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.
Footnotes
- Received August 30, 2017.
- Accepted November 27, 2017.
↵1 J.-Z.J. and T.T. contributed equally to this work.
This work was supported in part by the National Natural Science Foundation of China [Grant 81473286], the Ministry of Human Resource and Social Security of China [Grant 2012-258], the Department of Science and Technology of the Province of Jiangsu [Grant BL2013001], and Nanjing First Hospital [Grant 31010300010339], China (all to Dr. H.-G. Xie). In addition, Dr. J.-Z. Ji is a recipient of the Technology Development Training Program funded by Nanjing Medical University [Grant 2015NJMUZD044], and Dr. H.-G. Xie is a recipient of the Distinguished Medical Experts of the Province of Jiangsu, People’s Republic of China.
- Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics
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