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Drug–Grapefruit Juice Interactions

  • Garvan C. Kane
    Affiliations
    Department of Internal Medicine, Mayo Clinic, Rochester, Minn.
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  • James J. Lipsky
    Correspondence
    Address reprint requests and correspondence to James J. Lipsky, MD, Department of Molecular Pharmacology and Experimental Iherapeutics, Clinical Pharmacology Unit, Mayo Clinic, 200 First St SW, Rochester, MN 55905
    Affiliations
    Department of Molecular Pharmacology and Experimental Pherapeutics, Clinical Pharmacology Unit, Mayo Clinic, Rochester, Minn.

    Division of General Internal Medicine, Mayo Clinic, Rochester, Minn.
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      Grapefruit juice, a beverage consumed in large quantities by the general population, is an inhibitor of the intestinal cytochrome P-450 3A4 system, which is responsible for the first-pass metabolism of many medications. Through the inhibition of this enzyme system, grapefruit juice interacts with a variety of medications, leading to elevation of their serum concentrations. Most notable are its effects on cyclosporine, some 1,4-dihydropyridine calcium antagonists, and some 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. In the case of some drugs, these increased drug concentrations have been associated with an increased frequency of dose-dependent adverse effects. The P-glycoprotein pump, located in the brush border of the intestinal wall, also transports many cytochrome P-450 3A4 substrates, and this transporter also may be affected by grapefruit juice. This review discusses the proposed mechanisms of action and the medications involved in drug–grapefruit juice interactions and addresses the clinical implications of these interactions.
      AUC (area under the plasma concentration–time curve), CYP (cytochrome P-450), HMG-CoA (3-hydroxy-3-methyl glutaryl coenzyme A), Pgp (P-glycoprotein)
      Purchased by 21 % of all households in the United States,'grapefruit juice carries the American Heart Association's healthy “heart-check” food mark and contains compounds that may both reduce atherosclerotic plaque formation
      • Cerda JJ
      • Normann SJ
      • Sullivan MP
      • et al.
      Inhibition of atherosclerosis by dietary pectin in microswine with sustained hypercholesterolemia.
      and inhibit cancer cell proliferation.
      • So FV
      • Gulhrie N
      • Chambers AF
      • Moussa M
      • Carroll KK
      Inhibition of human breast cancer cell proliferation and delay of mammary tumorigencsis by flavonoids and citrus juices.
      • Guthrie N
      • Carroll KK
      Inhibition of mammary cancer by citrus flavonoids.
      However, unlike other citrus fruit juice, grapefruit juice interacts with a variety of prescription medications, raising the potential for concern. This is particularly worrying in that juice and medications are commonly consumed together at breakfast. This drug-food interaction seems to occur through inhibition by grapefruit juice of one of the intestinal cytochrome P-450 (CYP) enzyme systems, cytochrome P-450 3A4 (CYP3A4). This enzyme system in the liver is well known for its involvement with drug-drug interactions. Most notably, terfenadine, mibefradil, and cisapride have been withdrawn from the US market in recent years, in part because of deaths due to drug-drug interactions involving the hepatic CYP3A4 system. This review discusses the mechanisms proposed for, the medications involved in, and the clinical implications of known drug-grapefruit juice interactions.

      Chance Discovery

      Almost 10 years have passed since investigators, by chance, observed an interaction between felodipine and grapefruit juice in a study of felodipine and ethanol that used grapefruit juice to mask the taste of ethanol.
      • Bailey DG
      • Spencc JD
      • Fdgar B
      • Bayliff CD
      • Arnold JM
      Ethanol enhances 1he hemodvnamie effects of felodipine.
      Subsequent studies confirmed that grapefruit juice significantly increased the oral bioavailability of felodipine.
      • Bailey DG
      • Spence JD
      • Munoz C
      • Arnold JM
      Interaction of citrus juices with felodipine and nifedipine.
      • Edgar B
      • Bailey D
      • Bergstrand R
      • Johnsson G
      • Regardh CG
      Acute effects of drinking grapefruit juice on the pharmacokinetics and dynamics of felodipine and its potential clinical relevance.
      Thus, a decade of grapefruit juice research was launched. Investigation has focused on the specific components of grapefruit juice, the medications with which it interacts, and, perhaps most fascinating, the mechanism of action.

      Mechanism Of Action

      Cytochrome P-450 is a large multigene family of heme-containing proteins found in the endoplasmic reticulum of cells throughout the body. The largest concentrations of these enzymes are located in the liver and the intestinal wall, where they play a role in the oxidative biotransformation of numerous endogenous substances and xenobiotics. Several isoforms have been distinguished on the basis of their structure, substrate specificity, or responses to various types of inducers. The CYP3A subfamily represents the predominant and most abundant enzyme group. In the liver, CYP3A comprises on average 30% of all CYP content and as much as 70% in small intestine epithelial cells (enterocytes).
      • Zhang QY
      • Dunbar D
      • Ostrowska A
      • Zeisloft S
      • Yang J
      • Kaminsky LS
      Characterization of human small intestinal eytoehromes P-450.
      Located in the apical brush border of the enterocytes is the P-glycoprotein (Pgp) membrane transporter, a member of the ABC (adenosine triphosphate–binding cassette) superfamily of proteins. The role of the Pgp transporter is to carry lipophilic molecules from the enterocyte back into the intestinal lumen. After uptake by the enterocyte, many lipophilic drugs are either metabolized by CYP3A4 or pumped back into the lumen by the Pgp transporter. Therefore, CYP3A4 and Pgp may act in tandem as a barrier to oral delivery of many drugs.
      Medications such as itraconazole, ketoconazole, cyclosporine, diltiazem, and erythromycin inhibit both intestinal CYP3A4 and hepatic CYP3A4. Thus, the reduced presystemic drug metabolism increases the quantity of drug absorbed (oral bioavailability).
      • Kivisto KT
      • Lamberg TS
      • Kanlola T
      • Neuvonen PJ
      Plasma buspirone concentrations are greatly increased by erythromyein and ilraconazole.
      • Kivislo KT
      • Kanlola T
      • Neuvonen PJ
      Different effects of itraconazole on the pharmaeokinetics of fluyastatin and lovastatin.
      • Floren LC
      • Bckersky I
      • Benet LZ
      • et al.
      Tacrolimus oral bio-availabilitv doubles vsi1h coadministration of ketoconazole.
      • Azie NE
      • Brater DC
      • Becker PA
      • Jones DR
      • Hall SD
      The interaction of diltiazem with lovastatin and pravastatin.
      Grapefruit juice has now also been recognized as an inhibitor of this intestinal enzyme system.
      • Lundahl J
      • Regardh CG
      • Edgar B
      • Johnsson G
      G.Effects of grapefruit juiceingestion—pharmaeokinetics and haemodynamics of intravenously and orally administered felodipine in healthy men.
      Several points indicate that grapefruit juice acts on the CYP system at the intestinal level, not at the hepatic level. First, the medications that interact with grapefruit juice undergo metabolism by the CYP3A4 enzyme system in the small bowel. Second, grapefruit juice increases the area under the plasma concentration–time curve (AUC) probably the best measure of the body's exposure to a drug, with minimal if any change in clearance or half-life. Third, in standard doses, grapefruit juice has no effect on the pharmacokinetics of these medications when they are given intravenously.
      • Lundahl J
      • Regardh CG
      • Edgar B
      • Johnsson G
      G.Effects of grapefruit juiceingestion—pharmaeokinetics and haemodynamics of intravenously and orally administered felodipine in healthy men.
      • Rashid TJ
      • Martini U
      • Clarke H
      • Waller DG
      • Renwick AG
      • George CF
      Factors affecting the absolute hioavailability of nifedipine.
      • Kupferschmidt HH
      • Fattinger KE
      • Ha HR
      • Follath F
      • Krahenbuhl S
      Grapefruit juice enhances the bioavailabilily of the HIV protcitse inhibitor saquinavir in man.
      • Kupferschmidt HH
      • Ha HR
      • Ziegler WH
      • Meier PJ
      • Krahenbuhl S
      Interaction between grapefruit juice and midazolam in humans.

