title: Long-lasting inhibitory effect of apple and orange juices, but not grapefruit juice, on OATP2B1-mediated drug absorption.
abstract: Enzyme-based grapefruit juice (GFJ)-drug interactions are mainly due to mechanism-based irreversible inhibition of metabolizing enzyme CYP3A4 by GFJ components, but the transporter organic anion transporting polypeptide (OATP)2B1 is also a putative site of interaction between drugs and fruit juices (FJ) in the absorption process. Here we aimed to investigate the effect of preincubation with FJ on OATP2B1-mediated transport of drugs in vitro. When OATP2B1-expressing Xenopus oocytes were preincubated with GFJ, orange juice (OJ), or apple juice (AJ), AJ induced a remarkable decrease in OATP2B1-mediated estrone-3-sulfate uptake in a concentration-dependent manner (IC(50) = 1.5%). A similar but less potent effect was observed with OJ (IC(50) = 21%), whereas GFJ had no effect. Similar results were obtained in preincubation studies using fexofenadine. Preincubation with OJ and AJ resulted in time-dependent inhibition of OATP2B1. Again, AJ had the more potent effect; its action lasted for at least 240 minutes, suggesting that AJ irreversibly inhibits OATP2B1-mediated drug uptake. Kinetic analysis revealed that coincubation and preincubation with AJ reduced OATP2B1-mediated estrone-3-sulfate uptake via competitive and noncompetitive mechanisms, respectively. Thus, OATP2B1 is functionally impaired through both competitive and long-lasting inhibition mechanisms by AJ and OJ, but not GFJ. Interestingly, although GFJ but not AJ is able to irreversibly inhibit CYP3A4, in the case of OATP2B1, AJ but not GFJ has a long-lasting inhibitory effect. Accordingly, complex FJ-drug interactions may occur in vivo, and their clinical significance should be examined.
authors.affiliation: Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Shirasaka
authors.forename: Megumi
authors.initials: M
authors.lastname: Shichiri
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Murata
authors.forename: Takanori
authors.initials: T
authors.lastname: Mori
authors.forename: Takeo
authors.initials: T
authors.lastname: Nakanishi
authors.forename: Ikumi
authors.initials: I
authors.lastname: Tamai
mesh_terms: D000042:Absorption; D000818:Animals; D001628:Beverages; D001665:Binding Sites; D001667:Binding, Competitive; D001692:Biological Transport; D032083:Citrus paradisi; D032084:Citrus sinensis; D004970:Estrone / Q000031:analogs & derivatives* / Q000378:metabolism; D018565:Food-Drug Interactions; D005638:Fruit; D007700:Kinetics; D027845:Malus; D009865:Oocytes; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016593:Terfenadine / Q000031:analogs & derivatives* / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D027361:Organic Anion Transporters; D004970:Estrone; D016593:Terfenadine; C093230:fexofenadine; C017296:estrone sulfate