Drug and bile acid transporters in rosuvastatin hepatic uptake: Function, expression, and pharmacogenetics
Drug and bile acid transporters in rosuvastatin hepatic uptake: Function, expression, and pharmacogenetics
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DOI：
10.1053/j.gastro.2006.02.034
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发表时间：
2006-05-01
期刊：
影响因子：
29.4
通讯作者：
Kim, Richard B.
中科院分区：
文献类型：
--
作者：
Ho, Richard H.;Tirona, Rommel G.;Kim, Richard B.
背景与目的：3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶抑制剂或他汀类药物以肝脏HMG-CoA为靶点，在预防冠心病方面已被证明是有益的。瑞舒伐他汀是一种有效的他汀类药物，具有明显的肝脏选择性和缺乏明显的代谢。我们评估了肝脏转运体对瑞舒伐他汀摄取的影响程度和相关性。方法：通过多个人和大鼠摄取转运蛋白的异源表达，确定参与罗舒伐他汀摄取的转运蛋白。人有机阴离子转运多肽(OATP1b1)和钠依赖的牛磺胆酸共转运多肽(NTCP)等位基因变异体也被评估。从人的肝脏样本中检测了OATP和NTCP信使RNA和蛋白的表达。结果：包括1B1、1B3、2B1和1A2在内的多个OATP家族成员能够转运瑞舒伐他汀。自然发生的0ATP1B1基因的多态，包括*5、*9、*15和*18，与对瑞舒伐他汀活性的严重丧失有关。有趣的是，主要的人肝胆汁酸摄取转运体NtCP，而不是大鼠Ntcp，也转运了罗舒伐他汀。人类肝细胞研究表明，仅NTP一项就占瑞舒伐他汀摄取的35%。值得注意的是，已知的对胆汁酸几乎完全丧失功能的NTCP*2变体，显示出对瑞舒伐他汀功能的显著增强。定量信使RNA分析显示，OATPs和Ntcp的表达在受试者之间存在显著的变异性。结论：多个转运体介导了肝脏对瑞舒伐他汀的整体摄取，而NTCP可能是迄今为止未知的转运体，对瑞舒伐他汀和其他药物/他汀类药物在临床上的处置很重要。因此，转运蛋白的表达和多态可能是他汀类药物治疗反应中受试者间差异的关键决定因素。
Background & Aims: The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, target liver HMG-CoA and are of proven benefit in the prevention of coronary heart disease. Rosuvastatin is an effective statin notable for liver selectivity and lack of significant metabolism. We assessed the extent and relevance of hepatic transporters to rosuvastatin uptake. Methods: Transporters involved in rosuvastatin uptake were determined through heterologous expression of multiple human and rat uptake transporters. Human organic anion transporting polypeptide (OATP) 1B1 and sodium-dependent taurocholate cotransporting polypeptide (NTCP) allelic variants were also assessed. Expression of OATP and NTCP messenger RNA and protein was determined from a bank of human liver samples. Results: Multiple OATP family members, including 1B1, 1B3, 2B1, and 1A2, were capable of rosuvastatin transport. Naturally occurring polymorphisms in 0ATP1B1, including *5, *9, *15, and *18, were associated with profound loss of activity toward rosuvastatin. Interestingly, the major human hepatic bile acid uptake transporter NTCP, but not rat Ntcp, also transported rosuvastatin. Human hepatocyte studies suggested that NTCP alone accounted for similar to 35% of rosuvastatin uptake. Remarkably, NTCP*2, a variant known to have a near complete loss of function for bile acids, exhibited a profound gain of function for rosuvastatin. Quantitative messenger RNA analysis revealed marked intersubject variability in expression of OATPs and NTCP. Conclusions: Multiple transporters mediate the overall hepatic uptake of rosuvastatin, and NTCP may be a heretofore unrecognized transporter important to the disposition of rosuvastatin and possibly other drugs/statins in clinical use. Accordingly, transporter expression and polymorphisms may be key determinants of intersubject variability in response to statin therapy in general.