Abstract
Grapefruit juice can alter oral drug pharmacokinetics by different mechanisms. Irreversible inactivation of intestinal cytochrome P450 (CYP) 3A4 is produced by commercial grapefruit juice given as a single normal amount (e. g. 200–300mL) or by whole fresh fruit segments. As a result, presystemic metabolism is reduced and oral drug bioavailability increased. Enhanced oral drug bioavailability can occur 24 hours after juice consumption. Inhibition of P-glycoprotein (P-gp) is a possible mechanism that increases oral drug bioavailability by reducing intestinal and/or hepatic efflux transport. Recently, inhibition of organic anion transporting polypeptides by grapefruit juice was observed in vitro; intestinal uptake transport appeared decreased as oral drug bioavailability was reduced.
Numerous medications used in the prevention or treatment of coronary artery disease and its complications have been observed or are predicted to interact with grapefruit juice. Such interactions may increase the risk of rhabdomyolysis when dyslipidemia is treated with the HMG-CoA reductase inhibitors atorvastatin, lovastatin, or simvastatin. Potential alternative agents are pravastatin, fluvastatin, or rosuvastatin. Such interactions might also cause excessive vasodilatation when hypertension is managed with the dihydropyridines felodipine, nicardipine, nifedipine, nisoldipine, or nitrendipine. An alternative agent could be amlodipine. In contrast, the therapeutic effect of the angiotensin II type 1 receptor antagonist losartan may be reduced by grapefruit juice. Grapefruit juice interacting with the antidiabetic agent repaglinide may cause hypoglycemia, and interaction with the appetite suppressant sibutramine may cause elevated BP and HR. In angina pectoris, administration of grapefruit juice could result in atrioventricular conduction disorders with verapamil or attenuated antiplatelet activity with clopidrogel. Grapefruit juice may enhance drug toxicity for antiarrhythmic agents such as amiodarone, quinidine, disopyramide, or propafenone, and for the congestive heart failure drug, carvediol.
Some drugs for the treatment of peripheral or central vascular disease also have the potential to interact with grapefruit juice. Interaction with sildenafil, tadalafil, or vardenafil for erectile dysfunction, may cause serious systemic vasodilatation especially when combined with a nitrate. Interaction between ergotamine for migraine and grapefruit juice may cause gangrene or stroke. In stroke, interaction with nimodipine may cause systemic hypotension.
If a drug has low inherent oral bioavailability from presystemic metabolism by CYP3A4 or efflux transport by P-gp and the potential to produce serious overdose toxicity, avoidance of grapefruit juice entirely during pharmacotherapy appears mandatory. Although altered drug response is variable among individuals, the outcome is difficult to predict and avoiding the combination will guarantee toxicity is prevented. The elderly are at particular risk, as they are often prescribed medications and frequently consume grapefruit juice.
