Received for publication March 12, 2009.
Revised June 15, 2009.
Accepted for publication June 16, 2009.

Metabolism of ticlopidine in rats: Identification of the main biliary metabolite as a GSH conjugate of S-oxide

Abstract

We have identified several novel metabolites of ticlopidine, a well-known anti-platelet agent, and have revealed its metabolic route in rats. The main biliary metabolite of ticlopidine was characterized as a GSH conjugate of ticlopidine S-oxide, in which conjugation had occurred at carbon 7a in the thienopyridine moiety. Quantitative analysis revealed that 29% of the dose was subjected to the formation of reactive intermediates followed by conjugation with GSH after oral administration of ticlopidine (22 mg /kg) to rats. In vitro incubation of ticlopidine with rat liver S9 fractions led to the formation of multiple metabolites, including 2-oxo-ticlopidine, the precursor for the pharmacologically active ticlopidine metabolite, [1-(2-chlorobenzyl)-4-mercaptopiperidin-(3Z)-ylidene]-acetic acid. A novel thiophene-ring opened metabolite with a thioketone group and a carboxylic acid moiety has also been detected after incubation of 2-oxo-ticlopidine with rat liver microsomes or upon incubation of ticlopidine with rat liver S9 fractions.

Key words: bioactivation, cytochrome P450 catalyzed oxidations, glutathione conjugates, reactive intermediate, reactive metabolites