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 [3H]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-17β-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.
Footnotes
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This investigation was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology, Japan, and by a grant from the Nakatomi Foundation.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.104.001909.
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ABBREVIATIONS: SN-38, 7-ethyl-10-hydroxycamptothecin; OATP, organic anion-transporting polypeptide; MRP, multidrug resistance-associated protein; P-gp, P-glycoprotein; BCRP, breast cancer resistance protein; SNP, single nucleotide polymorphism; SN-38G, SN-38 glucuronide; CPT-11, irinotecan hydrochloride; cRNA, complementary RNA; HPLC, high-performance liquid chromatography.
- Received August 19, 2004.
- Accepted December 16, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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