1986 Volume 1 Issue 4 Pages 363-376
The in vivo and in vitro metabolism of argipidine, the potential anti-thrombin agent, was studied in rats. Four metabolites were isolated from the bile of rats after intravenous administration of 14C-argipidine and from the incubation medium of argipidine supplemented with rat liver 9000 × g supernatant or rat hepatic microsomes, and were identified or presumed to be as follows; aromatized derivative of 3-methyltetrahydroquinoline (3 MTHQ) ring of argipidine (M-1), cis and trans forms of 4-hydroxy derivatives of 3 MTHQ ring (M-2 and M-3, respectively) and N-hydroxy derivative of 3 MTHQ ring (M-4). When added to rat hepatic microsomes, M-4 was also metabolized to M-1, and the conversion was NADPH and oxygen dependent. These findings suggested the aromatization of argipidine in the rat hepatic microsomes was stepwise oxidative reaction, with N-hydroxylation of argipidine as the initial step. And also, it was suggested that two independent pathways were present for biotransformation of argipidine in rat hepatic microsomes. Namely, M-2 and M-3 were produced by the catalysis of cytochrome P-450 monoxygenase system, and M-4 was produced by the catalysis of flavin-containing monoxygenase.
