In 1989, it was noted that co-administration of the

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1 AJH 2006; 19: REVIEW Therapeutics Interaction of Grapefruit Juice and Calcium Channel Blockers Domenic A. Sica Drug drug interactions are commonly recognized occurrences in the hypertensive population. Drug nutrient interactions, however, are less well appreciated. The grapefruit juice calcium channel blocker interaction is one that has been known since The basis for this interaction has been diligently explored and appears to relate to both flavanoid and nonflavanoid components of grapefruit juice interfering with enterocyte CYP3A4 activity. In the process, presystemic clearance of susceptible drugs decreases and bioavailability increases. A number of calcium channel In 1989, it was noted that co-administration of the calcium antagonist felodipine with usual doses of commercially available grapefruit juice substantially decreased the pre-systemic clearance of felodipine. This interaction substantially increased the systemic exposure to felodipine and by this amplified its pharmacodynamic effects. 1,2 This interaction was discovered by coincidence in the course of an ethanol drug interaction study in which grapefruit juice was used to mask the taste of the ethanol vehicle. 2 This singular observation has fueled a large volume of grapefruit juice drug interaction research, with in excess of 225 publications involving more than 25 drugs appearing in the scientific literature. 3 This literature has been extensively reviewed, and the reader is directed to several of these reviews for additional information. 4 8 The emphasis in this review will be on the interaction between grapefruit juice and calcium channel blockers (CCB). Several findings point to grapefruit juice having a principal effect on the intestinal CYP system with a minor effect at the hepatic level. First, medications interacting with grapefruit juice typically are subject to metabolism by the enterocyte CYP3A4 enzyme system. Only the CYP3A isoforms localized to mucosal cells of the small intestine are inhibited by grapefruit juice. Hepatic CYP3A is at best moderately affected by grapefruit juice administration and only with its chronic administration. 9 Second, blockers are prone to this interaction, with the most prominent interaction occurring with felodipine. The calcium channel blocker and grapefruit juice interaction should be incorporated into the knowledge base of rational therapeutics for the prescribing physician. Am J Hypertens 2006;19: American Journal of Hypertension, Ltd. Key Words: Calcium channel blockers, grapefruit juice, felodipine, bergamottin, 6=, 7=-dihydroxybergamottin, flavanoids, furanocoumarins. grapefruit juice increases the area under the plasma concentration time curve, a calculable measure of whole-body medication exposure, with minimal if any change in drug half-life. An interaction involving hepatic CYP3A would be expected to influence drug half-life. Third, in standard dose amounts, grapefruit juice has no effect on the pharmacokinetics of these medications when they are intravenously administered. 4,10 Action of Grapefruit Juice on Intestinal CYP Enzymes The effect of some CYP3A4 inhibitors dissipates with repeated administration, because they produce a time-dependent induction of CYP3A4 via up-regulation of CYP3A messenger RNA and protein, which appears not to be the case with grapefruit juice. 11 Grapefruit juice appears to reduce CYP3A4 activity by both reversible (competitive or noncompetitive) and irreversible (mechanism-based or suicide inhibition) mechanisms as well as through a true loss of CYP3A4. The latter mechanism was first detected when it was observed that recurrent ingestion of grapefruit juice selectively decreased enterocyte expression (obtained by small bowel biopsy) of both CYP3A4 and CYP3A5, thereby increasing drug bioavailability. 4,12 This effect was selective in that concentrations of CYP1A1 and CYP2D6 did not fall. Moreover, this phenomenon was reproducible when human cell lines modified to express Received July 10, First decision November 8, Accepted November 13, From the Department of Clinical Pharmacology and Hypertension, Medical College of Virginia of Virginia Commonwealth University, Richmond, Virginia. Address correspondence and reprint requests to Dr. Domenic A. Sica, Section of Clinical Pharmacology and Hypertension, Division of Nephrology, Box , Virginia Commonwealth University Health System, Richmond, VA 23298; dsica@hsc.vcu.edu /06/$ by the American Journal of Hypertension, Ltd. doi: /j.amjhyper Published by Elsevier Inc.

