PT  - JOURNAL ARTICLE
AU  - Jin-Zi Ji
AU  - Ting Tai
AU  - Bei-Bei Huang
AU  - Tong-Tong Gu
AU  - Qiong-Yu Mi
AU  - Hong-Guang Xie
TI  - Mrp3 transports clopidogrel acyl glucuronide from the hepatocytes into blood
AID  - 10.1124/dmd.117.078329
DP  - 2017 Jan 01
TA  - Drug Metabolism and Disposition
PG  - dmd.117.078329
4099  - http://dmd.aspetjournals.org/content/early/2017/12/07/dmd.117.078329.short
4100  - http://dmd.aspetjournals.org/content/early/2017/12/07/dmd.117.078329.full
AB  - 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 MRP3 is predominantly expressed in the sinusoidal side of hepatocytes, and preferentially transports glucuronide conjugates of drug metabolites from hepatocytes into bloodstream, it was hypothesized that MRP3 could be such an efflux transporter for CLP-G. In this study, the liver-to-plasma ratios of clopidogrel and its metabolites (including CLP-G) were compared between Abcc3 knock-out (KO) and wild-type (WT) mice, and ATP-dependent uptake of clopidogrel and CLP-G as well as estradiol-17-β-d-glucuronide into human recombinant MRP3 inside-out membrane vesicles was evaluated in the presence or absence of ATP. 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 αM 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. It is concluded that Mrp3 transports CLP-G from the hepatocytes into blood in an ATP-dependent manner.