The effect of the cytochrome P-450 suicide inactivator, 1-aminobenzotriazole, on the in vivo metabolism and pharmacologic activity of flurazepam.
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.
Capello
S
S
Department of Drug Metabolism, Hoffmann-La Roche Inc., Nutley, NJ 07110.
Henderson
L
L
DeGrazia
F
F
Liberato
D
D
Garland
W
W
Town
C
C
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*
D000927:Anticonvulsants; D065607:Cytochrome P-450 Enzyme Inhibitors; D006993:Hypnotics and Sedatives; D014230:Triazoles; C033020:1-aminobenzotriazole; D005479:Flurazepam; D010433:Pentylenetetrazole