| Formation, Reactivity, and Anti-platelet Activity Of Mixed Disulfide Conjugates Of Clopidogrel. | |
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MedLine Citation:
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PMID: 23348501 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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In this work we investigated the formation, reactivity and anti-platelet activity of various mixed disulfide conjugates of clopidogrel. Our results showed that the production of the active metabolite (AM) from 2-oxoclopidogrel by human liver microsomes (HLMs) is greatly affected by the thiol reductants used. Among the ten thiol compounds tested, glutathione (GSH) is most efficient in producing the AM at a rate of 167 pmoles AM/min/mg HLM. Interestingly, no AM but only the mixed disulfide conjugates were formed in the presence of 6-chloropyridazine-3-thiol (CPT), 2,5-dimethylfuran-3-thiol (DFT), and 3-nitropyridine-2-thiol (NPT). The MS and MS2 spectra of the conjugates of these thiol compounds confirmed the presence of a mixed disulfide bond linkage between the AM and the thiol reductants. Kinetic studies revealed that the mixed disulfide conjugates were capable of exchanging thiols with GSH to release the AM with second order rate constants ranging from 1.2 to 28 M(-1)s(-1). The mixed disulfide conjugates of CPT and NPT showed potent inhibition of platelet aggregation after pre-treatment with 1 mM GSH, confirming that the AM is responsible for the anti-platelet activity of clopidogrel. Collectively, our results provide strong support for a P450-mediated bioactivation mechanism involving the initial formation of a glutathionyl conjugate followed by thiol-disulfide exchange with another GSH molecule to release the AM. Furthermore, the stable mixed disulfide conjugates identified in this study provide a platform to quantitatively generate the therapeutic AM without the need for P450-mediated bioactivation. This property can be further explored in order to overcome the inter-individual variability in clopidogrel therapy. |
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Authors:
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Haoming Zhang; D Adam Lauver; Benedict R Lucchesi; Paul F Hollenberg |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2013-1-24 |
Journal Detail:
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Title: Molecular pharmacology Volume: - ISSN: 1521-0111 ISO Abbreviation: Mol. Pharmacol. Publication Date: 2013 Jan |
Date Detail:
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Created Date: 2013-1-25 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0035623 Medline TA: Mol Pharmacol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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1 The University of Michigan; |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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