![]() Shirasaka Y, Mori T, Murata Y, Nakanishi T, Tamai I.Naringin is a major and selective clinical inhibitor of organic anion-transporting polypeptide 1A2 (OATP1A2) in grapefruit juice. ![]() Bailey DG, Dresser GK, Leake BF, Kim RB.Fruit juices inhibit organic anion transporting polypeptide-mediated drug uptake to decrease the oral availability of fexofenadine. Dresser GK, Bailey DG, Leake BF, et al.Fruit juice inhibition of uptake transport: a new type of food-drug interaction. Inhibition of P-glycoprotein transport function by grapefruit juice psoralen. Wang EJ, Casciano CN, Clement RP, Johnson WW.Role of furanocoumarin derivatives on grapefruit juice-mediated inhibition of human CYP3A activity. Effects of grapefruit juice ingestion-pharmacokinetics and haemodynamics of intravenously and orally administered felodipine in healthy men. Lundahl J, RegÄrdh CG, Edgar B, Johnsson G. ![]() Drug metabolism and variability among patients in drug response. Decreased enterocyte CYP3A4 concentration and mechanism-based inactivation by furanocoumarins. Mechanisms of enhanced oral availability of CYP3A4 substrates by grapefruit constituents. Schmiedlin-Ren P, Edwards DJ, Fitzsimmons ME, et al.Interaction of citrus juices with felodipine and nifedipine. Bailey DG, Spence JD, Munoz C, Arnold JM.Bailey DG, Malcolm J, Arnold O, Spence JD.Ethanol enhances the hemodynamic effects of felodipine. Bailey DG, Spence JD, Edgar B, Bayliff CD, Arnold JM.Studies have determined that this drug-nutrient interaction is mediated by potent and selective inhibition of OATP1A2 and OATP2B1 by naringin in grapefruit juice, hesperidin in orange juice, and multiple components in apple juice. In fact, all 3 juices (grapefruit, orange, and apple) markedly reduced the oral bioavailability of fexofenadine when dosed in quantities that would typically be consumed. Surprisingly, grapefruit juice had the opposite effect: it decreased uptake of fexofenadine by 50% to 90%. 11 Fexofenadine is not metabolized by cytochrome P450 enzymes, but the investigators expected that P-gp inhibition might increase its bioavailability. 10 In 2002, Bailey and colleagues (the same researchers who made the initial discovery of grapefruit juice-drug interactions) designed an investigation to assess the effects of grapefruit, orange, and apple juices on the absorption of the antihistamine fexofenadine (Allegra). Organic anion-transporter polypeptides (OATPs) constitute a family of transport proteins that enhance intestinal absorption of drugs by shuttling them through enterocytes and into circulation. This review summarizes the mechanisms, common medications affected, and practical implications of grapefruit juice-drug interactions to date. While grapefruit juice is best known for its ability to increase plasma drug concentrations, more recent research has identified situations where it has the opposite effect. ![]() 3 Felodipine is the most extensively studied medication related to grapefruit juice-drug interactions, but hundreds of studies and articles have been written on this topic since its initial discovery more than 25 years ago. This unexpected finding led to subsequent investigations and a 1991 publication in the Lancet, which reported an almost 3-fold increased bioavailability of felodipine when taken with grapefruit juice. 2 To their surprise, when the medication was taken with nonintoxicating amounts of grapefruit juice-flavored ethanol, Bailey and his colleagues detected felodipine concentrations severalfold higher than previous studies would have predicted. 1 Following an evening of taste-testing from the home refrigerator, assuming that fruit juice would not affect the outcome, they chose white grapefruit as the most effective vehicle to mask the flavor of ethanol for this study. In 1989, David Bailey and his colleagues at the University of Western Ontario designed a study to assess the interaction between ethanol and the calcium channel blocker felodipine (Plendil). The discovery that grapefruit juice could affect the bioavailability of oral medications came quite by accident.
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