grapefruit juice in the form of glyco-sides, with naringin being the most abundant. Uponingestion, these are converted to aglycones and sugars bythe action of intestinal flora. Being polyphenolic and elec-tron rich, these compounds can theoretically inhibit theCYP enzymes. However, studies have at most shown an in

vitro effect by these compounds on the these enzymes andhave failed to identify any in vivo effect by them [37,38],leading to an implication that they are probably not themain active ingredients of grapefruit juice [1,39]. Studieshave even failed to demonstrate any sort of activity in nar-ingin although its metabolite naringinin was observed to

be active in vitro. Yet, because of their huge quantities ingrapefruit juice, and the fact that naringin is not present inother citrus juices, flavanoids remain a subject of research.

The main focus at present, however, is on furanocou-marins. This group includes Bergamottin, its derivative 6'7' dihydroxybergamottin (DHB) and a host of other com-pounds [40]. Controversy still exists on the degree of theirrole in the inhibitory effects of grapefruit juice. Severalstudies have shown DHB [23,35,40] and to an extent Ber-gamottin [23] to be important contributors to the grape-fruit juice effect. In one study, the inhibitory potency ofDHB and four recently isolated furanocoumarins, when

mixed with one another, almost approached that of grape-fruit juice. Omission of any of the components resulted indecreased potency, suggesting that all major furanocou-marins contribute to the inhibitory effects of grapefruitjuice [40]. However, others have suggested that DHB andBergamottin are not the primary substances responsiblefor inhibition of CYP activity clinically [41,42]. For now,this topic also remains a subject of intense research.

Drug-grapefruit juice interactionsAnti-hypertensive drugs and amiodarone

1,4-Dihydropyridine calcium antagonists are lipid solubledrugs used in the treatment of essential hypertension and

angina pectoris and metabolized in vivo by CYP3A4.Since the effects of grapefruit juice were first noticed withfelodipine, this class of drugs has been intensively studied

with grapefruit juice. The degree to which the intestinalCYP system metabolizes this class of drugs and affectstheir oral bioavailability varies markedly. In a study doneby Lundahl J et al., it was found that the intake of grape-fruit juice led to an increase in the oral bioavailability by112% [43]. However, this study also found out that theintravenous pharmacokinetics of felodipine were not sig-nificantly altered with grapefruit juice. The main acute
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effect of the grapefruit juice on the plasma concentrationsof felodipine was believed to be mediated by inhibition ofgut wall metabolism. Grapefruit juice-felodipine interac-tion increases with increasing frequency and amount ofgrapefruit juice ingestion, hence it has been determined

that an interval of 23 days between grapefruit juiceintake and felodipine administration is necessary if theinteraction is to be avoided [44]. Blood pressure responsesto felodipine with grapefruit juice have also been assessedin the elderly and the systolic and diastolic blood pres-sures were found to be lower with grapefruit juice in thesingle-dose state, whereas they were not different betweentreatments in the steady-state dose [45]. The differentblood pressure results between the studies can beexplained by felodipine concentration-blood pressureresponse relationships. The elderly should be particularlycautioned about concomitant grapefruit juice andfelodipine ingestion.

In the benzothiazepine calcium channel antagonistsgroup, diltiazem has been found to have an increased bio-availability on co administration of a single intake ofgrapefruit juice. Inhibition of intestinal metabolism and/or P-glycoprotein efflux transport was believed to be pos-sibly responsible for this effect [46]. However in contrastto this, another study showed the bioavailability to beunchanged with grapefruit juice suggesting that factorsother than biotransformation may be contributing [47].

Compared with water, grapefruit juice increased the max-imum concentration of nisoldipine and reduced the time

to reach maximum nisoldipine concentration [48]. How-ever, the effects of grapefruit pulp intake were smallerthan those produced by grapefruit juice intake, indicatingthat grapefruit pulp and juice have different effects on thepharmacokinetics [49].

