Mrp3 Transports Clopidogrel Acyl Glucuronide from the Hepatocytes into Blood
Mrp3 Transports Clopidogrel Acyl Glucuronide from the Hepatocytes into Blood
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DOI：
10.1124/dmd.117.078329
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发表时间：
2018-02
影响因子：
3.9
通讯作者：
Jin-Zi Ji;T. Tai;Bei-Bei Huang-Bei;Tong-Tong Gu-Tong;Qiong-Yu Mi;Hong-Guang Xie
中科院分区：
文献类型：
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作者：
Jin-Zi Ji;T. Tai;Bei-Bei Huang-Bei;Tong-Tong Gu-Tong;Qiong-Yu Mi;Hong-Guang Xie
氯吡格雷酰基葡萄糖醛酸苷(CLP-G)是氯吡格雷在肝脏中产生的主要II相代谢物，可进一步排泄到尿液中；然而，目前尚不清楚CLP-G是否从肝细胞转运到血液中。由于多药耐药相关蛋白3(MRP3)主要表达在肝细胞的血窦侧，并优先将药物代谢产物的葡醛酸偶联物从肝细胞转运到血流中，我们推测MRP3可能是CLP-G的外流转运体。在这项研究中，我们比较了Abcc3(ATP结合盒，C亚家族，成员3)基因敲除(KO)小鼠和野生型(WT)小鼠肝/血浆中氯吡格雷及其代谢物(包括CLP-G)的比例。我们还评估了在有或没有三磷酸腺苷存在的情况下，氯吡格雷和氯吡格雷-G以及雌二醇-17β-d-葡萄糖醛酸苷依赖于三磷酸腺苷摄取重组人MRP3内向外膜囊泡的情况。结果表明，KO小鼠的肝/血浆比是WT小鼠的11倍，膜囊泡对CLP-G(各1或10μM)的摄取分别是AMP的11.8倍和3.8倍。我们认为，MRP3以一种依赖于ATP的方式将CLP-G从肝细胞转运到血液中。
Clopidogrel acyl glucuronide (CLP-G) is a major phase II metabolite of clopidogrel generated in the liver for further excretion into urine; however, it is unclear whether CLP-G transports from hepatocytes into blood. Because multidrug resistance-associated protein 3 (MRP3) is predominantly expressed in the sinusoidal side of hepatocytes and preferentially transports glucuronide conjugates of drug metabolites from hepatocytes into bloodstream, we hypothesized that MRP3 could be such an efflux transporter for CLP-G. In this study, we compared the liver-to-plasma ratios of clopidogrel and its metabolites (including CLP-G) between Abcc3 (ATP-binding cassette, subfamily C, member 3) knockout (KO) and wild-type (WT) mice. We also evaluated the ATP-dependent uptake of clopidogrel and CLP-G as well as estradiol-17β-d-glucuronide into human recombinant MRP3 inside-out membrane vesicles in the presence or absence of ATP. The results indicated that the liver-to-plasma ratio of CLP-G was 11-fold higher in KO mice than in WT mice, and that uptake of CLP-G (1 or 10 μM each) into the membrane vesicles was 11.8- and 3.8-fold higher in the presence of ATP than in the presence of AMP, respectively. We conclude that Mrp3 transports CLP-G from the hepatocytes into blood in an ATP-dependent manner.