RT Journal Article
SR Electronic
T1 Metabolism of an anxiolytic imidazobenzodiazepine by the dog.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 324
OP 328
VO 11
IS 4
A1 S J Kolis
A1 E J Postma
A1 T H Williams
A1 G J Sasso
A1 M A Schwartz
YR 1983
UL http://dmd.aspetjournals.org/content/11/4/324.abstract
AB 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.