TY - JOUR T1 - Metabolism of Ticlopidine in Rats: Identification of the Main Biliary Metabolite as a Glutathione Conjugate of Ticlopidine <em>S</em>-Oxide JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1904 LP - 1915 DO - 10.1124/dmd.109.027524 VL - 37 IS - 9 AU - Shinji Shimizu AU - Ryo Atsumi AU - Tsunenori Nakazawa AU - Yuko Fujimaki AU - Kenichi Sudo AU - Osamu Okazaki Y1 - 2009/09/01 UR - http://dmd.aspetjournals.org/content/37/9/1904.abstract N2 - We have identified several novel metabolites of ticlopidine, a well known antiplatelet agent and have revealed its metabolic route in rats. The main biliary metabolite of ticlopidine was characterized as a glutathione (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 9000g supernatant fraction (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. ER -