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Research ArticleArticle

Effects of Omeprazole and Genetic Polymorphism of CYP2C19 on the Clopidogrel Active Metabolite

Xavier Boulenc, Nassim Djebli, Juan Shi, Laurent Perrin, William Brian, Robert Van Horn and Fabrice Hurbin
Drug Metabolism and Disposition January 2012, 40 (1) 187-197; DOI: https://doi.org/10.1124/dmd.111.040394
Xavier Boulenc
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Nassim Djebli
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Juan Shi
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Laurent Perrin
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William Brian
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Robert Van Horn
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Fabrice Hurbin
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Abstract

Clopidogrel is an antiplatelet agent widely used in cardiovascular diseases and an inactive prodrug that needs to be converted to an active metabolite in two sequential metabolic steps. Several CYP450 isoforms involved in these two steps have been described, although the relative contribution in vivo of each enzyme is still under debate. CYP2C19 is considered to be the major contributor to active metabolite formation. In the current study, net CYP2C19 contribution to the active metabolite formation was determined from exposure of the active metabolite in two clinical studies (one phase I study with well balanced genetic polymorphic populations and a meta-analysis with a total of 396 healthy volunteers) at different clopidogrel doses. CYP2C19 involvements were estimated to be from 58 to 67% in intermediate metabolizers (IMs), from 58 to 72% in extensive metabolizers (EMs), and from 56 to 74% in ultrarapid metabolizers (UMs), depending on the study and the dose. For this purpose, a static model was proposed to estimate the net contribution of a given enzyme to the secondary metabolite formation. This static model was compared with a dynamic approach (Simcyp model) and showed good consistency. In parallel, in vitro investigations showed that omeprazole is a mechanism-based inhibitor of CYP2C19 with KI of 8.56 μM and Kinact of 0.156 min−1. These values were combined with the net CYP2C19 contribution to the active metabolite formation, through a static approach, to predict the inhibitory effect at 80-mg omeprazole doses in EM, IM, and UM CYP2C19 populations, with good consistency, compared with observed clinical values.

Footnotes

  • This work was supported by sanofi-aventis and Bristol-Myers Squibb. The authors are all employees of sanofi-aventis. Editorial support was funded by sanofi-aventis and provided by Alpha-Plus Medical Communications Ltd.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    http://dx.doi.org/10.1124/dmd.111.040394.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    P450
    cytochrome P450
    clopi-H4 metabolite
    active metabolite of clopidogrel (H4)
    PPI
    proton pump inhibitor
    DDI
    drug-drug interaction
    MBI
    mechanism-based inhibition
    IM
    intermediate metabolizer
    EM
    extensive metabolizer
    UM
    ultrarapid metabolizer
    PBPK
    physiologically based pharmacokinetic
    HLM
    human liver microsomes
    LC
    liquid chromatography
    MS/MS
    tandem mass spectrometry
    AUC
    area under the plasma concentration versus time curve
    PM
    poor metabolizer
    LLOQ
    lower limits of quantification
    CI
    confidence interval.

  • Received May 6, 2011.
  • Accepted October 17, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (1)
Drug Metabolism and Disposition
Vol. 40, Issue 1
1 Jan 2012
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Research ArticleArticle

CLOPIDOGREL: OMEPRAZOLE EFFECT AND CYP2C19 POLYMORPHISM

Xavier Boulenc, Nassim Djebli, Juan Shi, Laurent Perrin, William Brian, Robert Van Horn and Fabrice Hurbin
Drug Metabolism and Disposition January 1, 2012, 40 (1) 187-197; DOI: https://doi.org/10.1124/dmd.111.040394

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Research ArticleArticle

CLOPIDOGREL: OMEPRAZOLE EFFECT AND CYP2C19 POLYMORPHISM

Xavier Boulenc, Nassim Djebli, Juan Shi, Laurent Perrin, William Brian, Robert Van Horn and Fabrice Hurbin
Drug Metabolism and Disposition January 1, 2012, 40 (1) 187-197; DOI: https://doi.org/10.1124/dmd.111.040394
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