2 AJH July 2006 VOL. 19, NO. 7 GRAPEFRUIT JUICE AND CALCIUM CHANNEL BLOCKERS 769 CYP3A4 were exposed to grapefruit juice. The failure of messenger RNA expression to decrease with grapefruit juice would suggest that this process is not transcriptionally regulated. The mechanism of the decrease in CYP3A4 protein likely represents either accelerated protein degradation or reduced messenger RNA translation. It is not unreasonable to presume that one or more components of grapefruit juice degrade intestinal CYP3A4 enzyme by way of irreversible suicide inhibition. 4 Such a hypothesis explains the rapid and sustained onset of CYP3A4 inhibition upon exposure to grapefruit juice. For example, upon ingestion of grapefruit juice intestinal CYP3A4 concentration is reduced by 47% within 4 h, and the bioavailability-enhancing effect of ingested grapefruit juice is sustained for at least 24 h. 13,14 Complete recovery from the grapefruit juice effect may take up to 72 h after the last exposure with a recovery half-life from enteric CYP3A4 inhibition of approximately 24 h. 15 Such a recovery pattern is consistent with the time sequence of enzyme regeneration after irreversible (mechanism-based) inhibition. 16 Interindividual Variability in the Effect of Grapefruit Juice The expression of the CYP3A4 enzyme shows striking interindividual variability in both the liver and intestine with as much as an eightfold difference found in its intestinal content. 17 Higher concentrations of CYP3A4 in the intestine, as logic would suggest, correlate with greater first-pass metabolism and lower attainable drug levels for felodipine. 12 Ingestion of grapefruit juice reduces enteric CYP3A4 levels similarly in all subjects irrespective of the tissue CYP3A4 concentrations before ingestion. 12 However, patients with the highest intestinal CYP3A4 concentrations will exhibit the greatest effects from grapefruit juice; a finding that is apparent upon scrutiny of felodipine bioavailability data. 12 Alternatively, felodipine-treated patients with very low CYP3A4 activity should experience a lesser effect on bioavailability from grapefruit juice. P-Glycoprotein, Organic Anion Transporting Polypeptide, and Grapefruit Juice Given the overlap in substrate specificity between p- glycoprotein, organic anion transporting polypeptide, and CYP 3A4, grapefruit juice might be expected to interact also with these transporter systems. In fact, in vitro data in intestinal cell monolayer experiments suggests that grapefruit juice activates p-glycoprotein 18 and inhibits multiple oat polypeptides. 19 If relevant effects on p-glycoprotein or oat polypeptides were to be present in vivo, drug bioavailability would be expected to be reduced, thereby partially counteracting the increased bioavailability that arises from inhibition of enterocyte CYP3A4. This concept is supported by the observation that some drugs displaying a reduced grapefruit juice effect are also known substrates for p-glycoprotein. 4,20 However, current information on the in vivo effect of grapefruit juice on CYP3A4, p- glycoprotein, and oat polypeptides is insufficient to make a qualified statement concerning their mutual interactive effect on bioavailability. 21 Quantity of Grapefruit Juice and Bioavailability Effect Early studies of this interaction used multiple glasses of frozen juice reconstituted with half the recommended water. 4,5,7 Most of the subsequent studies evaluating pharmacokinetic interactions between drugs and grapefruit juice have been performed using one 200-mL glass of juice, as CYP3A4 is substantially inhibited after ingestion of a single glass of grapefruit juice. 4 For example, one glass of regular-strength grapefruit juice is comparable to two to three glasses of double-strength juice in how the pharmacokinetics of felodipine are influenced. 