BIOPHARMACEUTICAL CHARACTERIZATION OF 450191-S, A RINGOPENED DERIVATIVE OF 1,4-BENZODIAZEPINE. I. ACTIVE METABOLITE LEVELS IN RAT PLASMA

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5-[(2-Aminoacetamido) methyl]-1-[p-chloro-2-(o-chlorobenzoyl) phenyl]-N, N-dimethyl-1H-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.
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