Pharmacokinetics and metabolism of brotizolam in animals

Distribution, and excretion of [14C]-brotizolam were determined after oral and intravenous administration in the rat, dog, rhesus monkey, and, in part, in cattle. Main metabolites were identified. Brotizolam was rapidly and extensively absorbed. In the rat, dog, and monkey blood levels were analysed according to the time and height of maximum radioactivity concentration. Elimination half-lives ranged from 14.8 to 20.8 h. Whole body autoradiographic studies in the rat showed that [14C]-brotizolam and its metabolites were distributed throughout the organism. The placenta was crossed, and brotizolam was found in the milk of rats as well as in that of cows. In the rat, dog and monkey, brotizolam was almost completely metabolized into hydroxylated compounds which were rapidly eliminated as conjugates. After multiple-dose treatment, neither a tendency to accumulation of brotizolam and its metabolites nor enzyme induction were found in the rat or monkey.