2,4,22 Daily ingestion of grapefruit juice over several weeks may slightly attenuate the effect of the juice, 12,23 because 24 h after ingestion of a glass of grapefruit juice a 30% residual effect exists. 13,14 Consumption of grapefruit juice in the order of six to eight glasses per day is required if hepatic CYP3A4 is to be inhibited. 24 The lag phase for the effect from grapefruit juice is an additional consideration with this interaction. Rogers et al 24 showed that the daily consumption of a glass of regular-strength grapefruit juice has a minimal effect on plasma concentrations of the 3-hydroxy-3-methylglutary/coenzyme A (HMG-CoA) reductase inhibitor lovastatin (approximately 30% to 40% increase) taken approximately 12 h later; however, the length of a lag phase effect for grapefruit juice is likely to be both compound specific and highly individualized. Active Constituents of Grapefruit Juice Soon after the initial report of the grapefruit juice felodipine interaction, it was shown that other citrus fruit products such as orange juice were not similarly interactive, suggesting that grapefruit juice contained specific causative substances. Many compounds, both flavanoids and nonflavanoids, have been offered as the active inhibitory ingredients in grapefruit juice. 4 The candidate flavanoid compounds have included naringenin, naringin, quercetin, and kaempferol, 25,26 and the nonflavanoid compounds most commonly cited have been bergamottin and 6=, 7= dihydroxybergamottin. 27,28 Grapefruit contains several flavanoids (mainly as glycosides), which are presumed to be electron-rich substrates for CYP 450 enzymes that are ultimately hydrolyzed to the corresponding aglycons and sugar by intestinal microflora. Naringin, the glycoside of naringenin, is found in grapefruit juice in concentrations of 450 g/ml (10% of the dry weight of juice), making it the most abundant flavanoid in grapefruit juice. 4 Naringin is what gives grapefruit juice its distinctive aroma and pungent taste, and it is not found in other citrus or fruit juices. Although naringenin, the metabolite of narginin, is a potent in vitro inhibitor of both the

3 770 GRAPEFRUIT JUICE AND CALCIUM CHANNEL BLOCKERS AJH July 2006 VOL. 19, NO. 7 CYP3A 25,29 and CYP1A2 30 isozymes the in vivo demonstration of the same is less striking. Studies of other flavanoids have yielded similar results, that is, strong in vitro inhibition and at best modest in vivo inhibition of the CYP3A system Among different strains of grapefruit juice (white or pink), origin (United States, Australia, or Israel), packages (in glass, paper, plastic, or metal containers), and ways of processing (reconstituted, straight, or containing 10% pulp), furanocoumarin compositions appear to be qualitatively similar. 33 Among the furanocoumarins, 6=, 7= dihydroxybergamottin and its parent compound bergamottin are particularly prominent inhibitors of CYP3A4. 28,31 These two compounds are the furanocoumarins found in the highest concentration in fresh grapefruit and are present in the low micromolar range. The substances 6=, 7= dihydroxybergamottin and bergamottin, either individually or collectively, are not solely responsible for the CYP3A4 inhibitory activity of grapefruit juice as is evident from two experimental findings. First, when specific furanocoumarins are added to grapefruit juice the level of CYP3A4 inhibition reached is not as significant as that seen with the weakest grapefruit juice studied. 33 Second, the furanocoumarin bergamottin (but not 6=, 7= dihydroxybergamottin) is found in significant Table 1. Grapefruit juice and calcium channel blocker interactions quantitites in lime juice. However, despite an ample quantity of bergamottin in lime juice its CYP3A4 inhibitory potential is less than that of grapefruit juice. 