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Paraoxonase-1 is a major determinant of clopidogrel efficacy

Nature Medicine volume 17, pages 110–116 (2011)Cite this article

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A Corrigendum to this article was published on 07 September 2011

This article has been updated

Abstract

Clinical efficacy of the antiplatelet drug clopidogrel is hampered by its variable biotransformation into the active metabolite1,2. The variability in the clinical response to clopidogrel treatment has been attributed to genetic factors, but the specific genes and mechanisms underlying clopidogrel bioactivation remain unclear. Using in vitro metabolomic profiling techniques, we identified paraoxonase-1 (PON1) as the crucial enzyme for clopidogrel bioactivation, with its common Q192R polymorphism determining the rate of active metabolite formation. We tested the clinical relevance of the PON1 Q192R genotype in a population of individuals with coronary artery disease who underwent stent implantation and received clopidogrel therapy. PON1 QQ192 homozygous individuals showed a considerably higher risk than RR192 homozygous individuals of stent thrombosis, lower PON1 plasma activity, lower plasma concentrations of active metabolite and lower platelet inhibition. Thus, we identified PON1 as a key factor for the bioactivation and clinical activity of clopidogrel. These findings have therapeutic implications and may be exploited to prospectively assess the clinical efficacy of clopidogrel.

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Figure 1: Kinetics of clopidogrel-metabolizing enzymes.
Figure 2: Kaplan-Meier curves for individuals with coronary stent implantation and their pharmacokinetic and pharmacodynamic responses to clopidogrel.

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Change history

  • 21 December 2010

     In the version of this article originally published online, the affiliations for Hans-Günther Schmalz and Dirk Taubert appeared incorrectly. Hans-Günther Schmalz is in the Department für Chemie, Universität zu Köln, Cologne, Germany, and Dirk Taubert is in the Department of Pharmacology, University Hospital of Cologne, Cologne, Germany. These errors have been corrected for the print, PDF and HTML versions of the article.

  • 07 September 2011

     In the first paragraph on page 112, the authors made a typographical error: "constitutes part the active histidine dyad" should have been "is proximate to the active histidine dyad."

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Acknowledgements

We are grateful to all subjects who participated in the study. We thank numerous unnamed staff of our institutions for their efforts in subject recruitment, clinical, laboratory and experimental assessments.

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Authors and Affiliations

  1. Department of Cardiology, St. Antonius Hospital Nieuwegein, Nieuwegein, The Netherlands

    Heleen J Bouman, Jochem W van Werkum, Christian M Hackeng & Jurriën M ten Berg

  2. St. Antonius Center for Platelet Function Research, St. Antonius Hospital Nieuwegein, Nieuwegein, The Netherlands

    Heleen J Bouman, Jochem W van Werkum & Jurriën M ten Berg

  3. Department of Biochemistry, Cardiovascular Research Institute Maastricht, University Maastricht, Maastricht, The Netherlands

    Heleen J Bouman

  4. Department of Pharmacology, University Hospital of Cologne, Cologne, Germany

    Edgar Schömig & Dirk Taubert

  5. Department für Chemie, Universität zu Köln, Cologne, Germany

    Janna Velder, Christoph Hirschhäuser & Hans-Günther Schmalz

  6. Department of Clinical Chemistry, St. Antonius Hospital Nieuwegein, Nieuwegein, The Netherlands

    Christian M Hackeng

  7. Klinik und Poliklinik für Nuklearmedizin, Universität Münster, Münster, Germany

    Christopher Waldmann

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Contributions

J.W.v.W. and D.T. conceived the project. E.S., J.M.t.B. and D.T. supervised the project. H.J.B., J.W.v.W., J.V., C.M.H., C.H., C.W., H.-G.S. and D.T. conducted or directed bioanalytics of clopidogrel and its metabolites, metabolomic profiling, blood collection and sample preparation, aggregometry, genotyping and PON1 phenotyping. H.J.B., E.S., J.W.v.W., C.M.H., J.M.t.B. and D.T. conducted or directed recruitment of subjects, disease assessment and follow-up assessments. H.J.B., J.W.v.W. and D.T. did the computational and statistical data analyses. H.J.B. and D.T. wrote the manuscript.

Corresponding author

Correspondence to Dirk Taubert.

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The authors declare no competing financial interests.

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Supplementary Tables 1–10, Supplementary Figures 1–9 and Supplementary Methods (PDF 589 kb)

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Bouman, H., Schömig, E., van Werkum, J. et al. Paraoxonase-1 is a major determinant of clopidogrel efficacy. Nat Med 17, 110–116 (2011). https://doi.org/10.1038/nm.2281

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