Biopharmaceutical characterization of 450191-S, a ring-opened derivative of 1, 4-benzodiazepine. I.

Desglycylated 450191-S, a labile precursor to M-1, can avoid extensive first-pass metabolism.

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    Study Author(s):
    Koike, M., Norikura, R., Yoshimori, T., Futaguchi, S., & Sugeno, K.
    Journal Name:
    Journal of pharmacobio-dynamics, 9, 7, 563-569
    Publication Date:
    1986
    Biopharmaceutical characterization of 450191-S, a ring-opened derivative of 1,4-benzodiazepine. I. Active metabolite levels in rat plasma.

    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.