34,35 Thus, the clinical drug interaction between grapefruit juice and CYP3A4 may depend on the net effect of all furanocoumarins and possibly other substances, in grapefruit juice. To this end, many of the furanocoumarin constituents of grapefruit juice are present in 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. 13,36 Finally, furanocoumarins are present in similar quantities in grapefruit juice, lime juice, and grapefruit segments and to a lesser degree in peel extract, suggesting that any therapeutic concern for a drug interaction with commercial grapefruit juice should now be extended to whole fruit and perhaps confectioneries produced from grapefruit peel. 37 Calcium Channel Blockers The 1, 4 dihydropyridine CCB are lipid-soluble drugs metabolized by CYP3A4. The observation that felodipine 1,2 interacted with grapefruit juice served as the impetus for the study of most other CCB as to their potential for interacting with grapefruit juice 10,12,14,22,26,37 (Table 1). Drug Reference Grapefruit juice Compound Interaction Severity/onset Amlodipine ml 5 mg, C max 1 15% Minor/delayed AUC 1 16% Diltiazem 50, ml 120 mg IR*, C max 1 22% 37% Minor/delayed Felodipine 1,2,10,14,21,37, ml single-strength; peeled grapefruit segments; intact grapefruit Several single and multiple dose studies AUC 1 20% 25% Bioavailability can 1 by two to three fold with similar size hemodynamic changes Isradipine Not studied Unavailable Nicardipine ml concentrated grapefruit juice 40 mg, Nifedipine 38, g of grapefruit pulp 20 mg, Nimodipine ml (751 mg naringin/l) 30 mg, Nisoldipine 42, ml single-strength 20 mg, Nitrendipine ml at 15, 10, 1/4, 5, and 10 h Verapamil 49, ml, normal strength 20-mg, 60 to 240-mg immediate release from twice daily AUC 1 43% 3.4% for [ ] nicardipine and 1 91% 6.4% for [ ] nicardipine C max 1 40% AUC 1 30% C max 1 24% AUC 1 51% C max 1 406% 73% AUC 1 198% 46% C max 1 99% AUC 1 106% No significant in C max or AUC Some interindividual variability Minor/delayed Minor/delayed * Immediate release.

4 AJH July 2006 VOL. 19, NO. 7 GRAPEFRUIT JUICE AND CALCIUM CHANNEL BLOCKERS 771 FIG. 1. Sequential presystemic felodipine metabolism by CYP3A4 in enterocytes of the small bowel (A) and hepatocytes (B) in the presence and absence of grapefruit juice. The percent of unmetabolized felodipine is presented before and after transmural movement through the gut wall and liver. Grapefruit juice selectively inactivates CYP3A4 in apical enterocytes. Reproduced with permission from Ref. 7. The degree to which the intestinal CYP system metabolizes each of the members of the CCB class varies considerably and hence the varying effect on absolute bioavailability. Grapefruit juice has the greatest effect on those CCB with the lowest oral bioavailability. 2,38,39 One glass of grapefruit juice more than doubles the bioavailability of standard 14,22,40 and extended-release felodipine, 41 although with considerable interindividual variability (Fig. 1). Many studies have shown an enhanced blood pressure reduction, a rise in heart rate, and an increase in vasodilatory effects when felodipine is taken together with grapefruit juice. 1,10,14,40,41 Other dihydropyridines exhibiting the interaction to a similar extent are nisoldipine 42,43 and nicardipine. 44 A lesser but still significant interaction has been observed with nimodipine 45 and nitrendipine, 46 which have shown a 50% and 100% increase in bioavailability when given together with grapefruit juice. Amlodipine and nifedipine have better inherent bioavailability and hence are less effected by grapefruit juice. 38,39,47,48 However, studies still show a 20% to 30% increase in the blood levels of these CCB in the setting of grapefruit juice ingestion but much less in the way of altered hemodynamic responses or concentration-related adverse effects. 