title: Biopharmaceutical characterization of 450191-S, a ring-opened derivative of 1,4-benzodiazepine. I. Active metabolite levels in rat plasma.
abstract: 5-[(2-Aminoacetamido)methyl]-1-[p-chloro-2-(o-chlorobenzoyl)phenyl ]-N,N-dimethyl-1 H-s-triazole-3-carboxamide hydrochloride dihydrate (450191-S), a sleep inducer, is a ring-opened derivative of 1,4-benzodiazepine and has been reported to be activated by intestinal aminopeptidases. In order to determine the biopharmaceutical significance of 450191-S as the ring-opened derivative of 1,4-benzodiazepine, we examined plasma levels of active metabolites in rats following oral administration of 450191-S or its primary active metabolite, 8-chloro-6-(2-chlorophenyl)-N,N-dimethyl-4H-1,2,4-triazolo [1,5-a] [1,4]benzodiazepine-2-carboxamide (M-1). By increasing the dose of 450191-S, the plasma level of the active metabolites increased dose-dependently, which appeared to be due to saturation of hepatic elimination. The areas under the plasma concentration-time curves of active metabolites at a dose of 30 mg/kg of 450191-S were 2- to 20-fold higher than those at the same dose of M-1 administration per se. These results appeared to be attributable to the presence of a labile precursor of M-1, desglycylated 450191-S, which could avoid extensive first-pass extraction by the liver. In conclusion, the results suggested that 450191-S is superior to M-1, since the former maintained higher plasma levels of the active metabolites.
mesh_terms: D000818:Animals; D001646:Bile / Q000378:metabolism; D001702:Biopharmaceutics; D001711:Biotransformation; D006993:Hypnotics and Sedatives / Q000097:blood* / Q000652:urine; D007700:Kinetics; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D014230:Triazoles / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D006993:Hypnotics and Sedatives; D014230:Triazoles; C041075:rilmazafone