Metabolism of a New Antiplatelet Agent, Ethyl 2-[4, 5-bis(4-methoxyphenyl)thiazol2-yl]pyrrol-1-ylacetate (KBT-3022), in Rats, Mice, Dogs and Humans

Abstract

The metabolism of a new antiplatelet agent, ethyl 2-[4, 5-bis(4-methoxyphenyl)thiazol-2-yl]pyrrol-1-ylacetate (KBT 3022), was studied in rats, mice, dogs and humans. We found 12 metabolites (M1-M12) after oral administration of KBT-3022 in rat's feces and bile, and identified M3, M5, M6 and M9. After KBT-3022 was hydrolyzed to M9, the demethylation of the methoxyphenyl groups in 4-or/and 5-positions of thiazol ring of M9 resulted in the formation of M3, M5, M6. Furtheremore, these metabolites may be conjugated to glucuronides or sulfates. M8 is probably a glucuronide of M9 as revealed by the results of treatments of with β-glucuronidase. There is the species difference in the rate of the demethylation, the rate of the demethylation in mouse and dog was slower than that in rat. In human, the unconjugated M9 was only detected in plasma, similarly as in mouse, while the unconjugated M9 and glucuronides of M3 and M5 were found in urine. Urinary excretion of the metabolites accounted for 0.32% of dose in human.
We considered that the metabolism of KBT-3022 in human was close to that in mouse.