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Research ArticleMetabolism, Transport, and Pharmacogenomics

Carboxylesterase 1 as a Determinant of Clopidogrel Metabolism and Activation

Hao-Jie Zhu, Xinwen Wang, Brian E. Gawronski, Bryan J. Brinda, Dominick J. Angiolillo and John S. Markowitz
Journal of Pharmacology and Experimental Therapeutics March 2013, 344 (3) 665-672; DOI: https://doi.org/10.1124/jpet.112.201640
Hao-Jie Zhu
Department of Pharmacotherapy and Translational Research (H.-J.Z., X.W., B.E.G., B.J.B., D.J.A., J.S.M.) and Center for Pharmacogenomics (H.-J.Z., J.S.M.), University of Florida, Gainesville, Florida; Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, People’s Republic of China (X.W.); and Division of Cardiology, University of Florida, Jacksonville, Florida (D.J.A.)
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Xinwen Wang
Department of Pharmacotherapy and Translational Research (H.-J.Z., X.W., B.E.G., B.J.B., D.J.A., J.S.M.) and Center for Pharmacogenomics (H.-J.Z., J.S.M.), University of Florida, Gainesville, Florida; Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, People’s Republic of China (X.W.); and Division of Cardiology, University of Florida, Jacksonville, Florida (D.J.A.)
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Brian E. Gawronski
Department of Pharmacotherapy and Translational Research (H.-J.Z., X.W., B.E.G., B.J.B., D.J.A., J.S.M.) and Center for Pharmacogenomics (H.-J.Z., J.S.M.), University of Florida, Gainesville, Florida; Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, People’s Republic of China (X.W.); and Division of Cardiology, University of Florida, Jacksonville, Florida (D.J.A.)
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Bryan J. Brinda
Department of Pharmacotherapy and Translational Research (H.-J.Z., X.W., B.E.G., B.J.B., D.J.A., J.S.M.) and Center for Pharmacogenomics (H.-J.Z., J.S.M.), University of Florida, Gainesville, Florida; Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, People’s Republic of China (X.W.); and Division of Cardiology, University of Florida, Jacksonville, Florida (D.J.A.)
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Dominick J. Angiolillo
Department of Pharmacotherapy and Translational Research (H.-J.Z., X.W., B.E.G., B.J.B., D.J.A., J.S.M.) and Center for Pharmacogenomics (H.-J.Z., J.S.M.), University of Florida, Gainesville, Florida; Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, People’s Republic of China (X.W.); and Division of Cardiology, University of Florida, Jacksonville, Florida (D.J.A.)
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John S. Markowitz
Department of Pharmacotherapy and Translational Research (H.-J.Z., X.W., B.E.G., B.J.B., D.J.A., J.S.M.) and Center for Pharmacogenomics (H.-J.Z., J.S.M.), University of Florida, Gainesville, Florida; Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, People’s Republic of China (X.W.); and Division of Cardiology, University of Florida, Jacksonville, Florida (D.J.A.)
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Abstract

Clopidogrel pharmacotherapy is associated with substantial interindividual variability in clinical response, which can translate into an increased risk of adverse outcomes. Clopidogrel, a recognized substrate of hepatic carboxylesterase 1 (CES1), undergoes extensive hydrolytic metabolism in the liver. Significant interindividual variability in the expression and activity of CES1 exists, which is attributed to both genetic and environmental factors. We determined whether CES1 inhibition and CES1 genetic polymorphisms would significantly influence the biotransformation of clopidogrel and alter the formation of the active metabolite. Coincubation 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 G18V, S82L, and A269S 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 may 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.

Footnotes

  • dx.doi.org/10.1124/jpet.112.201640.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Received November 5, 2012.
  • Accepted December 27, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 344 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 344, Issue 3
1 Mar 2013
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Research ArticleMetabolism, Transport, and Pharmacogenomics

CES1 Affects Clopidogrel Metabolism and Activation

Hao-Jie Zhu, Xinwen Wang, Brian E. Gawronski, Bryan J. Brinda, Dominick J. Angiolillo and John S. Markowitz
Journal of Pharmacology and Experimental Therapeutics March 1, 2013, 344 (3) 665-672; DOI: https://doi.org/10.1124/jpet.112.201640

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Research ArticleMetabolism, Transport, and Pharmacogenomics

CES1 Affects Clopidogrel Metabolism and Activation

Hao-Jie Zhu, Xinwen Wang, Brian E. Gawronski, Bryan J. Brinda, Dominick J. Angiolillo and John S. Markowitz
Journal of Pharmacology and Experimental Therapeutics March 1, 2013, 344 (3) 665-672; DOI: https://doi.org/10.1124/jpet.112.201640
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