      Grapefruit Juice Action On Intestinal Cyp Enzymes

      The effects of some CYP3A4 inhibitors wane with repeated administration, as they cause induction of CYP3A4 through up-regulation of CYP3A messenger RNA and protein over time.
      • Hosteller KA
      • Wrighton SA
      • Molowa DT
      • Thomas PE
      • Levin W
      • Guzelian PS
      Coinduction of multiple hepatic cytoehrome P-450 proteins and their mRNAs in rats treated with imidazole anti-mycotic agents.
      However, this is not the case with grape-fruit juice. Recurrent ingestion of grapefruit juice leads to a selective decrease of both CYP3A4 and CYP3A5 protein expression in enterocytes, resulting in increased drug bioavailability.
      • Lown KS
      • Bailey DG
      • Fontana RJ
      • et al.
      Crrapefruit juice increases felodipine oral availability in humans by decreasing intestinal CVP3A protein expression.
      Messenger RNA expression is not reduced, which suggests that this decrease in activity is not transcriptionally mediated. The mechanism of the decrease in CYP3A4 protein most likely reflects either accelerated protein degradation or reduced messenger RNA translation. It would be reasonable to suppose that 1 or more components of grapefruit juice cause a rapid intracellular degradation of the intestinal CYP3A4 enzyme through irreversible “suicide” inhibition. This would explain the rapid and sustained onset of inhibition by grapefruit juice. A 47% reduction in intestinal CYP3A4 concentration occurs within 4 hours of the ingestion of grapefruit juice, and grapefruit juice maintains a bioavailability-enhancing effect for up to 24 hours.
      • Sehmiedlin-Ren P
      • Edwards DJ
      • Fitzsimmons ML
      • et al.
      Mechanisms of enhanced oral avitilability of CYP3A4 suhslrales by grapefruit constituents: decreased enterocyte CYF3A4 concentration and mechanism-based inactivation by furanoeoumarins.
      • Lundahl J
      • Regardh CG
      • Edgar B
      • Johnsson G
      Relationship between time of intake of grapefruit juice and its effect on phannaco-kinetics and pharmacodvnamics of felodipine in healthy subjects.
      Grapefruit juice also inhibits the CYP1A2 enzyme system in vitro but not in vivo.
      • Maish WA
      • Hampton EM
      • Whitsett TL
      • Shepard JD
      • Lovallo WR
      Iniluence of grapefruit juice on caffeine phannacokinetics and phannaeody namies.
      • Fuhr D
      • Klitlieh K
      • Staib AH
      Inhibitory effect of grapefruit juice and its bitter principal, naringenin. on CYPlA2 dependent metabolism of caffeine in man.
      • Fuhr U
      • Maier A
      • Keller A
      • Sleinijans VW
      • Sauler R
      • Siaib All
      Lacking effect of grapefruit juice on theophylline phannacokinetics.
      • Runkel M
      • Tegtmeier M
      • Legrum W
      Metabolic and analytical interactions of grapefruit juice and 1.2-henzopyrone (coumarin) in man.
      • Merkel U
      • Sigusch H
      • Hoffmann A
      Grapefruit juice inhibits 7-hydroylation of eoumarin in healthy volunteers.
      This is consistent with the understanding that the effect of grapefruit juice occurs at the level of the intestinal wall where levels of CYP2A expression are low. These CYP2A substrates studied with grapefruit juice have included caffeine.
      • Maish WA
      • Hampton EM
      • Whitsett TL
      • Shepard JD
      • Lovallo WR
      Iniluence of grapefruit juice on caffeine phannacokinetics and phannaeody namies.
      • Fuhr D
      • Klitlieh K
      • Staib AH
      Inhibitory effect of grapefruit juice and its bitter principal, naringenin. on CYPlA2 dependent metabolism of caffeine in man.
      theophylline;
      • Fuhr U
      • Maier A
      • Keller A
      • Sleinijans VW
      • Sauler R
      • Siaib All
      Lacking effect of grapefruit juice on theophylline phannacokinetics.
      and coumarin.
      • Runkel M
      • Tegtmeier M
      • Legrum W
      Metabolic and analytical interactions of grapefruit juice and 1.2-henzopyrone (coumarin) in man.
      • Merkel U
      • Sigusch H
      • Hoffmann A
      Grapefruit juice inhibits 7-hydroylation of eoumarin in healthy volunteers.

      The Interpatient Variability Of The Grapefruit Juice Effect

      Wide variations exist among individuals in the expression of the CYP3A4 enzyme in the liver and intestine (8-fold intestinal variation).
      • Lown KS
      • Kolars JC
      • Thummel KE
      • et al.
      Interpatient heterogeneity in expression of CYP3A4 and CVP3A5 in small bowel: lack of prediction by the erythromycin breath test.
      Higher concentrations of CYP3A4 in the intestine correlated with greater first-pass metabolism and lower drug levels, eg, felodipine.
      • Lown KS
      • Bailey DG
      • Fontana RJ
      • et al.
      Crrapefruit juice increases felodipine oral availability in humans by decreasing intestinal CVP3A protein expression.
      Ingestion of grapefruit juice has been shown to reduce enteric CYP3A4 levels to virtually the same degree in all subjects studied.
      • Lown KS
      • Bailey DG
      • Fontana RJ
      • et al.
      Crrapefruit juice increases felodipine oral availability in humans by decreasing intestinal CVP3A protein expression.
      Thus, patients with the highest intestinal CYP3A4 concentrations display the greatest effects from grapefruit juice. This concept has been demonstrated clinically with felodipine.
      • Lown KS
      • Bailey DG
      • Fontana RJ
      • et al.
      Crrapefruit juice increases felodipine oral availability in humans by decreasing intestinal CVP3A protein expression.

      Grapefruit Juice Action on Pgp

      Given the overlap in substrate specificity between Pgp and CYP3A4, grapefruit juice might be expected to interact with this protein transporter also. In vitro data show that grapefruit juice activates Pgp in intestinal cell monolayers
      • Soldner A
      • Christians U
      • Susanto M
      • Wacher YJ
      • Silverman JA
      • Benet LZ
      Grapefruit juice activates P-glycoprotein-mediated drug transport.
      ; however, further studies are required. If grapefruit juice had this activating effect on Pgp in vivo, reducing drug bioavailability might partially counteract the increased bioavailability seen with inhibition of CYP3A. This notion is supported by the recognition that some drugs exhibiting a smaller grapefruit juice effect are also known to be substrates for Pgp.
      • Soldner A
      • Christians U
      • Susanto M
      • Wacher YJ
      • Silverman JA
      • Benet LZ
      Grapefruit juice activates P-glycoprotein-mediated drug transport.
      • Kim RD
      • Fromm MF
      • Wandel C
      • et al.
      The drug transporter F-glyeoprolein limits oral absorption and brain entry of HIV-1 protease inhibitors.
      Given that intestinal Pgp seems to be a more important determinant than intestinal CYP3A4
      • Lown KS
      • Mayo RR
      • Liehtman AB
      • et al.
      Role of intestinal P-glycoprotein (mdrl) in interpatient variation in the oral bioavail-ahility of cyclosporine.
      of the oral bioavailability of cyclosporine, grapefruit juice could be expected to decrease the oral bioavailability of cyclosporine. However, all clinical studies to date have shown, to the contrary, an increase in cyclosporine bioavailability.
      • Soldner A
      • Christians U
      • Susanto M
      • Wacher YJ
      • Silverman JA
      • Benet LZ
      Grapefruit juice activates P-glycoprotein-mediated drug transport.
      • Yee GC
      • Stanley DL
      • Pessa LJ
      • et al.
      Effect of grapefruit juice on blood cyclosporin concentration.
      • Proppe DG
      • Hoch OD
      • McLean AJ
      • Visser KE
      Influence of chronicingestion of grapefruit juice on steady-state blood concentrations of evclosporine A in renal transplant patients with stable grail function [letter].
      • Taniguchi S
      • Kohayashi H
      • Ishii M
      Treatment of psoriasis by evclosporine and grapefruit juice [letter].
      • Emilia G
      • Longo G
      • Bertesi M
      • Gandini G
      • Ferrara L
      • Valenti C
      Clinical interaction between grapefruit juice and evclosporine: is there any interest for the hemalologists? [letter].
      • Brunner LJ
      • Munar MY
      • Vallian J
      • et al.
      Interaction between evclosporine and grapefruit juice requires long-termingestion in stable renal transplant recipients.
      • Majeed A
      • Kareem A
      Effect of grapefruit juice on evclosporine phannacokinetics [letter].
      • Johnston A
      • Holt DW
      Effect of grapefruit juice on blood cyclosporin concentration [letter].
      Edwards et al
      • Edwards DJ
      • Fitsimmons ME
      • Sehnetz FG
      • et al.
      6′,7′-Dihy-droxybergamottin in grapefruit juice and Seville orange juice: effects on evclosporine disposition, enterocyte CVP3A4, and P-glycoprotein.
      showed that the effects of grapefruit juice on cyclosporine seemed independent of a reduction of intestinal CYP3A4 and suggested that there was in vivo inhibition of Pgp, findings opposite those discussed above. Thus, the current data on the in vivo effect of grapefruit juice on CYP3A4 and Pgp, particularly in relation to a drug like cyclosporine, conflict and require further investigation. The in vivo impact of grapefruit juice on medications that are solely substrates for Pgp such as digoxin and fexofenadine is yet to be determined.

