Pharmacokinetic aspects of the mode of action of EGYT-475, a new antidepressant agent.

EGYT-475 (N-benzyl-piperazine-picolinyl fumarate; Trelibet) metabolism was compared in rats, dogs and man. In the rat 7 urinary metabolites of EGYT-475 were found, and 4 were identified as: N-picolinyl-piperazine (EGYT-1354) (30%), picolinic acid (28.5%), hippuric acid (53%) and N-benzylpiperazine (EGYPT-2760) (3.7%). The results show that debenzylation is the main route of EGYT-475 metabolism in the rat. By this route EGYT-2760, the active EGYT-475 metabolite, is further metabolized. In the dog the main metabolic pathway is hydrolysis, and because of that the formed EGYT-2760 is not metabolized further and its urinary content exceeds 50%. In man, similarly as in the rat, debenzylation is the preferred route of EGYT-475 metabolism. These results explain much higher toxicity of EGYT-475 in dogs than in rats and man.