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References
Bailey DG, Spence JD, Munoz C, et al. Interaction of citrus juices with felodipine and nifedipine. Lancet 1991; 337: 268–9
Bailey DG, Arnold JMO, Spence JD. Grapefruit juice and drugs: how significant is the interaction? Clin Pharmacokinet 1994; 26: 91–8
Ameer B, Weintraub RA. Drug interactions with grapefruit juice. Clin Pharmacokinet 1997; 33: 103–21
Fuhr U. Drug interactions with grapefruit juice: extent, probable mechanism of action and clinical relevance. Drug Saf 1998; 18: 251–72
Bailey DG, Arnold JMO, Spence JD. Grapefruit juice-drug interactions. Br J Clin Pharmacol 1998; 46: 101–10
Guengerich FP. Cytochrome P-450 3A4: regulation and role in drug metabolism. Annu Rev Pharmacol Toxicol 1999; 39: 1–17
Kolars JC, Schmiedlin-Rem P, Schuetz JD, et al. Identification of rifampicin-inducible P450IIIA4 (CYP3A4) in human small bowel enterocytes. J Clin Invest 1992; 90: 1871–8
Lown KS, Kolars JC, Thummel KE, et al. Interpatient heterogeneity in expression of CYP3A4 and CYP3A5 in small bowel: lack of prediction by the erythromycin breath test. Drug Metab Dispos 1994; 22: 947–55
Edgar B, Regardh CG, Johnsson G, et al. Felodipine kinetics in healthy man. Clin Pharmacol Ther 1985; 38: 205–11
Blychert E, Edgar B, Elmfeldt D, et al. A population study of the pharmacokinetics of felodipine. Br J Clin Pharmacol 1991; 31: 15–24
Lown KS, Bailey DG, Fontana RJ, et al. Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression. J Clin Invest 1997; 99: 2545–53
Lundahl J, Regardh CG, Edgar B, et al. Relationship between time of intake of grapefruit juice and its effect on pharmacokinetics and pharmacodynamics of felodipine in healthy subjects. Eur J Clin Pharmacol 1995; 49: 61–7
Takanaga H, Ohnishi A, Murakami H, et al. Relationship between time after intake of grapefruit juice and the effect on the pharmacokinetics and pharmacodynamics of nisoldipine in healthy subjects. Clin Pharmacol Ther 2000; 67: 201–14
Lilja JJ, Kivisto KT, Neuvonen PJ. Duration of effect of grapefruit juice on the pharmacokinetics of the CYP3A4 substrate simvastatin. Clin Pharmacol Ther 2000; 68: 384–90
Lundahl J, Regardh CG, Edgar B, et al. Effects of grapefruit juice ingestion: pharmacokinetics and haemodynamics of intravenously and orally administered felodipine in healthy men. Eur J Clin Pharmacol 1997; 52: 139–45
Ducharme MP, Warbasse LH, Edwards DJ. Disposition of intravenous and oral cyclosporine after administration with grapefruit juice. Clin Pharmacol Ther 1995; 57: 485–91
Bailey DG, Dresser GK, Kreeft JH, et al. Grapefruit-felodipine interaction: effect of unprocessed fruit and probable active ingredients. Clin Pharmacol Ther 2000; 68: 468–77
Edgar B, Bailey DG, Bergstrand R, et al. Acute effects of drinking grapefruit juice on the pharmacokinetics and pharmacodynamics of felodipine: and its potential clinical relevance. Eur J Clin Pharmacol 1992; 42: 313–7
Lilja JJ, Kivisto KT, Backman JT, et al. Effect of grapefruit juice dose on grapefruit juice: triazolam interaction: repeated consumption prolongs triazolam half-life. Eur J Clin Pharmacol 2000; 56: 411–5
Bailey DG, Arnold JMO, Bend JR, et al. Grapefruit juice-felodipine interaction: reproducibility and characterization with the extended release drug formulation. Br J Clin Pharmacol 1995; 40: 135–40
Bailey DG, Arnold JMO, Munoz C, et al. Grapefruit juice-felodipine interaction: mechanism, predictability and effect of naringin. Clin Pharmacol Ther 1993; 53: 637–42
