Studies on drug metabolism by use of isotopes. XVI. Species differences in metabolism of 1-butyryl-4-cinnamylpiperazine hydrochloride.

Abstract

Species differences in the metabolism of 1-butyryl-4-cinnamyl [γ-14C] piperazine (I-14C) hydrochloride in mice, rabbits, guinea pigs, and rats were studied by a tracer technique in an attempt to select the most appropriate species of animals for the evaluation of safety use of this drug in man. After the administration of a single dose of 20 mg/kg I-14C, radioactive metabolites excreted in urine were analyzed. The excretion of I-14C and its metabolites in mice and rabbits was mostly in the urine (69.3%, 89.6%), while in rats and guinea pigs approximately a half of the total radioactivity appeared in the feces (57.1%, 41.7%). In these experimental animals, the main metabolic route of compound I was through p-hydroxylation, but the ratio of the p-hydroxylated metabolites to the total metabolites identified was differed considerably among these species (mice 95.4%, rabbits 97.7%, guinea pigs 68.7%, rats 74.2%). In guinea pigs and rats, 5-12% (percentage of the 14C-activity in the urine) of unchanged I-14C was detected in the urine, but in mice and rabbits, the amount of the unchanged compound was rather small (0.2-0.9%). The amount of benzoic acid, hippuric acid and their hydroxylated metabolites varied and were found to be 1-17% in guinea pigs and rats. In rabbits, a larger part of metabolites of I-14C were excreted as its conjugated form.