A clinical study was performed to see the duration of thisinteraction in the body. Eight healthy volunteers weregiven grapefruit juice at 14, 38, 72 and 96 hours. Com-pared with the control group, the maximum plasma con-centration of nisoldipine was significantly increased aftergrapefruit juice intake in at 0 and 14 hours, and theplasma concentration was significantly increased at each

time till 72 hours [50]. It is therefore necessary to with-hold grapefruit juice for at least 3 days before administra-tion of the drug to prevent grapefruit juice -nisoldipineinteraction.

Regarding verapamil, there are conflicting reports aboutits interaction with grapefruit juice. One study showed anincrease in its bioavailability at steady state [51] whileanother showed no significant change in pharmacokinet-ics on a single administration.

ACE-inhibitors like enalapril, captopril, lisinopril andramipril have not shown any interaction with grapefruitjuice although such an interaction might be possible withangiotensin II type 1 receptor antagonists like losartanand valsartan [18]. Thiazide diuretics and alph 1 adrener-

gic antagonists (doxazosin, terazosin, prazosin) have alsoshown no interaction with grapefruit juice [18].

Amiodarone, an antiarrythmic, is metabolized by CYP3Ato N-desethylamiodarone (N-DEA), a metabolite morepotent than the parent drug [17]. On interaction withgrapefruit juice, there has been shown to be completeinhibition of N-DEA production [52] leading to an overalldecrease in the arrythmogenic side effects of amiodarone[17]. These results are in agreement with in vitro datapointing to the involvement of CYP3A in the metabolismof amiodarone and other Ca antagonists, suggesting thatthis interaction should be taken into account when pre-

scribing this antiarrhythmic drug. Similarly grapefruitjuice has been found to increase oral nimodipine bioa-

vailability [53]. The same cannot be said of amlodipine,on which grapefruit juice has no appreciable effect [54].

One of the possible active ingredients in commercialgrapefruit juice is Bergamottin, as mentioned before. This

was determined after studying the effects of the furano-coumarin derivative on nifedipine (NFP) pharmacokinet-ics, suggesting that bergamottin in grapefruit might be thesubstance that elevates the NFP plasma concentrations[55].

Further studies have also been done to determine if evenunprocessed grapefruit could cause drug interactions. Ithas been shown that unprocessed grapefruit can cause adrug interaction with felodipine [56]. 6', 7'-Dihydroxyber-gamottin and naringin were implicated to be more impor-tant in this case because they are present in higherconcentrations in grapefruit extracts.

Antimicrobials

With antivirals, authors concluded that concomitantadministration of grapefruit juice increases gastric pH anddelays indinavir absorption but does not uniformly affectthe systemic bioavailability of indinavir in HIV-infected

subjects [57,58]. Similarly grapefruit juice has beenshown clinically to not significantly affect amprenavirpharmacokinetics [59]. It is suggested that this may bebecause the primary metabolism of these drugs is not inthe small intestine.

On the other hand regarding saquinavir, it has beenshown that grapefruit juice increases the bioavailability ofsaquinavir without affecting its clearance, suggesting thatinhibition of intestinal CYP3A4 may contribute [60]. Andsince the antiretroviral effect of saquinavir is dose-
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dependent, it has been suggested that inhibition ofCYP3A4 may represent a way to enhance its effectiveness

without increasing the dose.

Amongst anti malarials, grapefruit juice significantly

increases the oral bioavailability of artemether but doesnot prevent the time-dependent reduction in bioavailabil-ity or elimination half-life, suggesting a role for intestinalCYP3A4 in the presystemic metabolism of artemether[61,62]. Similar results have also been seen after a singleoral dose of praziquantel with 250 ml of grapefruit juice[63].

Quinine appears to be unaffected in its pharmacokinetics.Since quinine is a low clearance drug with a relatively highoral bioavailability, and is primarily metabolised byhuman liver CYP3A4, the lack of effect of grapefruit juiceon quinine pharmacokinetics again supports the view that

the site of CYP inhibition by grapefruit juice is mainly inthe gut [17,64]. However for quinidine, grapefruit juicereduces its total clearance and increases the eliminationhalf-life by 19% [65].