Kim RB. Transporters and drug disposition. Curr Opin Drug Discov Dev 2000; 3: 94–101
Lin JH, Yazamaki M. Role of P-glycoprotein in pharmacokinetics: clinical implications [review]. Clin Pharmacokinet 2003; 42: 59–98
Malhotra S, Bailey DG, Paine MF, et al. Seville orange juice-felodipine interaction: comparison with dilute grapefruit juice and involvement of the furanocoumarins. Clin Pharmacol Ther 2001; 69: 14–23
Edwards DJ, Fitzsimmons ME, Schuetz EG, et al. 6’,7’-Dihydroxybergamottin in grapefruit juice and Seville orange juice: effects on cyclosporine disposition, enterocyte CYP3A4, and P-glycoprotein. Clin Pharmacol Ther 1999; 65: 237–44
Becquemont L, Verstuyft C, Kerb R, et al. Effect of grapefruit juice on digoxin pharmacokinetics in humans. Clin Pharmacol Ther 2001; 70: 311–6
Spahn-Langguth H, Langguth P. Grapefruit juice enhances intestinal absorption of the P-glycoprotein substrate talinolol. Eur J Pharm Sci 2001; 12: 316–7
Tian R, Koyabu N, Takanaga H, et al. Effects of grapefruit on the intestinal efflux of P-glycoprotein substrates. Pharm Res 2002; 19: 802–9
Takanaga H, Ohnishi A, Matsuo H, et al. Inhibition of vinblastine efflux mediated by P-glycoprotein by grapefruit juice components in Caco-2 cells. Biol Pharm Bull 1998; 21: 1062–6
Soldner A, Christians U, Susanto M, et al. Grapefruit juice activates P-glycoprotein-mediated drug transport. Pharm Res 1999; 16: 478–85
Dresser GK, Bailey DG, Leake BF, et al. Fruit juices inhibit organic anion transporting polypeptide-mediated drug uptake to decrease the oral availability of fexofenadine. Clin Pharmacol Ther 2002; 71: 11–20
Lea AP, McTavish D. Atorvastatin: a review of its pharmacology and therapeutic potential in the management of hyperlipidaemias. Drugs 1997; 53: 828–47
Kantola T, Kivisto KT, Neuvonen PJ. Grapefruit juice greatly increases serum concentrations of lovastatin and lovastatin acid. Clin Pharmacol Ther 1998; 63: 397–402
Vickers S, Duncan CA, Chen IW, et al. Metabolic disposition studies on simvastatin, a cholesterol-lowering prodrug. Drug Metab Dispos 1990; 18: 138–45
Lilja JJ, Kivisto KT, Neuvonen PJ. Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin. Clin Pharmacol Ther 1999; 66: 118–27
Rogers JD, Zhao J, Liu L, et al. Grapefruit juice has minimal effects on plasma concentrations of lovastatin-derived 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Clin Pharmacol Ther 1999; 66: 358–66
Bailey DG, Dresser GK. Grapefruit juice: lovastatin interaction [letter]. Clin Pharmacol Ther 2000; 67: 690
Lilja JJ, Kivisto KT, Neuvonen PJ. Grapefruit juice-simvastatin interaction: effect on serum concentrations of simvastatin, simvastatin acid, and HMG-CoA reductase inhibitors. Clin Pharmacol Ther 1998; 64: 477–83
Dreier JP, Endres M. Statin-associated rhabdomyolysis triggered by grapefruit consumption. Neurology 2004; 62(4): 670
Dresser GK, Spence JD, Bailey DG. Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clin Pharmacokinet 2000; 38: 41–57
Cooper KJ, Martin PD, Dane AL, et al. Lack of effect of ketoconazole on the pharmacokinetics of rosuvastatin in healthy subjects. Br J Clin Pharmacol 2003; 55: 94–9
Bailey DG, Kreeft JH, Munoz C, et al. Grapefruit juice-felodipine interaction: effect of naringin and 6’,7’-dihydroxybergamottin in humans. Clin Pharmacol Ther 1998; 64: 248–56
Dresser GK, Bailey DG, Carruthers SG. Grapefruit juice-felodipine interaction in the elderly. Clin Pharmacol Ther 2000; 68: 28–34
Bailey DG, Bend JR, Arnold JMO, et al. Erythromycin-felodipine interaction: magnitude, mechanism, and comparison with grapefruit juice. Clin Pharmacol Ther 1996; 60: 25–33
