RT Journal Article
SR Electronic
T1 Metabolic fate of premazepam, a new anti-anxiety drug, in the rat and the dog.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 257
OP 263
VO 12
IS 2
A1 A Assandri
A1 D Barone
A1 P Ferrari
A1 A Perazzi
A1 A Ripamonti
A1 G Tuan
A1 L F Zerilli
YR 1984
UL http://dmd.aspetjournals.org/content/12/2/257.abstract
AB A study of the disposition and metabolism of premazepam, 3,7-dihydro-5-phenyl-6,7-dimethyl-pyrrole[3,4-e][1,4]diazepin-2-(1 H) -one, a new anti-anxiety agent, was carried out in rats and dogs given the 14C-labeled compound iv and po. In both species, after oral administration, both total radioactivity and the unchanged drug are rapidly absorbed and peak plasma levels are reached within 0.5-1 hr in rats and 2 hr in dogs. Unchanged premazepam is cleared faster in rats than in dogs, with half-lives about 1.7 and 2.7 hr, respectively. Following oral dosage, two-thirds of the dose is eliminated in urine. From the urine of the two species, eight metabolites and unchanged premazepam were identified. N-7-Desmethyl premazepam (l) is the major metabolite in rat urine (18% of the dose) but is not present in dog urine, while 6-hydroxymethyl premazepam is the most abundant metabolite in dog urine (25% of the dose) but is absent in rat urine. Metabolites III and IV from rat and dog urine are stable derivatives of the intermediate formed by the cleavage of the imine bond of the diazepine ring. A successive hydrolysis of the amidic bond of the same intermediate originates metabolites V-VIII, which are quantitatively minor ones.