SPECIES DIFFERENCES IN THE METABOLISM OF IMIPRAMINE AND DESMETHYLIMIPRAMINE (DMI)

Evidence presented in this paper indicates that differences in the metabolism of imipramine and DMI may partially explain the species variations in the pharmacologic response of these "antisedative" compounds.

Abstract

Imipramine and desmethylimipramine (DMI) in rats prevent and even reverse the sedative effects of reserpine and certain benzoquinolizines such as Ro 4-1284. The effects of these compounds, however, are not as apparent in rabbit or mouse. Evidence presented in this paper indicates that differences in the metabolism of imipramine and DMI may partially explain the species variations in the pharmacologic response of these antisedative compounds. In rats, imipramine is rapidly converted to DMI but this metabolite is slowly metabolized to other products. In rabbits and mice, imipramine and DMI are rapidly metabolized at about the same rate. Evidence is presented that man converts imipramine to DMI slowly, but metabolizes DMI even less rapidly. In accord with these findings, rat liver microsomes convert imipramine mainly to DMI and slowly metabolize DMI to other metabolites, whereas those from rabbit rapidly metabolize both imipramine and DMI mainly by reactions other than demethylation. These findings thus explain why DMI accumulates only in rat and man after the administration of imipramine and not in rabbits and mice.