Laitinen T, Hartikainen J, Vanninen E, et al. Age and gender dependency of sensitivity in healthy subjects. J Appl Physiol 1998; 84: 576–83
Landahl S, Edgar B, Gabrielsson M, et al. Pharmacokinetics and blood pressure effects of felodipine in elderly hypertensive patients: a comparison with young healthy subjects. Clin Pharmacokinet 1998; 14: 374–83
Uno T, Ohkubo T, Sugawara K, et al. Effect of grapefruit juice on the stereoselective disposition of nicardipine in humans: evidence for dominant presystemic elimination at the gut site. Eur J Clin Pharmacol 2000; 56: 643–9
Rashid J, McKinstry C, Renwick AG, et al. Quercetin, an in vitro inhibitor of CYP3A, does not contribute to the interaction between nifedipine and grapefruit juice. Br J Clin Pharmacol 1993; 36: 460–3
Rashid TJ, Martin U, Clarke H, et al. Factors affecting the absolute bioavailability of nifedipine. Br J Clin Pharmacol 1995; 40: 51–8
Sigusch H, Hippius M, Henschel L, et al. Influence of grapefruit juice on the pharmacokinetics of a slow release nifedipine formulation. Pharmazie 1994; 49: 522–4
Bailey DG, Arnold JMO, Strong HA, et al. Effect of grapefruit juice and naringin on nisoldipine pharmacokinetics. Clin Pharmacol Ther 1993; 54: 589–94
Soons PA, Vogels BAPM, Roosemalen MCM, et al. Grapefruit juice and cimetidine inhibit stereoselective metabolism of nitrendipine in man. Clin Pharmacol Ther 1991; 50: 394–403
Bailey DG, Munoz C, Arnold JMO, et al. Grapefruit juice and naringin interaction with nitrendipine [abstract]. Clin Pharmacol Ther 1992; 51: 156
Josefsson M, Zackrisson AL, Ahlner J. Effect of grapefruit juice on the pharmacokinetics of amlodipine in healthy volunteers. Eur J Clin Pharmacol 1996; 51: 189–93
Vincent J, Harris SI, Foulds G, et al. Lack of effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of amlodipine. Br J Clin Pharmacol 2000; 50: 455–63
Zaidenstein R, Soback S, Gips M, et al. Effect of grapefruit juice on the pharmacokinetics of losartan and its active metabolite E3174 in healthy volunteers. Ther Drug Monit 2001; 23: 369–73
Atacand® (candesartin cilexetil). Product monograph. Mississauga, Ontario: AstraZeneca Canada Inc., 2004
Teveten® (eprosartin mesylate). Product monograph. Markham, Ontario: Solvay Pharma Inc., 2004
Micardis® (telmisartan). Product monograph. Burlington, Ontario: Boehringer Ingelheim Canada Ltd. 2003
Diovan® (valsartan). Product monograph. Corval, Quebec: Novartis Pharmaceuticals Canada Inc., 2002
Stangier J, Su CA, Hendrick MG, et al. The effect of telmisartan on the steady state pharmacokinetics of digoxin in healthy male volunteers. J Clin Pharmacol 2000; 40: 1373–9
Weber MA. Vasopeptidase inhibitors. Lancet 2001; 358: 1525–32
Malhotra BK, Iyer RA, Soucek KM, et al. Oral bioavailability and disposition of [14C]omapatrilat in healthy subjects. J Clin Pharmacol 2001; 41: 833–41
Iyer RA, Malhotra B, Khan S, et al. Comparative biotransformation of radiolabeled [(14)C]omapatrilat and stable-labeled [(13)C(2)]omapatrilat after oral administration to rats, dogs, and humans. Drug Metab Dispos 2003; 31: 67–75
Niemi M, Neuvonen PJ, Kivisto KT. The cytochrome P4503A4 inhibitor clarithromycin increases the plasma concentrations and effects of repaglinide. Clin Pharmacol Ther 2001; 70: 58–65
Hanefeld M. Pharmacokinetics and clinical efficacy of pioglitazone. Int J Clin Pract Suppl 2001; 121: 19–25
Avandia® (rosiglitazone maleate). Product monograph. Mississauga, Ontario: GlaxoSmithKline Inc., 2004