2,38,39,47 Although metabolized in vivo by CYP3A4, the nondihydropyridine CCB diltiazem and verapamil do not have their bioavailability meaningfully altered by the co-administration of grapefruit juice Patient Issues with CCB and Grapefruit Juice The experimental design for the assessment of a grapefruit juice and CCB interaction has typically involved a small number of healthy subjects studied in an unblinded fashion. Hemodynamic changes and vasodilator side effects under such contrived study conditions are poorly extrapolable to the hypertensive population. The patient population studied is an important consideration in assessing a grapefruit juice and CCB drug drug interaction in that hypertensive patient s typically experience more prominent drug concentration-dependent CCB effects. Patients receiving an established CCB dose, in whom an unexpected blood pressure response or vasodilator side effect is noted, should be questioned with regard to their intake of grapefruit juice. 54 The question can also be raised as to whether there is a therapeutic role for grapefruit juice in the hypertensive patient receiving a CCB. In this regard, the most reasonable treatment guidelines are to maintain one s current intake of grapefruit juice unless advised otherwise. Unfortunately, no guiding principle exists for which grapefruit juice brand (and thereby the amount ingested) is best matched to the pattern and type CCB used in a particular patient. Moreover, multiple components of grapefruits including grapefruit sections and rind as well as dietary supplements containing grapefruit bioflavonoids can bring about this interaction. The question also comes up as to whether this interaction occurs with other types of citrus fruit. Seville oranges contain 6=, 7=-dihydroxybergamottin and bergapten, which can prompt the same CCB interaction, observed with grapefruit juice. 55 Seville oranges are commonly used in marmalade production. To date, studies have not been conducted with finished marmalade products to establish the potential for interaction with CCB. Hybrids of grapefruits and mandarin oranges, such as tangelos, have not been directly studied for their interactive potential. Because they are genetically derived from grapefruits they could conceivably have the some potential for a drug drug interaction. In conclusion, data from epidemiologic studies reveal that approximately 1% to 2% of the population in the United States consumes at least one glass of regularstrength grapefruit juice per day. 56 This level of intake makes this a pertinent consideration in hypertensive individuals in the U.S., many of whom are receiving CCB therapy. Moreover, grapefruit juice inhibition of oral clearance of CYP 3A4 drug substrates needs to be considered in the broader context of food drug, nutrient drug, and environment drug interactions. Such interactions commonly receive initial wide medical and public acclaim, followed either by incorporation into the knowledge base of rational therapeutics or by a drift into obscurity as a forgotten and perhaps inconsequential annotation. 57 The former applies in this case. A number of regulatory agencies have now addressed the potential for grapefruit

5 772 GRAPEFRUIT JUICE AND CALCIUM CHANNEL BLOCKERS AJH July 2006 VOL. 19, NO. 7 juice to interact with a range of medications. For example, Health Canada issued an advisory alert in June 2002 warning the public not to take certain drugs with grapefruit juice. 58 In July 2002, the American Society of Clinical Pharmacology and Therapeutics in conjunction with the Food and Drug Administration sponsored a drug interaction conference in which the issue of grapefruit juice was prominently discussed. 59 However, despite the importance of this nutrient drug interaction, package inserts for many of the CCB (particularly in the United Kingdom and Japan) often fail to include the necessary quantitative information for clinical decision making. 