Blood level, distribution, excretion, and metabolite pattern of [14C]-brotizolam in the rat, dog, and rhesus monkey.

Following oral and intravenous administration the absorption, distribution, metabolite pattern and excretion of 14C-labeled brotizolam (2-bromo-4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f]-1,2,4-triazolo [4,3-a]-1,4-diazepine, We 941, Lendormin), a new hypnotic, was studied in rats, dogs, and rhesus monkeys. Given orally to these species, [14C]-brotizolam was rapidly and extensively absorbed. The distribution of the radiolabeled drug was very fast indicated by blood level curves as well as by rat whole body autoradiography. [14C]-Brotizolam and its metabolites crossed the placenta; they also occurred in the milk of rats. In all species studied radioactivity was eliminated from blood with very similar half-lives ranging from 14.8 to 20.8 h. The renal portion of the total radioactivity elimination increased from 5.5% of the dose given to rats to 33.5% in rhesus monkeys and to 51.4% in dogs. Total excretion was complete 3 to 4 days after [14C]-brotizolam administration. Biliary excretion also occurred. In the species studied thin layer chromatographic separation of the biliarily and renally excreted radioactivity indicated a similar but not the same pattern of 2 to 3 major metabolites which were mostly totally conjugated. Unchanged [14C]-brotizolam was only excreted in minor quantities, if at all.