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CHARACTERIZATION OF NOVEL DIHYDROTHIENOPYRIDINIUM AND THIENOPYRIDINIUM METABOLITES OF TICLOPIDINE IN VITRO: ROLE OF PEROXIDASES, CYTOCHROMES P450, AND MONOAMINE OXIDASES

Pharmacokinetics, Dynamics and Metabolism Department (D.K.D.) and Exploratory Medicinal Sciences (T.N.O.,), Pfizer Global Research and Development, Groton, Connecticut

Ticlopidine is an agent that inhibits adenosine diphosphate-induced platelet aggregation. Metabolic studies with ticlopidine have indicated that the principal routes of metabolism are N-dealkylation, N-oxidation, and oxidation of the thiophene ring. However, ticlopidine shares some structural features that are similar to those of cyclic tertiary amines such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and tetrahydroisoquinolines, which are converted to neurotoxic pyridinium metabolites, via the iminium (dihydropyridinium) species. The current in vitro studies examined the potential of ticlopidine to undergo a similar conversion by cytochrome P450 (P450), peroxidases, and monoamine oxidase (MAO). The results from these studies have suggested that ticlopidine undergoes an overall 4-electron oxidation to the novel thienopyridinium metabolite (M6) via the intermediate 2-electron oxidation product, the thienodihydropyridinium metabolite (M5) by P450, horseradish peroxidase, and myeloperoxidase and, to a lesser extent, by MAO. The structures of these metabolites were characterized by liquid chromatography (LC)-tandem mass spectrometry and LC-NMR. Qualitative studies with baculovirus-expressed P450s revealed the involvement of P450 3A4 in this conversion. Interestingly, M5 was the primary metabolite in the peroxidase-mediated reactions and was quite stable to air oxidation or disproportionation. It was less electrophilic and did not form cyanide, glutathione, or N-acetylcysteine adducts. On the other hand, M6 was the major metabolite in P450-catalyzed oxidation of ticlopidine. The results from this study have revealed that in addition to metabolism of the thiophene ring of ticlopidine, the tetrahydropyridine moiety of the compound is susceptible to a 2-electron and a 4-electron oxidation like other cyclic tertiary amines.

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