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Research ArticleArticle

Structure and Stereochemistry of the Active Metabolite of Clopidogrel

Jean-Marie Pereillo, Mohamed Maftouh, Alain Andrieu, Marie-Francoise Uzabiaga, Olivier Fedeli, Pierre Savi, Marc Pascal, Jean-Marc Herbert, Jean-Pierre Maffrand and Claudine Picard
Drug Metabolism and Disposition November 2002, 30 (11) 1288-1295; DOI: https://doi.org/10.1124/dmd.30.11.1288
Jean-Marie Pereillo
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Mohamed Maftouh
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Alain Andrieu
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Marie-Francoise Uzabiaga
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Olivier Fedeli
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Pierre Savi
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Marc Pascal
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Jean-Marc Herbert
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Jean-Pierre Maffrand
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Claudine Picard
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Abstract

Clopidogrel (SR25990C, PLAVIX) is a potent antiplatelet drug, which has been recently launched and is indicated for the prevention of vascular thrombotic events in patients at risk. Clopidogrel is inactive in vitro, and a hepatic biotransformation is necessary to express the full antiaggregating activity of the drug. Moreover, 2-oxo-clopidogrel has been previously suggested to be the essential key intermediate metabolite from which the active metabolite is formed. In the present paper, we give the evidence of the occurrence of an in vitro active metabolite after incubation of 2-oxo-clopidogrel with human liver microsomes. This metabolite was purified by liquid chromatography, and its structure was studied by a combination of mass spectometry (MS) and NMR experiments. MS results suggested that the active metabolite belongs to a family of eight stereoisomers with the following primary chemical structure: 2-{1-[1-(2-chlorophenyl)-2-methoxy-2-oxoethyl]-4-sulfanyl-3-piperidinylidene}acetic acid. Chiral supercritical fluid chromatography resolved these isomers. However, only one of the eight metabolites retained the biological activity, thus underlining the critical importance of associated absolute configuration. Because of its highly labile character, probably due to a very reactive thiol function, structural elucidation of the active metabolite was performed on the stabilized acrylonitrile derivative. Conjunction of all our results suggested that the active metabolite is of S configuration at C 7 and Z configuration at C 3–C 16 double bound.

Footnotes

  • Abbreviations used are::
    MS
    mass spectrometry
    SFC
    supercritical fluid chromatography
    PRP
    platelet-rich plasma
    HPLC
    high-performance liquid chromatography
    ESI
    positive electrospray ionization
    amu
    atomic mass unit(s)
    MS/MS
    tandem mass spectrometry
    EI
    electron impact
    CI
    chemical ionization
    DQF
    double quantum-filtered correlation spectroscopy
    ROESY
    rotating frame nuclear Overhauser enhancement spectroscopy
    HSQC
    heteronuclear single quantum correlation
    LC
    liquid chromatrography
    • Received February 15, 2002.
    • Accepted July 19, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (11)
Drug Metabolism and Disposition
Vol. 30, Issue 11
1 Nov 2002
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Research ArticleArticle

Structure and Stereochemistry of the Active Metabolite of Clopidogrel

Jean-Marie Pereillo, Mohamed Maftouh, Alain Andrieu, Marie-Francoise Uzabiaga, Olivier Fedeli, Pierre Savi, Marc Pascal, Jean-Marc Herbert, Jean-Pierre Maffrand and Claudine Picard
Drug Metabolism and Disposition November 1, 2002, 30 (11) 1288-1295; DOI: https://doi.org/10.1124/dmd.30.11.1288

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Research ArticleArticle

Structure and Stereochemistry of the Active Metabolite of Clopidogrel

Jean-Marie Pereillo, Mohamed Maftouh, Alain Andrieu, Marie-Francoise Uzabiaga, Olivier Fedeli, Pierre Savi, Marc Pascal, Jean-Marc Herbert, Jean-Pierre Maffrand and Claudine Picard
Drug Metabolism and Disposition November 1, 2002, 30 (11) 1288-1295; DOI: https://doi.org/10.1124/dmd.30.11.1288
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