In antibiotics, administration of grapefruit juice increasedthe time to peak concentration of clarithromycin but didnot affect other pharmacokinetic parameters [66] while inantiparasitics, albendazole showed an increase in bioa-

vailability upon administration of grapefruit juice [67].

Benzodiazepines and CNS drugs

A marked interaction between oral midazolam and grape-

fruit juice has been found and the data is consistent againwith a reduced first-pass metabolism of midazolam,resulting in increased bioavailability of midazolam[68,69]. The clinical importance of this is especially forpatients with other causes for increased midazolam bioa-

vailability such as advanced age, cirrhosis of the liver, andadministration of other inhibitors of cytochrome P450.

Thus, patients with liver cirrhosis are more dependent onthe intestine for metabolism of CYP3A4 substrates thansubjects with normal liver function. Another importantimplication of this interaction is in dentistry. Oral mida-zolam is a frequently used sedative in pediatric dentistry.

Although an oral form of midazolam is now commer-

cially available, some practitioners continue to use the IVmidazolam as an oral medication. If the injectible form ofmidazolam is administered orally, its bitter taste requiresthe use of a flavoring agent like grapefruit juice. Thisresults in increased blood plasma levels of midazolamcausing excessive levels of sedation for the pediatricpatient. Grapefruit juice therefore should be contraindi-cated for use with oral midazolam especially in suchpatients [70]. Similar results have also been seen with tri-azolam [71].

One study however, did show that grapefruit juice did nothave any particular interaction with oral doses of 10 mgmidazolam and 0.25 mg triazolam in healthy young sub-jects [72]. However, since more studies have determinedincreases in midazolam and triazolam bioavailbility,

grapefruit juice should be administered with caution withthese drugs. However, alprazolam remains unaffected inpharmacokinetics or pharmacodynamics due to its highbioavailability [73].

Among antipsychotics, clozapine remained unaffectedafter consumption of regular-strength grapefruit juice,usually taken as 250 mL b.i.d., for 14 days [74]. One rea-son for this is that enzymes other than CYP3A4 also medi-ate clozapine disposition. Haloperidol remainsunaffected by grapefruit juice [75].

In anti convulsants, grapefruit juice increases the bioavail-

ability of carbamazepine [76] but does not affect the phar-macokinetics of phenytoin [77].

Grapefruit juice considerably increases plasma buspironeconcentrations [78] and also increases sertraline bioavail-ability [79]. Grapefruit juice therefore should be contrain-dicated during administration of buspirone andsertraline.

Antihistamines and Serotonin Analogs

A number of studies have shown that a single glass ofgrapefruit juice produced an individual-dependent, varia-ble increase in the systemic bioavailability of cisapride by

inhibition of intestinal cytochrome P450 3A4 (CYP3A4)activity. [80-82] It has therefore been recommended thatconcomitant use of high amounts of grapefruit juice withcisapride should be avoided, at least in patients with riskfactors for cardiac arrhythmia.

The effect of grapefruit juice on racemic nitrendipine wasalso to increase its bioavailability and it was found that itinhibits the stereoselective metabolism of nitrendipine inhumans [83].

Regarding terfenidine, the ingestion of grapefruit juiceleads to its enhanced systemic bioavailability [84,85].

This is especially important because the raised levels ofterfenidine can prolong the QT interval in the electrocar-diogram sufficiently to precipitate the ventricular arrhyth-mia of Torsade-des-pointes [86]. Incidentally, bothterfenidine and cisapride have been globally withdrawnfrom the market due to serious cardiac arrythmias precip-itated by their interaction with other drugs if simultane-ously taken.
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Statins and other cholesterol-lowering agents

Taking simvastatin first, the active ingredient bergamottinhas been shown to inhibit simvastatin (SV) metabolismand increase the serum concentrations of simvastatin andits active metabolite simvastatin acid, and, to a lesser

extent, those of active and total HMG-CoA reductaseinhibitors [87,88]. The probable mechanism of this inter-action was also the inhibition of CYP3A4-mediated first-pass metabolism of simvastatin by grapefruit juice in thesmall intestine. Bergamottin (BG) and naringenin (NRG)could therefore be applied as markers in food-drug inter-action studies in order to adjust posology and the dose ofsimvastatin should be accordingly reduced.

