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The previous studies have shown that there was the species difference between rat and mouse inthe metabolic fate of KBT-3022, and that the O-demethylation of two methoxyphenyl groups of desethyl KBT-3022 (M9) was main metabolic pathway. The study of metabolism of M9 by rat liver, lung, kidney and small intestine 9, 000×g supernatant suggested that liver was the most active metabolizing organ. In this study, we have investigated the in vitro metabolism of M9 using 9, 000×g supern atant of liver homogenates of male rats and mice in order to clarify the species difference in the metabolic fate of M9. The metabolic activity of M9 and the O-demethylase activity of 9, 000×g supernatant of liver homogenates of rats were much higher than those of mice. The activity of demethylation of 5 methoxyphenyl group of M9 was higher than that of 4-methoxyphenyl group, both in rats and mice. However, in the demethylation of monodesmethylated M9 in rats, the activity of demethylation of 4-methoxyphenyl group was higher than that of 5-methoxyphenyl group. These results suggest that the species difference in the demethylation of M9 by 9, 000×g supernatant of liver homogenates relates to the species difference in the metabolic fate of KBT-3022.

yakubutsu dōtai

In Vitro Metabolism of Active Metabolite M9 of a New Antiplatelet Agent, Ethyl 2-(4,5-bis(4-methoxyphenyl)thiazol-2-yl)pyrrol-1-ylacetate (KBT-3022), in 9,000*g Supernatant of liver from Rats and Mice.