Meridia® (sibutramine). Product monograph. Saint-Laurent, Quebec: Abbott Laboratories Ltd. 2002
Sigusch H, Henschel L, Kraul H, et al. Lack of effect of grapefruit juice on diltiazem bioavailability in normal subjects. Pharmazie 1994; 49: 675–9
Christensen H, Asberg A, Holmboe AB, et al. Coadministration of grapefruit juice increases systemic exposure of diltiazem in healthy volunteers. Eur J Clin Pharmacol 2002; 58: 515–20
Isoptin® (verapamil). Product monograph. Saint-Laurent, Quebec: Abbott Laboratories Ltd., 2004
Zaidenstein R, Dishi V, Gips M, et al. The effect of grapefruit juice on the pharmacokinetics of orally administered verapamil. Eur J Clin Pharmacol 1998; 54: 337–40
Ho PC, Ghose K, Saville D, et al. Effect of grapefruit juice on pharmacokinetics and pharmacodynamics of verapamil enantiomers in healthy volunteers. Eur J Clin Pharmacol 2000; 56: 693–8
Fuhr U, Muller-Peltzer H, Kern R, et al. Effects of grapefruit juice and smoking on verapamil concentrations in steady state. Eur J Clin Pharmacol 2002; 58: 45–53
Lau WC, Waskell LA, Watkins PB, et al. Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction. Circulation 2003; 107: 32–7
Freedman MD, Somberg JC. Pharmacology and pharmacokinetics of amiodarone. J Clin Pharmacol 1991; 31: 1061–9
Fabre G, Julian B, Saint-Auber B, et al. Evidence of CYP3A-mediated N-deethylation of amiodarone in human liver microsomal fractions. Drug Metab Dispos 1993; 21: 978–85
Libersa CC, Brique SA, Motte KB, et al. Dramatic inhibition of amiodarone metabolism induced by grapefruit juice. Br J Clin Pharmacol 2000; 49: 373–8
Guentert TW, Holford N, Coates PE, et al. Quinidine pharmacokinetics in man: choice of a disposition model and absolute bioavailability studies. J Pharmacokinet Biopharm 1979; 7: 315–30
Kessler KM, Lowenthal DT, Warner H, et al. Quinidine elimination in patients with congestive heart failure or poor renal function. N Engl J Med 1974; 290: 706–9
Min DI, Ku YM, Geraets DR, et al. Effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of quinidine in healthy volunteers. J Clin Pharmacol 1996; 36: 469–76
Damkier P, Hansen LL, Brosen K. Effect of diclofenac, disulfiram, itraconazole, grapefruit juice and erythromycin on the pharmacokinetics of quinidine. Br J Clin Pharmacol 1999; 48: 829–38
Ragosta M, Weihl AC, Rosenfeld LE. Potentially fatal interaction between erythromycin and disopyramide. Am J Med 1989; 864: 465–6
Paar D, Terjung B, Sauerbruch T. Life-threatening interaction between clarithromycin and disopyramide. Lancet 1997; 349: 326–7
Hayashi Y, Ikeda U, Hashimoto T, et al. Torsades de pointes ventricular tachycardia induced by clarithromycin and disopyramide in the presence of hypokalemia. Pacing Clin Electrophysiol 1999; 22: 672–4
Braun J, Sorgel F, Gluth WP, et al. Bioavailability of disopyramide in normal volunteers using unbound concentration. Eur J Clin Pharmacol 1987; 32: 625–9
Rythmol® (propafenone). Product monograph. Saint-Laurent, Quebec: Abbott Laboratories Ltd., 2004
Munoz CE, Ito S, Bend JR, et al. Propafenone interaction with CYP3A4 inhibitors in man [abstract]. Clin Pharmacol Ther 1997; 61: 154
Duvelleroy Hommet C, Jonville-Bera AP, Autret A, et al. Convulsive seizures in a patient treated with propafenone and ketoconazole. Therapie 1995; 50: 164–5
Breckenridge A, Orme M, Wessling H, et al. Pharmacokinetics and pharmacodynamics of the enantiomers of warfarin in man. Clin Pharmacol Ther 1974; 15: 424–30
Miners JO, Birkett DJ. Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. Br J Clin Pharmacol 1998; 45: 525–38