Another study further found out that, when simvastatin istaken 24 hours after ingestion of "high-dose" grapefruitjuice, the effect on the concentration of simvastatin is onlyabout 10% of the effect observed during concomitant

intake of grapefruit juice and simvastatin. It was alsoshown that the interaction potential of even highamounts of grapefruit juice with CYP3A4 substrates dissi-pates within 3 to 7 days after ingestion of the last dose ofgrapefruit juice [89].

The grapefruit juice effect has also been studied on lovas-tatin. Lovastatin and its active metabolite, lovastatin acidhad greatly increased serum concentrations after grape-fruit juice administration [90]. However, one other studyhas shown a minimal effect of a glass of regular-strengthgrapefruit juice on plasma concentration after a 40 mgevening dose of lovastatin [91].

Although grapefruit juice also increases the AUC of atorv-astatin, the actual increase in activity is fairly modest, pos-sibly due to a simultaneous effect of decreasing the AUCof active metabolites of atorvastatin [17]. Regardless,grapefruit juice should not be concomitantly ingested

with atorvastatin, lovastatin or simvastatin. On the otherhand, pravastatin, fluvastatin and rosuvastatin are threestatin drugs that have been shown not to interact withgrapefruit juice [18]. These may be useful alternatives insettings where there is a concern regarding potential inter-action with grapefruit juice.

Other cholesterol-lowering agents like nicotinic acid andcommon fibric acid derivatives and bile acid sequestrantshave shown no interaction, and therefore may be safelyused, with grapefruit juice [18].

Chemotherapeutics

In patients with autoimmune diseases, the effect ofchronic grapefruit juice administration on steady stateblood concentrations of cyclosporine and metabolites isan increase in both parent and metabolite profiles [92].

This interaction was studied in renal transplant recipients.

Administration of cyclosporine with grapefruit juice com-pared with water induced a moderate, butsignificantincrease in the systemic exposure of cyclosporine [93,94].Most of these studies involving cyclosporine were doneon adult patients. However, one study was also done in

the paediatric population. This study showed that altera-tions in cyclosporine absorption and elimination onlyoccur with concurrent grapefruit juice ingestion when sta-ble pediatric renal transplant patients are taking the oralcyclosporine solution, but not the microemulsion formu-lation [95].

Regarding prednisolone and etoposide, grapefruit juicehas been found to have no significant effect on the metab-olism of prednisolone [96] but in the case of etoposide, ithas been shown to decrease its bioavailability [97].

Conclusion

In light of the wide ranging effects of grapefruit juice onthe pharmacokinetics of various drugs, physicians need tobe aware of these interactions and should make anattempt to warn and educate their patients regardingpotential consequences of concomitant ingestion of thesetwo items. Patient-to-patient variability should be kept inmind and elderly should be particularly warned aboutthese interactions since they are more prone to grapefruitjuice-drug interactions [17]. Physicians should also con-sider using these effects to their own advantage in order toreduce the dosage requirements of certain drugs. How-ever, since further research is required into the mechanismof action of grapefruit juice, it is still premature to recom-

mend it as an adjunctive booster with other drugs.

AbbreviationsAUC = area under the plasma concentration-time curve

CYP = cytochrome P -450

DEA = desethylamiodarone

DHB = dihydroxybergamottin

HMG CoA = 3 hydroxyl 3 methylglutaryl coen-zyme A

NFP = nifedipine

OATP = organic anion-transporting polypeptides

Pgp = P glycoprotein

RDA = Recommended daily allowance

SV = simvastatin
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Competing interestsThe author(s) declare that they have no competing inter-ests.

Authors' contributions

Both authors contributed equally.

AcknowledgementsThis was an independent review done by the authors.

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