METABOLIC-FATE OF PREMAZEPAM, A NEW ANTI-ANXIETY DRUG, IN THE RAT AND THE DOG

  • 1 January 1984
    • journal article
    • research article
    • Vol. 12  (2) , 257-263
Abstract
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-(1H)-one, a new anti-anxiety agent, was carried out in rats and dogs given the 14C-labeled compound i.v. and po [orally]. 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 h in rats and 2 h in dogs. Unchanged premazepam is cleared faster in rats than in dogs, with half-lives about 1.7 and 2.7 h, respectively. Following oral dosage, 2/3 of the dose is eliminated in urine. From the urine of the 2 species, 8 metabolites and unchanged premazepam were identified. N-7-Desmethyl premazepam (I) 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. Rat and dog urine metabolites 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 which are quantitatively minor ones.