Abstract

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.