title: Role of organic anion transporter OATP1B1 (OATP-C) in hepatic uptake of irinotecan and its active metabolite, 7-ethyl-10-hydroxycamptothecin: in vitro evidence and effect of single nucleotide polymorphisms.
abstract: Irinotecan hydrochloride (CPT-11) is a potent anticancer drug that is converted to its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), and other metabolites in liver. The disposition and gastrointestinal toxicity of irinotecan exhibit a wide interpatient variability. Here, we examined the contribution of an organic anion-transporting polypeptide, OATP1B1 (OATP-C), which transports a variety of drugs and their metabolites from blood to liver in humans, to the hepatic disposition of irinotecan, SN-38, and its glucuronide conjugate (SN-38G) by using HEK293 cells stably transfected with SLCO1B1*1a (OATP-C*1a) coding wild-type OATP1B1. We further examined the effect of single nucleotide polymorphisms in OATP1B1 by measuring uptake activity in Xenopus oocytes expressing OATP1B1*1a and three common variants. In all cases, transport activity for SN-38 was observed, whereas irinotecan and SN-38G were not transported. Moreover, SN-38 exhibited a significant inhibitory effect on OATP1B1-mediated uptake of [(3)H]estrone-3-sulfate. Among the variants examined, OATP1B1*15 (N130D and V174A; reported allele frequency 10-15%) exhibited decreased transport activities for SN-38 as well as pravastatin, estrone-3-sulfate, and estradiol-17beta-glucuronide. This study is the first to yield evidence that OATP1B1 is involved in the hepatic disposition of SN-38 and that genetic polymorphisms of OATP1B1 may contribute to the known interpatient variability in disposition of irinotecan.
authors.affiliation: Department of Molecular Biopharmaceutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamasaki, Noda, Chiba 278-8510, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nozawa
authors.forename: Hironobu
authors.initials: H
authors.lastname: Minami
authors.forename: Shigeki
authors.initials: S
authors.lastname: Sugiura
authors.forename: Akira
authors.initials: A
authors.lastname: Tsuji
authors.forename: Ikumi
authors.initials: I
authors.lastname: Tamai
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D002460:Cell Line; D002478:Cells, Cultured; D004970:Estrone / Q000031:analogs & derivatives / Q000378:metabolism; D005260:Female; D020719:Glucuronides / Q000493:pharmacokinetics; D006801:Humans; D000077146:Irinotecan; D008099:Liver / Q000378:metabolism; D027381:Liver-Specific Organic Anion Transporter 1 / Q000235:genetics* / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D059004:Topoisomerase I Inhibitors; D014981:Xenopus
chemical_list: C441475:7-ethyl-10-hydroxycamptothecin glucuronide; D000972:Antineoplastic Agents, Phytogenic; D020719:Glucuronides; D027381:Liver-Specific Organic Anion Transporter 1; D059004:Topoisomerase I Inhibitors; D004970:Estrone; D000077146:Irinotecan; C017296:estrone sulfate; D002166:Camptothecin