INDUCTION OF RAT LIVER MICROSOMAL DRUG-METABOLIZING ENZYMES BY A NEW SLEEP INDUCER 450191-S AND PLASMA LEVELS OF 450191-S-METABOLITES

Abstract

Liver microsomal 7-alkoxycoumarin O-dealkylase activities in rats were stimulated by the administration of large doses of 5-[(2-aminoacetamide) methyl]-1-[4-chloro-2-(o-chlorobenzoyl) phenyl]-N, N-dimethyl-1 H-s-triazole-3-carboxamide hydrochloride dihydrate (450191-s), a new sleep inducer which is a 1 H-1, 2, 4-triazolyl benzophenone derivative. To obtain the correlation between the stimulation or induction of hepatic enzymes and the plasma level of the metabolites of 450191-S, various amounts of 450191-S were administered orally to rats and the metabolites in plasma were determined by high performance liquid chromatography. Plasma concentration-time profiles for metabolites in rats showed the appearance of metabolites in plasma followed by their rapid disappearance from blood when the animals received non-inducing amounts of 450191-S. On the other hand, the profiles of metabolites in rats administered higher amounts of the drug showed very high plasma concentrations of metabolites, especially 8-chloro-6-(2-chlorophenyl)-N-methyl-4 H-1, 2, 4-triazolo [1, 5-a][1, 4] benzo diazepine-2-carboxamide (M-2) and 8-chloro-6-(2-chlorophenyl)-N-hydroxymethyl-4 H-1, 2, 4-triazolo [1, 5-a][, 4] benzodiazepine-2-carboxamide (M-A), which were maintained for a long time with slow elimination. These results led to the conclusion that the induction of hepatic drug-metabolizing enzymes is closely correlated with the high plasma concentrations of metabolites and their prolonged existence in plasma.