The Pharmacology of Imipramine and Related Antidepressants

Abstract

Publisher Summary This chapter describes the pharmacological characterization of the prototype agent—imipramine (I). The metabolism of imipramine, pharmacological effects utilized in the assessment of agents of the imipramine type, neurophysiological and behavioral explorations of imipramine, antidepressants chemically related to imipramine, and clinical studies with imipramine-like antidepressant agents are discussed. Three basic reactions participate in the metabolic transformation of imipramine in the body: (1) hydroxylation of the iminodibenzyl ring system at the 2-position; (2) glucuronide formation of the 2-hydroxy compound; and (3) demethylation. Of the known metabolites of I, 2-hydroxyimipramine occurs in the highest concentration in the brain of the rat. In the plasma, the main metabolite in several species, including monkeys and man, is 2-hydroxydemethylimipramine. There is marked difference between male and female rats in the demethylation of I. The brain levels of demethylimipramine (DMI) shortly after administration of I are much higher in the males than in the females. Because not only sex, but also considerable strain differences in the metabolism of I are observed, these differences may provide an explanation for the widely different results obtained in various laboratories concerning the relative efficacy of DMI and I in rat experiments as antireserpine agents.