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Paraoxonase-1 and clopidogrel efficacy

Nature Medicine volume 17, pages 1040–1041 (2011)Cite this article

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Opening of the thiolactone ring of 2-oxo-clopidogrel may lead to five thiol isomers: two cis-diastereoisomers with a Z configuration of the exocyclic double bond, two trans-diastereoisomers with an E configuration of this double bond and an endo-isomer in which the double bond has migrated from an exocyclic to an endocyclic position in the piperidine ring6 (Fig. 1). A recent optimized method for the specific, quantitative determination of clopidogrel-derived thiol metabolite isomers in human plasma of clopidogrel-treated subjects showed that the cis-thiol isomers are major metabolites and the endo-thiol isomer is a minor one6. One of the cis-thiol diastereoisomers was found to be very active toward the platelet P2Y12 receptor and is presumably responsible for clopidogrel activity6.

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Figure 1: Bioactivation of clopidogrel (CLO) and formation of different thiol isomers by esterase- and CYP-catalyzed metabolism of 2-oxo-clopidogrel.
Figure 2: HPLC profiles of incubations of 2-oxo-clopidogrel with or without NADPH.

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Acknowledgements

We thank F. Hurbin and S. Roy (Sanofi-Aventis, France) for a gift of authentic derivatives of the endo- and cis-thiols6.

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  1. Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8601, Université Paris Descartes, Paris, France

    Patrick M Dansette, Julien Rosi, Gildas Bertho & Daniel Mansuy

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  1. Patrick M Dansette
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  2. Julien Rosi
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  3. Gildas Bertho
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  4. Daniel Mansuy
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Correspondence to Patrick M Dansette.

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Dansette, P., Rosi, J., Bertho, G. et al. Paraoxonase-1 and clopidogrel efficacy. Nat Med 17, 1040–1041 (2011). https://doi.org/10.1038/nm.2436

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