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
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
复制标题
DOI：
10.1124/dmd.104.001909
复制
发表时间：
2005-03-01
影响因子：
3.9
通讯作者：
Tamai, I
中科院分区：
文献类型：
--
作者：
Nozawa, T;Minami, H;Tamai, I
盐酸伊立替康（CPT-11）是一种强效抗癌药物，在肝脏中转化为其活性代谢产物7-乙基-10-羟基喜树碱（SN-38）和其他代谢产物。伊立替康的分布和胃肠道毒性表现出广泛的患者间变异性。在此，我们使用编码野生型OATP 1B 1的SLCO 1B 1 *1a（OATP-C* 1a）稳定转染的HEK 293细胞，检查了有机阴离子转运多肽OATP 1B 1（OATP-C）（可将多种药物及其代谢产物从人体血液转运至肝脏）对伊立替康SN-38及其葡糖苷酸结合物（SN-38 G）肝脏处置的贡献。我们通过测量表达OATP 1B 1 * 1a和三种常见变体的非洲爪蟾卵母细胞的摄取活性，进一步研究了OATP 1B 1单核苷酸多态性的影响。在所有情况下，均观察到SN-38的转运活性，而伊立替康和SN-38 G未转运。此外，SN-38对OATP 1B 1介导的[H-3]雌酮-3-硫酸盐摄取具有显著抑制作用。在检查的变体中，OATP 1B 1 * 15（N130 D和V174 A;报告的等位基因频率10 - 15%）显示SN-38以及普伐他汀、雌酮-3-硫酸盐和雌二醇-17 β-葡糖苷酸的转运活性降低。本研究首次获得证据表明OATP 1B 1参与SN-38的肝脏分布，并且OATP 1B 1的遗传多态性可能导致伊立替康分布的已知患者间变异性。
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 [H-3] 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.