60 Thus, the clinician is often called upon to have a working knowledge of which antihypertensive medications are most likely to be influenced by intake of grapefruit juice. References 1. Bailey DG, Spence JD, Edgar B, Bayliff CD, Arnold JM: Ethanol enhances the hemodynamic effects of felodipine. Clin Invest Med 1989;12: Bailey DG, Spence JD, Munoz C, Arnold JM: Interaction of citrus juices with felodipine and nifedipine. Lancet 1991;337: Greenblatt DJ, Patki K, von Moltke LL, Shader RI: Drug interactions with grapefruit juice: an update. J Clin Psychopharmacol 2001;21: Kane GC, Lipsky JJ: Drug grapefruit juice interactions. Mayo Clin Proc 2000;75: Ameer B, Weintraub RA: Drug interactions with grapefruit juice. Clin Pharmacokinet 1997;33: Singh BN: Effect of food on clinical pharmacokinetics. Clin Pharmacokinet 1999;37: Bailey DG, Malcolm J, Arnold O, Spence JD: Grapefruit juice drug interactions. Br J Clin Pharmacol 1998;46: Dahan A, Altman H: Food drug interaction: grapefruit juice augments juice bioavailability mechanism, extent and relevance. Eur J Clin Nutr 2004;58: Lilja JJ, Kivisto KT, Backman JT, Neuvonen PJ: Effect of grapefruit juice dose on grapefruit juice triazolam interaction: repeated consumption prolongs triazolam half-life. Eur J Clin Pharmacol 2000; 56: Lundahl J, Regardh CG, Edgar B, Johnsson G: Effect of grapefruit juice ingestion pharmacokinetics and haemodynamics of intravenously and orally administered felodipine in healthy men. Eur J Clin Pharmacol 1997;52: Hostetler KA, Wrighton SA, Kremers P, Guzelian PS: Immunochemical evidence for multiple steroid-inducible hepatic cytochromes P-450 in the rat. Biochem J 1987;245: Lown KS, Bailey DG, Fontana RJ, Janardan SK, Adair CH, Fortlage LA, Brown MB, Guo W, Watkins PB: Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression. 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J Pharmacol Exp Ther 1992;261: Fukuda K, Ohta T, Oshima Y, Ohashi N, Yoshikawa M, Yamazoe Y: Specific CYP3A4 inhibitors in grapefruit juice: furocoumarin dimers as components of drug interaction. Pharmacogenetics 1997; 7: Kakar SM, Paine MF, Stewart PW, Watkins PB: 6=7= Dihydroxybergamottin contributes to the grapefruit juice effect. Clin Pharmacol Ther 2004;75: Ha HR, Chen J, Leuenberger PM, Freiburghaus AU, Follath F: In vitro inhibition of midazolam and quinidine metabolism by flavonoids. Eur J Clin Pharmacol 1999;48: Fuhr U, Klittich K, Staib AH: Inhibitory effect of grapefruit juice and its bitter principal, naringenin, on CYP1A2 dependent metabolism of caffeine in man. Br J Clin Pharmacol 1993;35: Edwards DJ, Bernier SM: Naringin and naringenin are not the primary CYP3A inhibitors in grapefruit juice. Life Sci 1996;59: Fukuda K, Ohta T, Yamazoe Y: Grapefruit component interacting with rat and human P450 CYP3A: possible involvement of nonflavonoid components in drug interaction. 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6 AJH July 2006 VOL. 19, NO. 7 GRAPEFRUIT JUICE AND CALCIUM CHANNEL BLOCKERS Edwards DJ, Bellevue FH 3rd, Woster PM: Identification of 6=, 7=-dihydroxybergamottin, a cytochrome P450 inhibitor, in grapefruit juice. Drug Metab Dispos 1996;24: He K, Iyer KR, Hayes RN, Sinz MW, Woolf TF, Hollenberg PF: Inactivation of cytochrome P450 3A4 by bergamottin, a component of grapefruit juice. Chem Res Toxicol 1998;11: Bailey DG, Dresser GK, Kreeft JH, Munoz C, Freeman DJ, Bend JR: Grapefruit-felodipine interaction: effect of unprocessed fruit and probable active ingredients. Clin Pharmacol Ther 2000;68: Rashid T, Martin U, Clarke H, Waller DG, Renwick AG, George CF: Factors affecting the absolute bioavailability of nifedipine. Br J Clin Pharmacol 1995;40: Josefsson M, Zackrisson AL, Ahlner J: Effect of grapefruit juice on the pharmacokinetics of amlodipine in healthy volunteers. Eur J Clin Pharmacol 1996;51: 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. Eur J Clin Pharmacol 1992;42: