The kinetic profiles of phenazepam and its hydroxylated derivative were compared in rat, dog, cat and man after administration of single oral doses of the parent compound. The absorption of phenazepam was reasonably rapid in all the species studied. Blood peak concentrations (Cmax) were reached at 1 h in rats (0.32 +/- 0.03 microgram/ml), at 0.5 h in dogs 0.54 +/- 0.10 microgram/ml), at about 2 h in cats (1.65 +/- 0.23 microgram/ml), about only at 4 h in man (0.038 microgram/ml) at the highest dose tested. The largest normalized (value/dose) Cmax and area under the curve (AUC) were observed in man, while the rat gave the lowest values. The half-life of phenazepam was about 60 h in man, 13.72 +/- 2.09 h in the cat, 6.35 +/- 2.32 h in the dog and 7.49 +/- 1.88 h in the rat (beta-half-life). 3-OH-phenazepam was rapidly detected in cat, rat, and dog blood but no measurable amounts (less than 3 ng/ml) were found in human blood. At the oral doses tested, the ratio of the AUC for 3-OH-phenazepam to phenazepam was 0.01, 0.48, and 0.53 in the dog, rat, and cat, respectively. The half-life of the metabolite was shorter than that of the parent compound in the dog, but it was comparable in the rat and longer in the cat. The results suggest that 3-OH-phenazepam might contribute to the overall pharmacological effects of the parent compound in those species in which it accumulates in significant amounts.

1. After intraperitoneal injection of rats with the new benzodiazepine (compound I), four metabolites (compounds II, III, IV and V) were found in the urine. 2. Compound II was identified as 7-bromo-5-(2'-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one by comparison of g.l.c. and mass spectral properties of the metabolite and synthetic compound. 3. Mass spectra of compound III and its acid hydrolysis products indicate that compound III contains a hydroxyl group in the C(5)-phenyl ring. 4. Compounds IV and V were identified by mass spectrometry as products of simultaneous aromatic hydroxylation and methoxylation of the diazepine I. 5. The major urinary excretion products are compounds III, IV and V. Only very small amounts of compounds I and II were detected.

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