1999 Volume 14 Issue 2 Pages 105-110
The in vitro metabolism of azasetron was investigated in the presence of liver microsomes each from male and female rats, and male dogs, in order to elucidate the cause of sex or species difference in the excretion of metabolites of azasetron hydrochloride observed in vivo. The NADPH generating system was required for each reaction process in azasetron metabolism. The N-oxidation of the azabicyclooctane ring was increased markedly with increasing pH from 7.4 to 8.5 in dog liver microsomal incubation mixture, while decreased markedly by exposure of microsomes to mild heat (50°C for 60 sec). Moreover, this N-oxidation was inhibited by methimazole (MTZ), but was hardly inhibited by metyrapone (MP). These results indicate that the N-oxidation of the azabicyclooctane ring is mainly catalyzed by the flavin-containing monooxygenases (FMO) in dog liver microsomes. The N-oxidation of the azabicyclooctane ring in rat liver microsomes were also increased markedly with increasing pH from 7.4 to 8.5 in the specimen, while still remained more than 40% of control activity when mildly heated microsomes were used. Moreover, this oxidation was partially inhibited by MTZ, MP and SKF-525A. These results indicate that both FMO and the cytochrome P-450 (P-450) take part equally in N-oxidation of the azabicyclooctane ring in rats. The activities of N-demethylation and hydroxylation of M1 were hardly decreased, when mildly heated microsomes were used, while strongly inhibited by SKF-525A and MP. Accordingly, it seems that N-demethylation and hydroxylation of Ml are catalyzed by P-450. As no difference was observed in the intrinsic clearance by liver (CLint) for azasetron N-demethylation between male rats and dogs, this reaction is apparently not related to species difference. The CLint of N-oxidation of the azabicyclooctane ring and hydroxylation of the benzene ring in male dogs were large in comparison with the values in male and female rats. Hence, the results strongly suggest that species difference in the excretion is caused by the difference of these enzyme activities. The CLint of N-demethylation of azasetron in male rats was large in comparison with the values in female rats. Therefore, sex difference in the excretion would attribute to the difference of this enzymatic activity between male and female rats.
