Utility of Oatp1a/1b-Knockout and OATP1B1/3-Humanized Mice in the Study of OATP-Mediated Pharmacokinetics and Tissue Distribution: Case Studies with Pravastatin, Atorvastatin, Simvastatin, and Carboxydichlorofluorescein
Utility of Oatp1a/1b-Knockout and OATP1B1/3-Humanized Mice in the Study of OATP-Mediated Pharmacokinetics and Tissue Distribution: Case Studies with Pravastatin, Atorvastatin, Simvastatin, and Carboxydichlorofluorescein
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DOI：
10.1124/dmd.113.054783
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发表时间：
2014-01-01
影响因子：
3.9
通讯作者：
Zamek-Gliszczynski, Maciej J.
中科院分区：
文献类型：
--
作者：
Higgins, J. William;Bao, Jing Q.;Zamek-Gliszczynski, Maciej J.
虽然有机阴离子转运多肽（OATP）介导的肝脏摄取在大体的药代动力学水平上在啮齿动物和人类之间通常是保守的，但存在三种主要的肝脏OATP，它们在底物和抑制剂亲和力上有广泛的重叠，并且缺乏啮齿动物与人类的同源物，这阻碍了单基因敲除/敲入结果的临床翻译。目前，我们研究了普伐他汀、阿托伐他汀、辛伐他汀和羧基二氯荧光素在缺乏三种主要肝脏oatp亚型的oatp1a/1b敲除小鼠和肝脏特异性敲除人OATP1B1或OATP1B3基因的敲除小鼠体内的药代动力学和组织分布的变化。与野生型对照相比，oatp1a/1b基因敲除小鼠的静脉药物暴露增加了1.6- 19倍，口服药物暴露增加了2.1- 115倍，原因是清除率降低了33%-75%，分布体积减少了14%-60%，并且
Although organic anion transporting polypeptide (OATP)-mediated hepatic uptake is generally conserved between rodents and humans at a gross pharmacokinetic level, the presence of three major hepatic OATPs with broad overlap in substrate and inhibitor affinity, and absence of rodent-human orthologs preclude clinical translation of single-gene knockout/knockin findings. At present, changes in pharmacokinetics and tissue distribution of pravastatin, atorvastatin, simvastatin, and carboxydichlorofluorescein were studied in oatp1a/1b-knockout mice lacking the three major hepatic oatp isoforms, and in knockout mice with liver-specific knockin of human OATP1B1 or OATP1B3. Relative to wild-type controls, oatp1a/1b-knockout mice exhibited 1.6- to 19-fold increased intravenous and 2.1- to 115-fold increased oral drug exposure, due to 33%-75% decreased clearance, 14%-60% decreased volume of distribution, and