title: 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 1H-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-4H-1,2,4-triazolo [1,5-a] [1,4]benzodiazepine-2-carboxamide (M-2) and 8-chloro-6-(2- chlorophenyl)-N-hydroxymethyl-4H-1,2,4-triazolo [1,5-a] [1,4]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.
mesh_terms: D015660:7-Alkoxycoumarin O-Dealkylase; D000284:Administration, Oral; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000097:blood* / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D010105:Oxygenases / Q000096:biosynthesis*; D051381:Rats; D011919:Rats, Inbred Strains; D014230:Triazoles / Q000008:administration & dosage / Q000097:blood* / Q000494:pharmacology
chemical_list: D006993:Hypnotics and Sedatives; D014230:Triazoles; C041075:rilmazafone; D010105:Oxygenases; D015660:7-Alkoxycoumarin O-Dealkylase