Abstract
Sulpho-conjugation and glucuronic acid conjugation of 4 stereoisomers of troglitazone, a new anti-diabetic agent, were comparatively investigated in vitro using microsomal and cytosolic fractions of livers from male KK and male RFVL mice, male and female F344 rats, male cynomolgus monkeys and male and female humans. Isomerization at the 5-position of the thiazolidinedione ring was relatively rapid in the incubation medium, while there was no marked difference in the conjugation reactions between the stereoisomers at this position. Therefore, the comparison was made between the stereoisomers at the 2-position, i.e., 2S(5S or 5R) isomer and 2R(5S or 5R) isomer. Following results were obtained:
1. There was no marked species difference in the sulpho-conjugation reaction. The 2S isomers were more rapidly sulpho-conjugated than the 2R isomers. Rats exhibited a sex-related difference in this conjugation reaction, and the activity in male rats was about two times greater than that in female rats.
2. There was a species difference in the glucuronic acid conjugation reaction, as revealed by much higher activities in mice and monkeys than in other animal species. KK mice showed a higher glucuronidation activity for the 2R isomers than the 2S isomers. In contrast, other animal species, including the human, showed a higher activity for the 2S isomers than the 2R isomers.
