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Abstract
1. Changes in ‘aggression’ and ‘activity’ observed in cynomolgus primates (Macaca fascicularis) following administration of a single 2·5 mg/kg oral dose of diazepam have been related to blood levels and tissue distribution of the parent compound and its major metabolites.
2. Distribution of 14C after a single oral dose of [2-14C]diazepam shows rapid absorption, 75% of the dose being absorbed by 2 h at which time highest blood concn. are observed. With the exception of muscle and carcass, tissue-to-blood ratios exceed 1·0 throughout 24 h. High 14C content in excreta between 2 and 12 h after dosing suggests hepatic recycling and/or tissue storage.
3. Analyses of blood, brain and muscle from 0·25 to 24 h after dosing show the presence of diazepam and its major metabolites as early as 0·25 h after dosing, the N-desmethyl derivative predominating throughout the 24 h period. The concn. of diazepam in all three tissues falls relatively faster than its metabolites.
4. Max. reduction in ‘aggression’ (79%) and ‘activity’ (14%) in primates occurs at 2 h. Both parameters return to control values 4–24 h after dosing.
5. Correlation of behavioural changes with tissue concn. of diazepam and its metabolites suggests that behaviour parallels change in concn. of unchanged diazepam, rather than its metabolites.