      Does the Quantity of Juice Matter?

      The majority of pharmacokinetic studies evaluating interactions between drugs and grapefruit juice have been performed using a single glass of juice (usually 200 mL). Many early studies, however, used frozen juice reconstituted with half the recommended water (“double-strength” juice) as well as multiple glasses of juice. The majority of the presystemic CYP3A4 inhibition is obtained following ingestion of 1 glass of grapefruit juice. One glass of regular-strength juice has a similar effect on the concentrations of felodipine and terfenadine as 2 or 3 glasses of double-strength juice.
      • Bailey DG
      • Spence JD
      • Munoz C
      • Arnold JM
      Interaction of citrus juices with felodipine and nifedipine.
      • Bailey DG
      • Arnold JM
      • Munoz C
      • Spence JD
      Grapefruit juice felodipine interaction: mechanism, predictability, and effect of naringin.
      • Ran SE
      • Bend JR
      • Arnold MO
      • Tran LT
      • Spenee JD
      • Bailey DG
      Grapefruit juice-1erfenadine single-dose interaction: magnitude, mechanism, and relevance.
      • Honig PK
      • Wortham DC
      • Lazarev A
      • Cantilena LR
      Grapefruit juice alters the systemic bioavailahilily and cardiac repolarization of tcrfenadinc in poor metabolizers of terfenadine.
      Daily ingestion of grapefruit juice over a few weeks may reduce slightly the juice's effect,
      • Lown KS
      • Bailey DG
      • Fontana RJ
      • et al.
      Crrapefruit juice increases felodipine oral availability in humans by decreasing intestinal CVP3A protein expression.
      • Lundahl JC
      • Regardh CG
      • Edgar B
      • Johnsson G
      The interaction effect of grapefruit juice is maximal after the first glass.
      because 24 hours after ingestion of a glass of grapefruit juice, 30% of its effect is still present.
      • Sehmiedlin-Ren P
      • Edwards DJ
      • Fitzsimmons ML
      • et al.
      Mechanisms of enhanced oral avitilability of CYP3A4 suhslrales by grapefruit constituents: decreased enterocyte CYF3A4 concentration and mechanism-based inactivation by furanoeoumarins.
      • Lundahl J
      • Regardh CG
      • Edgar B
      • Johnsson G
      Relationship between time of intake of grapefruit juice and its effect on phannaco-kinetics and pharmacodvnamics of felodipine in healthy subjects.
      However, consumption of very large quantities of grapefruit juice (6–8 glasses per day) may lead to inhibition of hepatic CYP3A4.
      • Rogers JD
      • Zhao J
      • Liu ID
      • et al.
      Grapefruit juice has minimal effects on plasma concentrations of lovastatin-derived 3-hydroxy-3-methylgtularyl coenzyme A reductase inhibitors.
      • Veronese M
      • Burke J
      • Dorval E
      • Pequignot E
      • Waldman S
      • Greenberg H
      Grapefruit juice (GFJ) inhibits hepatic and intestinal CYP3A4 dose-dependently [abstract].
      Rogers et al
      • Rogers JD
      • Zhao J
      • Liu ID
      • et al.
      Grapefruit juice has minimal effects on plasma concentrations of lovastatin-derived 3-hydroxy-3-methylgtularyl coenzyme A reductase inhibitors.
      showed that the effects seen on lovastatin are much less with a single glass of juice taken approximately
      • Azie NE
      • Brater DC
      • Becker PA
      • Jones DR
      • Hall SD
      The interaction of diltiazem with lovastatin and pravastatin.
      hours before the drug than with 3 glasses of double-strength juice per study day. Rogers et al
      • Rogers JD
      • Zhao J
      • Liu ID
      • et al.
      Grapefruit juice has minimal effects on plasma concentrations of lovastatin-derived 3-hydroxy-3-methylgtularyl coenzyme A reductase inhibitors.
      report personal communication of unpublished data stating that very high quantities of grapefruit juice influence the pharmacokinetics of intravenous erythromycin, implying sufficient absorption of grapefruit juice constituents, and that hepatic enzyme activity is affected. A recent abstract also suggested that 1 glass of double-strength juice 3 times a day for 3 days may inhibit hepatic CYP3A4.
      • Veronese M
      • Burke J
      • Dorval E
      • Pequignot E
      • Waldman S
      • Greenberg H
      Grapefruit juice (GFJ) inhibits hepatic and intestinal CYP3A4 dose-dependently [abstract].
      Certainly amounts of grapefruit juice in the range normally consumed (up to 3 glasses per day) seem to have intestinal activity only.

