Pharmacokinetic Interaction between Neuroleptics and Tricyclic Antidepressants in the Rat

The metabolism and disposition of 14C-nortriptyline and 14C-imipramine in the rat was studied after intraperitoneal administration of single doses of the drug. With 14C-nortriptyline, it was found that concomitant administration of perphenazine caused a rise in plasma level and tissue concentration of unchanged nortriptyline. With 14C-imipramine, it was found that administration of perphenazine caused an increase in tissue concentration of imipramine, desipramine, and iminodibenzyl. At the same time total excretion by the faeces and the urinary excretion of glucuronides and other polar metabolites was decreased. The urinary excretion of imipramine-N-oxide was increased in perphenazine pretreated rats. These results indicate that perphenazine in rats inhibits the hydroxylation and/or glucuronide formation of imipramine, whereas demethylation, N-oxidation, and dealkylation seem to be unaffected. Dose response studies showed that perphenazine and chlorpromazine have equivalent potency with regard to the increased tissue concentration of 14C-imipramine.