Metabolites of bromazepam, a benzodiazepine, in the human, dog, rat, and mouse

The biotransformation of bromazepam, 7‐bromo‐1,3‐dihydro‐5‐(2‐pyridyl)‐2H‐1,4‐benzodiazepin‐2‐one, was studied in four species. Four metabolites were identified and their excretion was quantitatively determined. The major urinary metabolites excreted by three women given single 12‐mg. oral doses of bromazepam‐5‐¹⁴C were the conjugated forms of 3‐hydroxybromazepam (I), accounting for 13‐30% of the dose, and 2‐(2‐amino‐5‐bromo‐3‐hydroxybenzoyl)pyridine (IV), accounting for 4‐25% of the dose. Conjugated I was also the major metabolite in three dogs and four groups of mice administered ¹⁴C‐bromazepam, but its excretion by four rats was very limited. Together with I, Metabolite IV and 2‐(2‐amino‐5‐bromobenzoyl)pyridine were detected in the excreta of the human, dog, rat, and mouse. Although the pyridyl N‐oxide derivative of bromazepam was not detected as a metabolite in any species, the N₄‐oxide was a minor metabolite in dog urine. This is the first reported instance of metabolic N₄‐oxidation of a 1,4‐benzodiazepin‐2‐one.