Abstract

Metabolic studies with chlordiazepoxide-2-C¹⁴ in 3 species revealed half-lives of the drug levels in plasma of 22-24 hours in man, of 10-14 hours in the dog, and of 4-6 hours in the rat, confirming values obtained previously by spectrophotometric assay (Koechlin and D'Arconte, 1963). Metabolic degradation was extensive in all three species; the major metabolic pathways were similar in man and in the dog, but different. in the rat. In man, primary hydrolytic cleavage of the methylamino substituent at. C₂ led to a lactam derivative (7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one-4-oxide) . This metabolite was excreted as well as further cleaved to the amino acid ( N-(2-amino-5-chloro-α-phenylbenzylidine) glycine-N- oxide) which was excreted as such or as alkalilabile conjugates, the structure of which is not vet established. In the rat a basic derivative, absent in the urines of the dog and of man, represeated the major metabolite. Its properties indicated a metabolic attack altering the N₁—C₂ bond, possibly by substitution or reduction. In none of the 3 species could metabolic alteration of the henzophenone moiety or of the 4N-oxide function be detected. In the rat chlordiazepoxide was found to be distributed into all the tissues. In this species gastric secretion of the intact drug and hepatic secretion of its metabolites were demonstrated. A high sensitivity of chlordiaz-epoxide to light and to β-radiation of the incorporated isotope was encountered, elucidated, and controlled by special precautionary procedures.