Schwartz J, Bachmann K, Perrigo E. Interaction between warfarin and erythromycin. South Med J 1983; 76: 91–3
Recker MW, Kier KL. Potential interaction between clarithromycin and warfarin. Ann Pharmacother 1997; 31: 996–8
Smith AG. Potentiation of oral anticoagulant effects by ketoconazole. BMJ 1984; 288: 188–9
Yeh J, Soo SC, Summerton C, et al. Potentiation of action of warfarin by itraconazole [letter]. BMJ 1990; 301: 669
Kates RE, Yee Y-G, Kirsten EB. Interaction between warfarin and propafenone in healthy volunteer subjects. Clin Pharmacol Ther 1987; 42: 305–11
Sullivan DM, Ford MA, Boyden TW. Grapefruit juice and the response to warfarin. Am J Health Syst Pharm 1998; 55: 1581–3
Dresser GK, Munoz C, Cruikshank M, et al. Grapefruit juice-warfarin interaction in anticoagulated patients [abstract]. Clin Pharmacol Ther 1999; 65: 193
van Rooij J, van der Meer FJM, Schoemaker HC, et al. Comparison of the effect of grapefruit juice and cimetidine on pharmacokinetics and anticoagulant effect of a single dose of acenocoumarol [abstract]. Br J Clin Pharmacol 1993; 35: 548P
Wakasugi H, Yano I, Ito T, et al. Effect of clarithromycin on renal excretion of digoxin: interaction with P-glycoprotein. Clin Pharmacol Ther 1998; 64: 123–8
Fromm MF, Kim RB, Stein CM, et al. Inhibition of P-glycoprotein-mediated drug transport: a unifying mechanism to explain the interaction between digoxin and quinidine. Circulation 1999; 99: 552–7
Verschraagen M, Koks CHW, Schellens JHM, et al. P-glycoprotein system as a determinant of drug interactions: the case of digoxin-verapamil. Pharmacol Res 1999; 40: 301–6
Fenster PE, White NW, Hanson CD. Pharmacokinetic evaluation of the digoxinamiodarone interaction. J Am Coll Cardiol 1985; 5: 108–12
Partanen J, Jalava KM, Neuvonen PJ. Itraconazole increases serum digoxin concentrations. Pharmacol Toxicol 1996; 79: 274–6
Jalava KM, Partanen J, Neuvonen PJ. Itraconazole decreases renal clearance of digoxin. Ther Drug Monit 1997; 19: 609–13
Coreg® (carvedilol). Product monograph. Mississauga, Ontario: GlaxoSmithKline Inc., 2004
Walker DK, Ackland MJ, James GC, et al. Pharmacokinetics and metabolism of sildenafil in mouse, rat, rabbit, dog and man. Xenobiotica 1999; 29: 297–310
Warrington JS, Shader RI, von Moltke LL, et al. In vitro biotransformations of sildenafil (Viagra): identification of human cytochromes and potential drug interactions. Drug Metab Dispos 2000; 28: 392–7
Jetter A, Kinzig-Schippers M, Walchner-Bonjean M, et al. Effects of grapefruit juice on the pharmacokinetics of sildenafil. Clin Pharmacol Ther 2002; 71: 21–9
Sanders SW, Haering N, Mosberg H, et al. Pharmacokinetics of ergotamine in healthy volunteers following oral and rectal dosing. Eur J Clin Pharmacol 1986; 30: 331–4
Health Canada, Health Products and Food Branch, Ottawa, Ontario. New contraindications for medications containing ergotamine and dihydroergotamine [online]. Available at URL: http://www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/ergotamine_public_e.html [Accessed 2004 Jun 8]
Fuhr U, Maier-Bruggemann A, Blume H, et al. Grapefruit juice increases oral nimodipine bioavailability. Int J Clin Pharmacol Ther 1998; 36: 126–32
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Bailey, D.D.G., Dresser, G.K. Interactions Between Grapefruit Juice and Cardiovascular Drugs. Am J Cordiovosc Drugs 4, 281–297 (2004). https://doi.org/10.2165/00129784-200404050-00002
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DOI: https://doi.org/10.2165/00129784-200404050-00002