      The Active Constituents of Grapefruit Juice

      Many compounds have been proposed to be the active ingredients in grapefruit juice. These include both flavonoids (eg, naringenin, naringin, quercetin, and kaempferol)
      • Bbeaud G
      • Hagenbach J
      • Yandensehrieek S
      • Jung L
      • Koffel JC
      In vitro inhibition of simvastatin metabolism in rat and human liver by naringenin.
      • Minisealco A
      • Lundahl J
      • Regardh CG
      • Edgar B
      • Eriksson UG
      Inhibition of dihydropyridine metabolism in rat and human liver mierosomes by flavonoids found in grapefruit juice.
      and nonflavonoids (eg,
      • Bailey DG
      • Spence JD
      • Munoz C
      • Arnold JM
      Interaction of citrus juices with felodipine and nifedipine.
      • Edgar B
      • Bailey D
      • Bergstrand R
      • Johnsson G
      • Regardh CG
      Acute effects of drinking grapefruit juice on the pharmacokinetics and dynamics of felodipine and its potential clinical relevance.
      -dihydroxybergamottin).
      • Fukuda K
      • Ohta T
      • Oshima Y
      • Yohashi N
      • Yoslukawa M
      • Yamazoe Y
      Specific CYP3A4 inhibitors in grapefruit juice: furocoumarin dimers as components of dmg interaction.
      All inhibit CYP3A4 in vitro; however, in vivo studies have shown modest if any effects.
      • Fuhr D
      • Klitlieh K
      • Staib AH
      Inhibitory effect of grapefruit juice and its bitter principal, naringenin. on CYPlA2 dependent metabolism of caffeine in man.
      • Bailey DG
      • Arnold JM
      • Munoz C
      • Spence JD
      Grapefruit juice felodipine interaction: mechanism, predictability, and effect of naringin.
      • Bbeaud G
      • Hagenbach J
      • Yandensehrieek S
      • Jung L
      • Koffel JC
      In vitro inhibition of simvastatin metabolism in rat and human liver by naringenin.
      • Ha HR
      • Chen J
      • Luenberger PM
      • Freiburghaus AU
      • Follath F
      In vitro inhibition of midazolam and quinidinc metabolism by flavonoids.
      • Bailey DG
      • Arnold JM
      • Strong HA
      • Munoz C
      • Spenee JD
      Effect of grapefruit juice and naringin on nisoldipine phannacokinetics.
      • Fuhr U
      • Kummert AL
      The fate of naringin in humans: a key 1o grapefruit juice-drug interactions?.
      • Edwards DJ
      • Bemier SM
      Naringin and naringenin are not the primary CYP3A inhibitors in grapefruit juice.
      • Fukuda K
      • Ohta T
      • Yamazoe Y
      Grapefruit component interacting with rat and human P450 CYP3A: possible involvement of non-llavonoid components in drug interaction.
      • Edwards DJ
      • Bellevue III, FH
      • Wosler PM
      Identification of 6′, 7′-dihydroxyhergamottin. a eyloehrome P450 inhibitor, in grapefruit juice.
      • He K
      • Iyer KR
      • Hayes RN
      • Sinz MW
      • Woolf TF
      • Hollenberg PF
      Inactivation of eyloehrome P450 3A4 by bergamottin, a component of grapefruit juice.
      • Bailey DG
      • Dresser GK
      • Kreelt JH
      • Munoz C
      • Freeman DJ
      • Bend JR
      Grapefruit juice-felodipine interaction: effect of segments and an extract from unprocessed fruit [abstract].
      • Bailey DG
      • Kreefl JH
      • Munoz C
      • Freeman DJ
      • Bend JR
      Grapefruit juice-felodipine interaction: effect of naringin and 6′.7′-dihydroxy-bergamottin in humans.
      Grapefruit contains several flavonoids, mainly as glycosides, which are hydrolyzed by intestinal microflora, to the corresponding aglycons and sugar.
      • Fuhr U
      • Kummert AL
      The fate of naringin in humans: a key 1o grapefruit juice-drug interactions?.
      These molecules are polyphenolic and electron-rich, implying a potential to act as substrate inhibitors for the CYP enzymes. Naringin, the glycoside of naringenin, is the most abundant flavonoid in grapefruit juice, constituting up to 10% of its dry weight with a concentration in juice of 450 μg/mL. Naringin is what gives grapefruit juice its distinctive smell and bitter taste and is not found in other citrus or fruit juices. Naringin has no effect on the activity of the human CYP system in vitro, but its metabolite naringenin is a potent inhibitor of both the CYP3A
      • Bbeaud G
      • Hagenbach J
      • Yandensehrieek S
      • Jung L
      • Koffel JC
      In vitro inhibition of simvastatin metabolism in rat and human liver by naringenin.
      • Ha HR
      • Chen J
      • Luenberger PM
      • Freiburghaus AU
      • Follath F
      In vitro inhibition of midazolam and quinidinc metabolism by flavonoids.
      and CYP1A2 22 isoforms in vitro. However, in vivo oral naringenin only weakly inhibits CYP3A4 and CYP1A2.
      • Bailey DG
      • Arnold JM
      • Munoz C
      • Spence JD
      Grapefruit juice felodipine interaction: mechanism, predictability, and effect of naringin.
      • Bailey DG
      • Arnold JM
      • Strong HA
      • Munoz C
      • Spenee JD
      Effect of grapefruit juice and naringin on nisoldipine phannacokinetics.
      For the CYP1A2 system, this is not surprising as most CYP1A2 is in the liver and not in the intestine, and only low levels of naringenin reach the plasma.
      • Fuhr U
      • Kummert AL
      The fate of naringin in humans: a key 1o grapefruit juice-drug interactions?.
      However, the inability of oral naringin to markedly inhibit intestinal CYP3A4 likely implies that it is not the main active agent in grapefruit juice. Studies of other flavonoids have yielded similar results, ie, inhibition in the Petri dish
      • Ha HR
      • Chen J
      • Luenberger PM
      • Freiburghaus AU
      • Follath F
      In vitro inhibition of midazolam and quinidinc metabolism by flavonoids.
      but not in the intestine.
      • Edwards DJ
      • Bemier SM
      Naringin and naringenin are not the primary CYP3A inhibitors in grapefruit juice.
      • Fukuda K
      • Ohta T
      • Yamazoe Y
      Grapefruit component interacting with rat and human P450 CYP3A: possible involvement of non-llavonoid components in drug interaction.
      Others have suggested the furanocoumarin
      • Bailey DG
      • Spence JD
      • Munoz C
      • Arnold JM
      Interaction of citrus juices with felodipine and nifedipine.
      • Edgar B
      • Bailey D
      • Bergstrand R
      • Johnsson G
      • Regardh CG
      Acute effects of drinking grapefruit juice on the pharmacokinetics and dynamics of felodipine and its potential clinical relevance.
      -dihydroxybergamottin or its parent compound bergamottin to be a major CYP3A4 inhibitor.
      • Edwards DJ
      • Bellevue III, FH
      • Wosler PM
      Identification of 6′, 7′-dihydroxyhergamottin. a eyloehrome P450 inhibitor, in grapefruit juice.
      Bergamottin is the furanocoumarin found in the highest concentration in fresh grapefruit. It is present in similar quantities in grapefruit juice and grapefruit segments and to a lesser degree in peel extract.
      • He K
      • Iyer KR
      • Hayes RN
      • Sinz MW
      • Woolf TF
      • Hollenberg PF
      Inactivation of eyloehrome P450 3A4 by bergamottin, a component of grapefruit juice.
      • Bailey DG
      • Dresser GK
      • Kreelt JH
      • Munoz C
      • Freeman DJ
      • Bend JR
      Grapefruit juice-felodipine interaction: effect of segments and an extract from unprocessed fruit [abstract].
      Some data from Bailey et al
      • Bailey DG
      • Kreefl JH
      • Munoz C
      • Freeman DJ
      • Bend JR
      Grapefruit juice-felodipine interaction: effect of naringin and 6′.7′-dihydroxy-bergamottin in humans.
      suggest that
      • Bailey DG
      • Spence JD
      • Munoz C
      • Arnold JM
      Interaction of citrus juices with felodipine and nifedipine.
      • Edgar B
      • Bailey D
      • Bergstrand R
      • Johnsson G
      • Regardh CG
      Acute effects of drinking grapefruit juice on the pharmacokinetics and dynamics of felodipine and its potential clinical relevance.
      dihydroxybergamottin is not the major active ingredient causing drug–grapefruit juice interaction.
      Many of these constituents of grapefruit juice are present as a mixture of chiral isomers that vary markedly in proportion and concentration, depending on the maturity of the fruit and the method of juice extraction and purification.
      • Sehmiedlin-Ren P
      • Edwards DJ
      • Fitzsimmons ML
      • et al.
      Mechanisms of enhanced oral avitilability of CYP3A4 suhslrales by grapefruit constituents: decreased enterocyte CYF3A4 concentration and mechanism-based inactivation by furanoeoumarins.
      • He K
      • Iyer KR
      • Hayes RN
      • Sinz MW
      • Woolf TF
      • Hollenberg PF
      Inactivation of eyloehrome P450 3A4 by bergamottin, a component of grapefruit juice.
      • Vanakoski J
      • Mattila MJ
      • Seppala T
      Grapefruit juice does not enhance the effects of midazolam and triazolam in man.
      It is possible that the inhibition of first-phase intestinal metabolism by grapefruit juice is mediated by a combination of flavonoid and furanocoumarin compounds and does not occur in isolation.
      The majority of studies to date have used either fresh grapefruit juice or reconstituted frozen juice. However, it is believed that the active factors in grapefruit juice are present not just in the juice but also in the pulp, peel, and core of the fruit. Bailey and colleagues recently reported that blended grapefruit segments and extract from grape-fruit peel cause a similar interaction with felodipine as does juice.
      • Bailey DG
      • Dresser GK
      • Kreelt JH
      • Munoz C
      • Freeman DJ
      • Bend JR
      Grapefruit juice-felodipine interaction: effect of segments and an extract from unprocessed fruit [abstract].

      Drug-Grapefruit Juice Interactions

      (Table 1, Table 2) Calcium Antagonists

      1,4-Dihydropyridine calcium antagonists are lipid-soluble drugs 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 with felodipine, this class of drugs has been intensively studied with grapefruit juice. The degree to which the intestinal CYP system metabolizes this class of drugs and hence their oral bioavailability varies markedly. Grapefruit juice has the most marked effect on those calcium antagonists with the lowest oral bioavailabilities. One glass of grapefruit juice more than doubles the bioavailability of both standard
      • Edgar B
      • Bailey D
      • Bergstrand R
      • Johnsson G
      • Regardh CG
      Acute effects of drinking grapefruit juice on the pharmacokinetics and dynamics of felodipine and its potential clinical relevance.
      • Lundahl J
      • Regardh CG
      • Edgar B
      • Johnsson G
      Relationship between time of intake of grapefruit juice and its effect on phannaco-kinetics and pharmacodvnamics of felodipine in healthy subjects.
      • Bailey DG
      • Arnold JM
      • Munoz C
      • Spence JD
      Grapefruit juice felodipine interaction: mechanism, predictability, and effect of naringin.
      and extended-release felodipine.
      • Bailey DG
      • Arnold JM
      • Bend JR
      • Tran LT
      • Spenee JD
      Grapefruit juice-felodipine interaction: reprodueibility and characterization wi1h the extended release drug fonnulation.
      The magnitude of this interaction varied widely among individuals. However, in the short term, this interaction is reproducible within individuals. Many studies have shown enhanced blood pressure reduction, an increase in heart rate, and an increase in vasodilatory adverse effects when felodipine is taken with grapefruit juice.
      • Edgar B
      • Bailey D
      • Bergstrand R
      • Johnsson G
      • Regardh CG
      Acute effects of drinking grapefruit juice on the pharmacokinetics and dynamics of felodipine and its potential clinical relevance.
      • Lundahl J
      • Regardh CG
      • Edgar B
      • Johnsson G
      G.Effects of grapefruit juiceingestion—pharmaeokinetics and haemodynamics of intravenously and orally administered felodipine in healthy men.
      • Lundahl J
      • Regardh CG
      • Edgar B
      • Johnsson G
      Relationship between time of intake of grapefruit juice and its effect on phannaco-kinetics and pharmacodvnamics of felodipine in healthy subjects.
      This effect of grapefruit juice is in similar magnitude to that seen with erythromycin. Pranidipine, nisoldipine, and nimodipine have shown 1.5-fold increased bioavailabilities when given with single glasses of grapefruit juice.
      • Bailey DG
      • Arnold JM
      • Strong HA
      • Munoz C
      • Spenee JD
      Effect of grapefruit juice and naringin on nisoldipine phannacokinetics.
      • Hashimoto K
      • Shirafuji T
      • Sekino H
      • et al.
      Interaction of citrus juices with pranidipine, a new 1.4-dihydropyridine calcium antagonist, in healthy subjects.
      • Fuhr U
      • Maier-Bruggemann A
      • Blume H
      • et al.
      Grapefruit juice increases oral nimodipine bioavailability.
      Amlodipine and nifedipine have better inherent oral bioavailabilities and hence are less affected by grapefruit juice. However, studies have still shown increased blood drug levels (20%-30% increases) but much less in the way of altered hemodynamic responses or adverse effects.
      • Bailey DG
      • Spence JD
      • Munoz C
      • Arnold JM
      Interaction of citrus juices with felodipine and nifedipine.
      • Rashid TJ
      • Martini U
      • Clarke H
      • Waller DG
      • Renwick AG
      • George CF
      Factors affecting the absolute hioavailability of nifedipine.
      • Josefsson M
      • Zaekrisson AL
      • Ahlner J
      Effect of grapefruit juice on the pharmaeokinetics üi' amlodipinc in hcalthv volunteers.
      Surprisingly, although metabolized in vivo by CYP3A4, the non–dihydropyridine calcium antagonists diltiazem and verapamil were not altered by grapefruit juice in small clinical studies.
      • Zaidenstein R
      • Dishi V
      • Glips M
      • et al.
      The effect of grapefruit juice on the phanuaeokmeties of orally administered verapamil.
      Table 1CYP3A4 Substrates and Interactions With Grapefruit Juice
      “Yes” and “No” indicate published evidence of the presence or absence of an interaction with grapefruit juice. “Yes” and “No” indicate expected findings based on available data. CYP3A4 = cytochrome P-450 3A4; HIV = human immunodeficiency virus: HMG-CoA = 3-hydroxy-3-methylglularyl coenzyme A.
      Interaction
      DrugYes?Yes?NoNo
      Calcium channel blockers
       AmlodipineX
       FelodipineX
       NifedipineX
       NiinodipineX
       NisoklipineX
       NitrendipineX
       PranidipineX
       DiltiazemX
       VeraparailX
      Antiarrhythmies
       QuinidineX
      Immimosuppressants
       CyelosporineX
       TaerolimusX
      HMG-CoA reduetase inhibitors
       AtorvastatinX
       CerivaslatinX
       FluvastatinX
       LovastatinX
       PravastatinX
       SimvastatinX
      Macrolides
       ClarilhromyeinX
      HIV protease inhibitors
       IndinavirX
       NelfinavirX
       RitonavirX
       SaquinavtrX
      Antihistamines
       EbastineX
       TerfenadineX
      Benzodiazepines
       AlprazolamX
       Clona/epamX
       DiazepamX
       FlurazepamX
       MidazolamX
       TriazolamX
      Other psychiatric medications
       BuspironeX
       Carbarn azepineX
       ClomipramineX
       HaloperidolX
       SortralincX
       TrazodoneX
       ZaleplonX
       ZolpidemX
      Corticosteroids
       Hthinyl estradiolX
       ProgesteroneX
       PrednisoneX
      Antiparasitic agents
       DapsoneX
       QuinineX
       ArtemetherX
       Prokinetics
       CisaprideX
      Others
       CarvedilolX
       CilostazolX
       LosaitanX
       MethadoneX
       MontelukastX
       OndanselronX
       SildenafilX
      * “Yes” and “No” indicate published evidence of the presence or absence of an interaction with grapefruit juice. “Yes” and “No” indicate expected findings based on available data. CYP3A4 = cytochrome P-450 3A4; HIV = human immunodeficiency virus: HMG-CoA = 3-hydroxy-3-methylglularyl coenzyme A.
      Table 2Meditations With Which Grapefruit Juice Should Not Be Consumed in an Unsupervised Manner
      HMG-CoA = 3-hydroxy-3-meuiy]ghitaryl coenzyme A.
      Calcium channel Mockers
       Pelodipine
       Nimodipine
       Nisoldipine
       Nitrendipine
       Pranidipine
      I mmunosuppressants
       Cyclosporine
       Tacrolimus
      HMG-CoA reductase inhibitors
       Atorvastatin
       Cerivastatin
       Lovastatin
       Simvastatin
      Antihistamines
       Ebastine
       Terfenadine
      Psychiatric medications
       Buspirone
       Carbamazepine
       Diazepam
       Midazolam
       Triazolam
      Prokinctics
       Cisapride
      Others
       Methadone
       Sildenafil
      * HMG-CoA = 3-hydroxy-3-meuiy]ghitaryl coenzyme A.
      Given the unpredictability of the effect of grapefruit juice on the bioavailability of the 1,4-dihydropyridine calcium antagonists in each patient, we should advise our patients to avoid this combination, thus preventing concern of potential adverse effects. This advice is particularly so for those with the greatest interaction with grapefruit juice such as nisoldipine and felodipine.

      Cyclosporine

      Cyclosporine is a potent T-cell immunosuppressant widely used as first-line therapy in the care of patients after solid organ and bone marrow transplantation. Its absorption is highly variable, ranging from less than 5% to 90%.
      • Placheinski RJ
      • Venkataramanan R
      • Burekart GJ
      Clinical pharrna-cokinetics of cyclosporin.
      Besides extensive metabolism by the CYP enzyme system in the liver, as discussed above, oral cyclosporine is affected in the intestine by the CYP3A4 and Pgp systems.
      Grapefruit juice, but not orange juice, increases the bioavailability of conventional oral cyclosporine by 62% as well as the microemulsion formulation.
      • Loannides-Demos LL
      • Christophidis N
      • Ryan P
      • Angelis P
      • Liolios L
      • McLean AJ
      Dosing implications of a clinical interaction between grapefruit juice and cyelosporine and metabolite concentrations in patients with autoimmune diseases.
      • Ku YM
      • Min DI
      • Flanigan M
      Effect of grapefruit juice on the pharmaeokinetics of mieroemulsion cyelosporine and its metabolite in healthy volunteers: does the formulation difference matter?..
      These effects have been shown in both healthy adults
      • Yee GC
      • Stanley DL
      • Pessa LJ
      • et al.
      Effect of grapefruit juice on blood cyclosporin concentration.
      and renal transplant recipients
      • Proppe DG
      • Hoch OD
      • McLean AJ
      • Visser KE
      Influence of chronicingestion of grapefruit juice on steady-state blood concentrations of evclosporine A in renal transplant patients with stable grail function [letter].
      taking cyclosporine for immunosuppression, leading to the elevation of trough concentrations by 77%.
      Coadministration of cyclosporine with a CYP3A4 inhibitor such as ketoconazole leads to increased cyclosporine levels and substantial cost savings to patients.
      • Keogh A
      • Spratt P
      • McCoskcr C
      • Macdonald P
      • Mundy J
      • Kaan A
      Ketoeonazole to reduce the need for evclosporine after cardiac transplantation.
      Grapefruit juice has been proposed as a “natural” and safe means of cost reduction for patients taking cyclosporine.
      • Taniguchi S
      • Kohayashi H
      • Ishii M
      Treatment of psoriasis by evclosporine and grapefruit juice [letter].
      • Emilia G
      • Longo G
      • Bertesi M
      • Gandini G
      • Ferrara L
      • Valenti C
      Clinical interaction between grapefruit juice and evclosporine: is there any interest for the hemalologists? [letter].
      Brunner et al
      • Brunner LJ
      • Munar MY
      • Vallian J
      • et al.
      Interaction between evclosporine and grapefruit juice requires long-termingestion in stable renal transplant recipients.
      studied the benefits of coadministration of grapefruit juice with cyclosporine in stable renal transplant patients. However, they found that this interaction was limited and variable, leading the authors to recommend that grapefruit juice not be used to increase cyclosporine levels.
      • Brunner LJ
      • Munar MY
      • Vallian J
      • et al.
      Interaction between evclosporine and grapefruit juice requires long-termingestion in stable renal transplant recipients.
      Other editorials and commentaries have agreed, describing the cyclosporine-grapefruit juice interaction as unpredictable and hazardous.
      • Majeed A
      • Kareem A
      Effect of grapefruit juice on evclosporine phannacokinetics [letter].
      • Johnston A
      • Holt DW
      Effect of grapefruit juice on blood cyclosporin concentration [letter].
      Much of this unpredictability is due to the inconsistency of the juice concentrations and the inability to standardize the active metabolites in grapefruit juice.
      In practice, given the fluctuating effects of grapefruit juice on the bioavailability of cyclosporine, the benefits in dose reduction are likely offset by the increased need for monitoring. We may in the future be able to harness the benefits of increases in drug bioavailability by grapefruit juice through either standardizing the constituents or isolating the active ingredients. This would then lead to a safe, effective, and cost-saving means to enhance the absorption of many therapeutic agents, including cyclosporine.

      Tacrolimus

      Tacrolimus, also metabolized by CYP3A4, is being used now extensively for immunosuppression in transplant patients. Its bioavailability is doubled when it is coadministered with the CYP3A4 inhibitor ketoconazole.
      • Floren LC
      • Bckersky I
      • Benet LZ
      • et al.
      Tacrolimus oral bio-availabilitv doubles vsi1h coadministration of ketoconazole.
      Although there are no published data, tacrolimus is suspected to interact with grapefruit juice also, and the combination should be avoided.

      Antihistamines

      The nonsedating H1-receptor antagonist terfenadine was widely used in the treatment of hay fever and other allergic conditions. It undergoes extensive presystemic first-phase metabolism in the gut wall by CYP enzymes to active carboxylic metabolites, including fexofenadine, to the extent that normally terfenadine levels are not measurable in the plasma. The parent compound has considerable potentiation to QTc prolongation via inhibition of the delayed rectifier potassium channel in the cardiomyocyte (whereas the metabolites do not), leading to an increased risk of ventricular tachycardia and torsades de pointes. The effects of a variety of CYP3A4 inhibitors (erythromycin, ketoconazole) on causing torsades de pointes by increasing the circulating levels of terfenadine are well recognized. Grapefruit juice also alters the presystemic metabolism of terfenadine, to a degree similar to the changes that occur with itraconazole and erythromycin, leading to the accumulation of a greater amount of terfenadine and QTc prolongation (presumably increasing the risk of torsades de pointes).
      • Lundahl JC
      • Regardh CG
      • Edgar B
      • Johnsson G
      The interaction effect of grapefruit juice is maximal after the first glass.
      • Benton RE
      • Honig PR
      • Zamani K
      • Cantilena DR
      • Woosley RL
      Grapefruit juice alters terfenadine pharmaeokinetics. resulting in prolongation of repolarization on the electrocardiogram.
      Of the other antihistamines, ebastine and loratadine are metabolized by CYP3A4 and could potentially interact with grapefruit juice, as could fexofenadine, which is also a Pgp substrate.

      Statins

      The statins are a family of drugs that act by inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase leading to reduction in plasma cholesterol. Lovastatin, simvastatin, cerivastatin, and atorvastatin undergo considerable intestinal metabolism by the CYP3A4 system and, to varying degrees, are affected by coadministered grapefruit juice. CYP3A4 plays only a minor role in the biotransformation of fluvastatin or pravastatin.
      • Jaeobsen W
      • Kirchner G
      • Hallensleben K
      • et al.
      Small intestinal metabolism of Ihe 3-hydroxy-3-methylglutaryl-coenzyme A re-ductase inhibitor lovastatin and comparison with pravastatin.
      Kantola et al
      • Kantola T
      • Kivisto KT
      • Neuvonen PJ
      Grapefruit juice greatly increases serum concentrations of lovastatin and lovastatin acid.
      caused much alarm when they showed grapefruit juice increasing the bioavailability of lovastatin 15-fold. The authors had used double-strength grapefruit juice 3 times a day (doses possibly high enough to inhibit hepatic metabolism). More recently 1 glass of regular-strength juice taken at breakfast, with the dose of lovastatin taken at night, increased mean lovastatin AUC by 2-fold, lovastatin acid by 1.6-fold, and mean AUC of active HMG-CoA reductase inhibitor by 36%.
      • Rogers JD
      • Zhao J
      • Liu ID
      • et al.
      Grapefruit juice has minimal effects on plasma concentrations of lovastatin-derived 3-hydroxy-3-methylgtularyl coenzyme A reductase inhibitors.
      Indeed, it is likely the levels of HMGCoA reductase inhibitors, and not the parent compounds, correspond most with both efficacy and the risk of adverse effects. “High-dose grapefruit juice” (6 glasses per day) increases the mean AUCs of simvastatin and simvastatin acid 16-fold and 7-fold, respectively, with the mean AUC of active HMG-CoA reductase inhibitor increasing 2.4- to 3.6-fold.
      • Lilja JJ
      • Kivisto KT
      • Neuvonen PJ
      Grapefruit juice-simvastatin interaction: effect on serum concentrations of simvastatin. simvastatin acid, and HMG-CoA reduetase inhibitors.
      Atorvastatin has also been studied with “high-dose juice” with the AUC of active and total HMG-CoA reductase inhibitors increased 1.3- and 1.5-fold.
      • Lilja JJ
      • Kivisto KT
      • Neuvonen PJ
      Crrapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin.
      These increases approximate those seen when atorvastatin is taken with itraconazole.
      • Kantola T
      • Kivisto KT
      • Neuvonen PJ
      Effect of itraeonazole on the pharmaeokinetics of atorvaslalin.
      Studies evaluating single glasses of grapefruit juice ingested with oral simvastatin, atorvastatin, or cerivastatin need to be done. Although the mechanism by which statins cause myopathy or rhabdomyolysis is unknown, it does seem to be related to high plasma levels of HMG-CoA reductase inhibitors. Rhabdomyolysis has been reported when simvastatin or lovastatin is coadministered with CYP3A4 inhibitors-cyclosporine, diltiazem, erythromycin, itraconazole, or mibefradil.
      • Corpier CL
      • Jones PH
      • Suki WN
      • et al.
      Rhabdomyolysis and renal injury with lovastatin use: report of two cases in cardiac transplant recipients.
      • Ahmad S
      Diltiazem mvopathy [letter].
      • Spach DH
      • Bauwens JE
      • Clark CD
      • Liurke WG
      Rhabdomyolysis associated with lovastatin and erythromyein use.
      • Lees RS
      • Lees AM
      Rhabdomyolysis from the coadministration of lovastatin and the antifungal agent itraeonazole [letter].
      • Sehmassmann-Suhijar D
      • Bullingham R
      • Gasser R
      • Sehmutz J
      • Haefeli WE
      Rhabdomyolysis due to interaction of simvastatin with mibefradil [letter].
      We conclude that grapefruit juice may predispose some patients taking statins, other than pravastatin, to these adverse effects. Unfortunately, at present, identification of patients who are at risk is not possible. This unpredictability may be due to a variety of factors such as genetic polymorphisms of CYP enzymes, the variable constituents of grapefruit juice, or the patient's susceptibility to adverse effects. Until these issues are defined, it seems prudent to dissuade patients from combining grapefruit juice with these statins, particularly when they are taking these drugs for the first time or in high doses.

      Antimalarial Drugs

      Quinine, a drug long used in the treatment of malaria, is metabolized in vivo by the CYP3A4 system. However, its metabolism is predominantly hepatic rather than intestinal, which explains why no effect is seen when grapefruit juice is coadministered.
      • Ho PC
      • Chalcroft SC
      • Coville PF
      • Wanwimolruk S
      Grapefruit juice has no effect on quinine pharmaeokinetics.
      These findings are similar to those seen with its isomer quinidine.
      • Min DI
      • Ku YM
      • Cieraets DR
      • Lee H
      Effect of grapefruit juice on the pharmaeokinetics and pharmacodynamics of quinidinc in healthy volunteers.
      Artemether, one of the artemisin family of drugs, is being increasingly used for the treatment of malaria in endemic areas, particularly falciparum. The oral bioavailability of artemether is doubled when taken with a glass of grapefruit juice.
      • van Agtmael MA
      • Gupta V
      • van der Wösten TH
      • Rutten J-PB
      • van Hostel CJ
      Grapefruit juice increases the bioavailability of artemcther.
      The impact of this with regard to efficacy and cost needs to be evaluated.

      Cisapride

      Elevated plasma concentrations of cisapride are associated with QTc prolongation and torsades de pointes, which has led to at least 80 reported deaths.
      • Food and Drug Administration
      For this reason, cisapride has recently been withdrawn from the US market and will only be prescribed on a limited-access basis. Since 1 glass of grapefruit juice increases the mean AUC of cisapride by 1.5-fold (range, 0.9- to 2.65-fold)
      • Ciross AS
      • Goh YD
      • Addison RS
      • Shenfield GM
      Influence of grapefruit juice on cisapride phanuaeokmeties.
      and 3 glasses of double-strength juice a day by 2.4-fold (range, 1.7- to 3.4-fold),
      • Kivisto KT
      • Lilja JJ
      • Backman JT
      • Neuvonen PJ
      Repeated consumption of grape fruit juice considerably increases plasma concentrations of cisapride.
      patients taking cisapride should not drink grapefruit juice to avoid potential risk.

      Cilostazol

      Cilostazol, used in the treatment of intermittent claudication, is extensively metabolized in vivo by CYP3A4. No studies evaluating an effect of grapefruit juice on cilostazol pharmacokinetics have been published; however, other CYP3A4 inhibitors such as erythromycin and diltiazem have been shown to increase cilostazol plasma concentrations.
      • Suri A
      • Forbes WP
      • Bramer SL
      Effects of CYP3A inhibition on ihe metabolism of cilostazol.
      Therefore, the manufacturers of cilostazol suggest that patients receiving the drug avoid grapefruit juice consumption until the magnitude and timing of this interaction is evaluated further.

      Protease Inhibitors

      Almost all protease inhibitors prescribed to treat human immunodeficiency virus infection are substrates for both CYP3A4 and Pgp. However, most have high oral bioavailabilities and hence are unlikely to be much affected by grapefruit juice. An exception to this is saquinavir, a potent protease inhibitor whose effectiveness is limited by low bioavailability (about 4%) because of extensive first-phase metabolism in the intestine. Grapefruit juice doubles the oral bioavailability of saquinavir.
      • Kupferschmidt HH
      • Fattinger KE
      • Ha HR
      • Follath F
      • Krahenbuhl S
      Grapefruit juice enhances the bioavailabilily of the HIV protcitse inhibitor saquinavir in man.
      A newer formulation of saquinavir mesylate with a softer gel coating provides increased drug exposure. It has improved bioavailability, with levels 3 to 4 times higher than conventional capsules. Although not yet formally studied with grapefruit juice, these soft gel capsules are expected to interact also but perhaps to a lesser degree.

      Clarithromycin

      Clarithromycin, a CYP3A4 substrate, was evaluated with fresh grapefruit juice, and no increase in drug levels was noted.
      • Cheng KL
      • Nafziger AN
      • Peloquin CA
      • Amsden GW
      Effect of grapefruit juice on elarithromvcin pharmaeokinetics.
      This is probably related to the fact that the oral bioavailability of clarithromycin is quite high (≤55%).

      Itraconazole

      Itraconazole is a broad-spectrum triazole antifungal that has erratic absorption and reduced oral bioavailability. Grapefruit juice, however, has not been shown to increase bioavailability
      • Kawakami M
      • Suzuki K
      • Ishizuka T
      • Hidaka T
      • Matsuki Y
      • Nakamura H
      Flfect of grapefruit juice on pharmaeokinetics of itraconazole in hcalthv subjects.
      and may even decrease it.
      • Penzak SR
      • Gubbins PO
      • Gurley BJ
      • Wang PL
      • Saccente M
      Crrapefruit juice decreases the systemic availability of itraconazole capsules in healthy volunteers.
      A potential mechanism of this effect could be stimulation of the Pgp transporter. The effect of grapefruit juice on the other members of the conazole family has not been evaluated to date.

      Neuropsychiatric Medications

      Benzodiazepines.—There have been mixed reports on the degree to which grapefruit juice interacts with a variety of One glass of grapefruit juice more than triples the bioavailability of diazepam.
      • Ozdemir M
      • Aktan Y
      • Boydag BS
      • Cingi MI
      • Musmul A
      Interaction between grapefruit juice and diazepam in humans.
      One study
      • Kupferschmidt HH
      • Ha HR
      • Ziegler WH
      • Meier PJ
      • Krahenbuhl S
      Interaction between grapefruit juice and midazolam in humans.
      has shown grapefruit juice increasing the bioavailability of oral midazolam by 50%, another
      • Rogers JD
      • Zhao J
      • Liu ID
      • et al.
      Grapefruit juice has minimal effects on plasma concentrations of lovastatin-derived 3-hydroxy-3-methylgtularyl coenzyme A reductase inhibitors.
      by a factor of 2.4. Hukkinen et al
      • Hukkincn SK
      • Varhe A
      • Olkkola KT
      • Neuvonen PJ
      Plasma concentrations of triazolam are increased by concomitantingestion of grapefruit juice.
      showed an increase in the bioavailability of with more drowsiness, and Kupferschmidt et al
      • Kupferschmidt HH
      • Ha HR
      • Ziegler WH
      • Meier PJ
      • Krahenbuhl S
      Interaction between grapefruit juice and midazolam in humans.
      showed at least an increase with respect to bioavailability. These studies, however, are contradicted by Vanakoskiet al
      • Vanakoski J
      • Mattila MJ
      • Seppala T
      Grapefruit juice does not enhance the effects of midazolam and triazolam in man.
      who found no effect on bioavailability of midazolam or triazolam by grapefruit juice. For these 3 benzodiazepines, patients should avoid drinking grapefruit juice with them to avoid the potential for interaction. No data exist for other commonly prescribed benzodiazepines: alprazolam, chlordiazepoxide, clonazepam, flurazepam, and lorazepam. However, they are all likely safe to take with grapefruit juice as their high oral bioavailability leaves little room for elevation by grapefruit juice.
      Buspirone.—Buspirone is an azapirone anxiolytic agent that produces less sedation and impairment of psychomotor performance than do benzodiazepines. It has poor bioavailability due to extensive first-pass metabolism. “High-dose grapefruit juice” has been shown to raise the AUC of buspirone between 3- and 20-fold (mean, 9-fold) and the maximum concentration between 2- and 16-fold (mean, about 4-fold).
      • Lilja JJ
      • Kivisto KT
      • Backman JT
      • Lamberg TS
      • Neuvonen PJ
      Grapefruit juice substantially increases plasma concentrations of buspirone.
      One can only speculate on the extent to which 1 glass of grapefruit juice would interact. It would be wise to counsel patients to avoid the coadministration of buspirone with grapefruit juice, particularly large amounts (more than 3 glasses per day).
      Sertraline.—Sertraline, a selective serotonin reuptake inhibitor used in the treatment of depression, panic disorder, and obsessive-compulsive disorder, undergoes first-pass metabolism by CYP3A4. A recent small study has shown both in vitro and in vivo evidence of grapefruit juice inhibiting this metabolism.
      • Lee AJ
      • Chan WK
      • Harralson AF
      • Huftum J
      • Bui B-CC
      The effects of grapefruit juice on sertraline metabolism: an in vitro and in vivo study.
      Four of the study's 5 patients had sertraline levels increased by approximately 1.5-fold when 1 glass of regular-strength grapefruit juice was drunk daily. The clinical implications of these findings are unclear.
      Carbamazepine.—Carbamazepine, an anticonvulsant widely used in the treatment of epilepsy, when coadministered with a large glass (300 mL) of fresh grapefruit juice results in increased oral bioavailability on average by 40%.
      • Garg SK
      • Kumar N
      • Bhargava DK
      • Prabhakar SK
      Effect of grapefruit juice on earbamazepine bioavailability in patients with epilepsy.
      Given carbamazepine's narrow therapeutic index, it is wise to avoid the potential toxic effects induced by the coadministration of grapefruit juice.
      Clomipramine.—Clomipramine is a tertiary amine tricyclic antidepressant also used in the treatment of obsessive-compulsive disorder. Oesterheld and Kallepalli
      • Oestcrhcld J
      • Kallepalli HR
      Cirapefruit juice and clomipramine: shifting melabolitic ratios [letter].
      reported their experience of using grapefruit juice to elevate the drug levels of clomipramine and improve efficacy in 2 children with obsessive-compulsive disorder. The authors postulated that in some patients demethylation of clomipramine may be largely mediated by the intestinal CYP3A4 system. These data support a considerable interaction between grapefruit juice and clomipramine, and coadministration should probably be done only in a controlled setting.
      Other medications used in the fields of neurology and psychiatry, such as haloperidol, trazodone, and zolidem, all metabolized in vivo by CYP3A4, may interact with grapefruit juice. However, such an interaction is unlikely. All these medications have high oral bioavailabilities ranging between 60% and 70%, and any intestinal metabolism and possible inhibition by grapefruit juice are probably insignificant. Zaleplon, recently approved by the US Food and Drug Administration for use in the management of insomnia, is at least partially metabolized by CYP3A4, and given its low oral bioavailability, it may interact with grapefruit juice. Methadone, a long -acting oral narcotic used for its analgesic properties and in the management of narcotic withdrawal, is metabolized by CYP3A4 in the intestine and also likely interacts with grapefruit juice.

      Hormones

      The oral bioavailability of ethinyl estradiol, an estrogen in oral contraceptive pills, is low due to considerable first-pass metabolism and does seem to be increased when taken with grapefruit juice, by a factor of about 30%
      • Weber A
      • Jager R
      • Bonier A
      • et al.
      Can grapefruit juice influence ethinylestradiol bioavailability?.
      (albeit with up to 4 glasses of grapefruit juice per day in that study). Progesterone is also metabolized by CYP3A4 and undergoes considerable first-pass metabolism resulting in low oral bioavailability. Grapefruit juice has not been evaluated with oral progesterone, but one could expect it to increase serum levels markedly. The clinical implications, particularly with respect to dose-dependent adverse effects, of such changes are unclear. Cortisol is oxidized to inactive cortisone by the enzyme 11 β-hydroxysteroid dehydrogenase. Lee et al
      • Lee YS
      • Lorenzo BJ
      • Koulis T
      • Reidenberg MM
      Grapefruit juice and its Havonoids inhibit 11 beta-hvdroxvsteroid dehydrogenase.
      suggested inhibition of this enzyme by grapefruit juice in vivo by lowering the urinary cortisone/cortisol ratios. They postulated that at high doses (more than 1 L per day) grapefruit juice might display mineralocorticoid activity. Grapefruit juice has been shown to have no effect on the metabolism of prednisone or prednisolone
      • Hollander AA
      • van Rooij J
      • Lentjes GW
      • et al.
      The effect of grapefruit juice on cyelosporine and prednisone metabolism in transplant patients.
      and would not be expected to affect oral thyroid hormone supplementation.

      Sildenafil

      Sildenafil oral therapy for erectile dysfunction has rapid absorption after oral administration with an absolute bioavailability of 40% and is known to be extensively metabolized by the CYP3A4 system. Erythromycin and itraconazole, potent inhibitors of this system, increase sildenafil plasma levels. Most recently the interaction of sildenafil with a number of protease inhibitors (also CYP3A4 substrates) has been reported.
      • Hall MCS
      • Ahmad S
      Interaction between sildenafil and HIV-1 combination therapy [letter].
      • Merry C
      • Barry MG
      • Ryan M
      • et al.
      Interaction of sildenafil and indinavir then co-administered to HIV-positive patients.
      Although there are no published data, one can assume that grapefruit juice would also increase sildenafil if it were concurrently administered. Theoretically this would improve efficacy as well as increase the incidence of adverse effects, eg, headache, flushing, dyspepsia, and vision changes, albeit in a variable manner.

      Conclusion

      What does all this discussion mean for the practicing physician? The American public is consuming grapefruit juice in greater quantities,

      Lesser PF. Florida grapefruil-juiee developments. Presented al: FoodNews Second International Fruit-Juice Conference; October 7. 1997: Amsterdam, the Netherlands.

      with 14% of men drinking the juice at least weekly.
      • Curhan GC
      • Willett WC
      • Rimm EH
      • Spiegelman D
      • Stampfer MJ
      Prospective study of beverage use and the risk of kidney stones.
      One can expect that, with the recent fortification of citrus juices with calcium, the intake of both orange juice and grapefruit juice will increase, particularly in middle-aged and elderly populations, groups in which the intake of medications is highest. There is an increased awareness of this potential for drug-food interaction in the clinical pharmacology and drug regulatory communities, although drug-grapefruit juice interactions may be underappreciated by general physicians.
      We have summarized the clinical findings on drug–grapefruit juice interactions. The majority of these studies are pharmacodynamic evaluations on small numbers of healthy adult volunteers, some of which provide secondary data on adverse effects. No specific studies have addressed the adverse effects of drug–grapefruit juice interactions. From the existing studies we have attempted to extract the extent of the risk to our patients. Although there are no published case reports of adverse effects due to such interactions, we must assume they do occur.
      Cisapride, cyclosporine, carbamazepine, tacrolimus, methadone, and many of the HMG-CoA reductase inhibitors and dihydropyridine calcium antagonists have severe dose-dependent adverse effects. Grapefruit juice is known or presumed to cause a marked increase in the serum levels of these medications. The effect of grapefruit juice varies from patient to patient, at least in part because of wide variations in intestinal concentrations of CYP3A4. The effect is similar in magnitude to that with itraconazole and erythromycin, and so if a drug should not be taken with these medications, then it should not be taken with grapefruit juice either.
      An argument could be made that, if a patient has been taking medication with grapefruit juice for some time without ill effect, it is probably safe to continue to do so. However, with the wide variability in the level of interaction with different types of juice and the sporadic manner in which grapefruit juice is commonly consumed, this approach may not be entirely safe. Each patient's situation should be considered, and advice should be based on consumption history and the specific medications involved.
      There are exciting implications for research in this field for the future. Perhaps through modulation of the process of intestinal CYP3A4 metabolism, it may be possible to standardize absorption of many medications in the future, with possible identification and isolation of the active ingredients of grapefruit juice and coadministration of them in a controlled fashion.

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