Chlordiazepoxide Metabolism as Related to the Reduction in the Aggressive Behaviour of Cynomolgus Primates

Abstract

1. Blood levels and tissue distribution of chlordiazepoxide and its major metabolites have been correlated with observed changes in ‘aggression” and ‘activity” following oral administration of the compound to cynomolgus (Macaca fascicularis) primates.

2. Distribution of ¹⁴C after a single oral dose of [2-¹⁴C] chlordiazepoxide (5 mg/kg) is indicative of rapid absorption, approximately 30% and 80% dose being absorbed by 0.25 h and 2 h respectively. Highest blood concentrations are observed 2-6 h after dosing. The relatively high content of ¹⁴C in the tissues and the corresponding low content in urine and faeces at 2-12 h after dosing are suggestive of tissue storage and/or enterohepatic recirculation.

3. Analysis of blood, brain and muscle for chlordiazepoxide and its major metabolites indicate that these are present 0.25 h after dosing. Chlordiazepoxide and its N-desmethylated derivative reach peak concentrations in all three tissues 2 h after dosing while the peak for ‘lactam” is attained at 6 h. In all 3 tissues chlordiazepoxide concentration falls relatively faster than its metabolites, the latter maintaining relatively constant and predominating concentration at 6-24 h after drug administration.

4. Reduction in ‘aggression” (72%) and ‘activity” (17%) observed in innately vicious primates takes place 2-4 h following administration of chlordiazepoxide. Between 6 and 24 h after dosing both ‘aggression” and ‘activity” returned to normal values.

5. Correlation of the tissue concentration of chlordiazepoxide and its metabolites with behavioural changes suggests that the observed reduction in aggressive behaviour is associated with the presence in blood, brain and muscle of unchanged chlordiazepoxide rather than its biotransformation products.