Bailey DG, Arnold JM, Bend JR, Tran LT, Spence JD: Grapefruit juice felodipine interaction: reproducibility and characterization with the extended release drug formulation. Br J Clin Pharmacol 1995;40: Takanaga H, Ohnishi A, Murakami H, Matsuo H, Higuchi S, Urae A, Irie S, Furuie H, Matsukuma K, Kimura M, Kawano K, Orii Y, Tanaka T, Sawada Y: Relationship between time after intake of grapefruit juice and the effect on pharmacokinetics and pharmacodynamics of nisoldipine in healthy subjects. Clin Pharmacol Ther 2000;67: Bailey DG, Arnold JM, Strong HA, Munoz C, Spence JD: Effect of grapefruit juice and naringin on nisoldipine pharmacokinetics. Clin Pharmacol Ther 1993;54: Uno T, Ohkubo T, Sugawara K, Higashiyama A, Motomura S, Ishizaki T: Effects 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: Fuhr U, Maier-Bruggemann A, Blume H, Muck W, Unger S, Kuhlmann J, Huschka C, Zaigler M, Rietbrock S, Staib AH: Grapefruit juice increases oral nimodipine bioavailability. Int J Clin Pharmacol Ther 1998;36: Soons PA, Vogels BA, Roosemalen MC, Schoemaker HC, Uchida E, Edgar B, Lundahl J, Cohen AF, Breimer DD: Grapefruit juice and cimetidine inhibit stereoselective metabolism of nitrendipine in humans. Clin Pharmacol Ther 1991;50: Vincent J, Harris SI, Foulds G, Dogolo LC, Willavize S, Friedman HL: Lack of effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of amlodipine. Br J Clin Pharmacol 2000;50: Ohtani M, Kawabata S, Kariya S, Uchino K, Itou K, Kotaki H, Kasuyama K, Morikawa A, Seo I, Nishida N: [Effect of grapefruit pulp on the pharmacokinetics of the dihydropyridine calcium antagonists nifedipine and nisoldipine] (in Japanese). Yakugaku Zasshi 2002; 122: Zaidenstein R, Dishi V, Gips M, Soback S, Cohen N, Weissgarten J, Blatt A, Golik A: The effect of grapefruit juice on the pharmacokinetics of orally administered verapamil. Eur J Clin Pharmacol 1998;54: Sigusch H, Henschel L, Kraul H, Merkel U, Hoffmann A: Lack of effect of grapefruit juice on diltiazem bioavailability in normal subjects. Pharmazie 1994;49: Ho PC, Ghose K, Saville D, Wanwimolruk S: Effect of grapefruit juice on pharmacokinetics and pharmacodynamics of verapamil enantiomers in healthy volunteers. Eur J Clin Pharmacol 2000;56: Fuhr U: Drug interactions with grapefruit juice. Extent, probable mechanism and clinical relevance. Drug Saf 1998;18: Christensen H, Asberg A, Homboe AB, Berg KJ: Coadministration of grapefruit juice increases systemic exposure of diltiazem in healthy volunteers. Eur J Clin Pharmacol 2002;58: Pisarik P: Blood-pressure lowering effect of adding grapefruit juice to nifedipine and terazosin in a patient with severe renovascular hypertension. Arch Fam Med 1996;6: Malhotra S, Bailey DG, Paine MF, Watkins PB: Seville orange juice felodipine interaction: comparison with dilute grapefruit juice and involvement of furocoumarins. Clin Pharmacol Ther 2001;69: Curhan GC, Willett WC, Rimm EB, Spiegelman D, Stampfer MJ: Prospective study of beverage use and the risk of kidney stones. Am J Epidemiol 1996;143: Abernethy D: Grapefruits and drugs: when is statistically significant clinically significant. J Clin Invest 1997;99: Health Canada is advising Canadians not to take certain drugs with grapefruit juice. Ottawa: Health Canada; 2002 Jun 21. Available: Accessed January 1, Huang SM, Hall SD, Watkins P, Love LA, Serabjit-Singh C, Betz JM, Hoffman FA, Honig P, Coates PM, Bull J, Chen ST, Kearns GL, Murray MD, Center for Drug Evaluation and Research and Office of Regulatory Affairs, Food and Drug Administration: Drug interactions with herbal products and grapefruit juice: a conference report. Clin Pharmacol Ther 2004;75: Saito M, Hirata-Koizumi M, Miyake S, Hasegawa R: Comparison of information on the pharmacokinetic interactions of Ca antagonists in the package inserts from three countries (Japan, USA, and UK). Eur J Clin Pharmacol 2005;61: