Clorazepate, correlation between metabolism and anticonvulsant activity

The metabolism and the anticonvulsant effect of clorazepate were followed for 2 h after its i.v. administration to mice. The ED50 of the drug was 12 mg/kg at 1 min against pentetrazole-induced convulsions (45 mg/kg i.v.), it reached a minimum at 1 h (2.0 mg/kg) and rose to 2.7 mg/kg at 2 h. The concentrations of unchanged clorazepate and its metabolites, desmethyldiazepam and oxazepam, were determined in plasma and brain after administration of the respective ED50s. Unchanged clorazepate could be detected in plasma for the first hour but never in brain, so it can be considered as inactive pro-drug. The brain concentrations of desmethyldiazepam and oxazepam after the respective ED50s of clorazepate were considerably higher at 1 and 15 min than after longer time intervals. This may be explained by a time lag needed to reach and bind to the benzodiazepine receptor.