Metabolism of 8-Chloro-6-phenyl-4H-s-triazolo[4,3-α][1,4]-benzodiazepine (D–40TA), a New Central Depressant. III. Metabolism and Tolerance Studies in Rats

Abstract

1. Induction in metabolism of D–40TA was studied in rats in relation to tolerance of its muscle relaxant effect. Pre-treatment with either D–40TA, nitrazepam or chlordiazepoxide reduced the paralysis time induced by D–40TA without concomitant alteration of its metabolism. D–40TA levels in blood, brain and spinal cord at the time of recovery from its muscle relaxant action were much higher in tolerant rats than in control ones. These results suggest that tolerance was caused by a decrease in the neuronal sensitivity to D–40TA.

2. Pre-treatment of D–40TA induced metabolism of aniline, aminopyrine, and zoxazolamine, while chlordiazepoxide induced that of aniline, aminopyrine, hexobarbital and zoxazolamine. These inducing properties of the benzodiazepines were somewhat different from those of phenobarbital or 3-methylcholanthrene. Phenobarbital also enhanced the metabolism of D–40TA.