RT Journal Article SR Electronic T1 Carboxylesterase 1 as a determinant of clopidogrel metabolism and activation JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP jpet.112.201640 DO 10.1124/jpet.112.201640 A1 Hao-Jie Zhu A1 Xinwen Wang A1 Brian Gawronski A1 Bryan Brinda A1 Dominick Angiolillo A1 John Markowitz YR 2013 UL http://jpet.aspetjournals.org/content/early/2013/01/02/jpet.112.201640.abstract AB Clopidogrel pharmacotherapy is associated with substantial interindividual variability in clinical response which can translate into an increased risk of adverse outcomes. Clopidogrel is a recognized substrate of hepatic carboxylesterase 1 (CES1), and undergoes extensive hydrolytic metabolism in the liver ultimately forming an active metabolite. Significant interindividual variability in the expression and activity of CES1 exists, which is attributed to both genetic and environmental factors. The aim of the present study was to determine whether CES1 inhibition and CES1 genetic polymorphisms would significantly influence the biotransformation of clopidogrel and alter formation of the active metabolite. Co-incubation of clopidogrel with the CES1 inhibitor bis(4-nitrophenyl) phosphate in human liver s9 fractions significantly increased the concentrations of clopidogrel, 2-oxo-clopidogrel, and clopidogrel active metabolite, while the concentrations of all formed carboxylate metabolites were significantly decreased. As anticipated, clopidogrel and 2-oxo-clopidogrel were efficiently hydrolyzed by the cell s9 fractions prepared from wild type CES1 transfected cells. The enzymatic activity of the CES1 variants G143E and D260fs were completely impaired in terms of catalyzing the hydrolysis of clopidogrel and 2-oxo-clopidogrel. However, the natural variants G19V, S83L, and A270S failed to produce any significant effect on CES1-mediated hydrolysis of clopidogrel or 2-oxo-clopidogrel. In summary, deficient CES1 catalytic activity resulting from CES1 inhibition or CES1 genetic variation may be associated with higher plasma concentrations of clopidogrel-active metabolite and hence, enhance antiplatelet activity. Additionally, CES1 genetic variants have the potential to serve as a biomarker to predict clopidogrel response, and individualize clopidogrel dosing regimens in clinical practice.