Metabolism of an anxiolytic imidazobenzodiazepine by the dog

Abstract

14C-labeled 8-chloro-6-(2-chlorophenyl)-4H-imidazo [1,5a][1,4]-benzodiazepine-3-carboxamide hydrochloride, 1 X HCl, was administered iv to two dogs. 14C-1 X HCl was extensively metabolized; in one dog, only 2% of the administered radioactivity was excreted as unchanged 1. The 4-hydroxy derivative of 1, compound 2, accounted for an additional 5% of the dose. Three urinary metabolites were identified by enzyme hydrolysis and NMR spectroscopy as conjugates of the phenolic 3'-, 4'-, and 5'-hydroxy derivatives of 1. In both dogs, the 4'-hydroxy derivative was the major identified metabolite (21 and 15% of the dose). Oral administration of 100 mg/kg/day of unlabeled 1 to dogs for 11 weeks resulted in the excretion of four urinary metabolites, the conjugated 3'-hydroxy and 4'-hydroxy derivatives of both 1 and 2. This prominent excretion of conjugated phenolic metabolites does not fit the usual pattern of 1,4-benzodiazepine metabolism in the dog.