Pharmacological action of some known and possible metabolites of brotizolam.

The two major metabolites of 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) in man are the hydroxylation products We 964 (hydroxylation in the methyl group at 9-position) and We 1061 (hydroxylation in 6-position). A structural isomer originating from the latter, We 1064, was found in the urine of dogs. In the same species the demethylation product We 956 was identified. In line with this demethylation the oxidation product Web 1175 might also be formed but was not yet detected. The dihydroxylated product Web 1073 which could arise either from We 964 or from We 1061 was discovered in monkeys. All compounds were investigated with respect to their pharmacological and acute toxicological properties in various experimental situations in mice and rats, and exhibited a profile of action quite similar to brotizolam. Effects of other kinds did not occur. None of the examined metabolites had a longer duration of action than the parent substance. The strength of activity in the various tests was, with very minor exceptions, less than that of brotizolam. All findings favor the conclusion that the various actions of brotizolam are mainly caused by the latter itself and not by its active metabolites. Also, the duration of action of brotizolam is not substantially determined by the pharmacokinetics of its metabolites.