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Xenobiotica
the fate of foreign compounds in biological systems
Volume 39, 2009 - Issue 3
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Research Article

Comparison of formation of thiolactones and active metabolites of prasugrel and clopidogrel in rats and dogs

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Pages 218-226 | Received 08 Oct 2008, Accepted 26 Nov 2008, Published online: 01 Mar 2009
 

Abstract

  1. Prasugrel and clopidogrel are antiplatelet prodrugs that are converted to their respective active metabolites through thiolactone intermediates. Prasugrel is rapidly hydrolysed by esterases to its thiolactone intermediate, while clopidogrel is oxidized by cytochrome P450 (CYP) isoforms to its thiolactone. The conversion of both thiolactones to the active metabolites is CYP mediated. This study compared the efficiency, in vivo, of the formation of prasugrel and clopidogrel thiolactones and their active metabolites.

  2. The areas under the plasma concentration versus time curve (AUC) of the thiolactone intermediates in the portal vein plasma after an oral dose of prasugrel (1 mg kg−1) and clopidogrel (0.77 mg kg−1) were 15.8 ± 15.9 ng h ml−1 and 0.113 ± 0.226 ng h ml−1, respectively, in rats, and 454 ± 104 ng h ml−1 and 23.3 ± 4.3 ng h ml−1, respectively, in dogs, indicating efficient hydrolysis of prasugrel and little metabolism of clopidogrel to their thiolactones in the intestine.

  3. The relative bioavailability of the active metabolites of prasugrel and clopidogrel calculated by the ratio of active metabolite AUC (prodrug oral administration/active metabolite intravenous administration) were 25% and 7%, respectively, in rats, and 25% and 10%, respectively, in dogs.

  4. Single intraduodenal administration of prasugrel showed complete conversion of prasugrel, resulting in high concentrations of the thiolactone and active metabolite of prasugrel in rat portal vein plasma, which demonstrates that these products are generated in the intestine during the absorption process.

  5. In conclusion, the extent of in vivo formation of the thiolactone and the active metabolite of prasugrel was greater than for clopidogrel’s thiolactone and active metabolite.

Acknowledgements

Declaration of interest: The authors report no conflicts of interest.

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