title: The effect of the cytochrome P-450 suicide inactivator, 1-aminobenzotriazole, on the in vivo metabolism and pharmacologic activity of flurazepam.
abstract: Flurazepam (F) is an extensively prescribed hypnotic (Dalmane) whose in vivo activity has been suggested to be due to its primary metabolites, hydroxyethyl flurazepam (HEF) and N-desalkylflurazepam (DAF). In order to determine the intrinsic pharmacologic activity of F, mice were administered various doses of the cytochrome P-450 suicide inactivator, 1-aminobenzotriazole (ABT), 1 hr before the ip administration of 1 mg/kg 14C-F. One hr after 14C-F, 70 mg/kg pentylenetetrazole was administered iv and the mice were observed for convulsions. F alone offered no protection from convulsion (mean brain concentrations were 3.9, 32, and 11 ng/g for F, DAF, and HEF, respectively). F with 25 mg/kg ABT also offered no protection despite a 6-fold increase in brain concentrations of F. F with 100 mg/kg ABT offered a 57% protection from convulsions (mean brain concentrations were 99, 62, and 41 ng/g for F, DAF, and HEF, respectively). One mg/kg F with 400 mg/kg ABT offered 100% protection from convulsions (brain concentrations were 190, 47, and 18 ng/g for F, DAF, and HEF, respectively). These data indicate that F has intrinsic pharmacologic activity which must be considered when evaluating the pharmacodynamics of F.
authors.affiliation: Department of Drug Metabolism, Hoffmann-La Roche Inc., Nutley, NJ 07110.
authors.forename: S
authors.initials: S
authors.lastname: Capello
authors.forename: L
authors.initials: L
authors.lastname: Henderson
authors.forename: F
authors.initials: F
authors.lastname: DeGrazia
authors.forename: D
authors.initials: D
authors.lastname: Liberato
authors.forename: W
authors.initials: W
authors.lastname: Garland
authors.forename: C
authors.initials: C
authors.lastname: Town
mesh_terms: D000818:Animals; D000927:Anticonvulsants; D001921:Brain / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D005479:Flurazepam / Q000378:metabolism* / Q000494:pharmacology; D006993:Hypnotics and Sedatives; D051379:Mice; D010433:Pentylenetetrazole / Q000037:antagonists & inhibitors; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D000927:Anticonvulsants; D065607:Cytochrome P-450 Enzyme Inhibitors; D006993:Hypnotics and Sedatives; D014230:Triazoles; C033020:1-aminobenzotriazole; D005479:Flurazepam; D010433:Pentylenetetrazole