Parallel pathway interactions in imipramine metabolism in rats

The in vitro metabolic inhibitions between imipramine and its metabolites were investigated in rat liver microsomes. A type of precursor-metabolite interaction similar to that shown with lidocaine was observed in imipramine metabolism. Desipramine competitively inhibited the formation of 2-hydroxyimipramine from imipramine. Similarly, imipramine inhibited the formation of 2-hydroxydesipramine from desipramine. As in the cases of those 2-hydroxylations, a competitive inhibitory relationship also existed in the N-demethylation pathways of imipramine and 2-hydroxyimipramine. Studies on age-associated alterations of the metabolic rates of imipramine and its metabolites in rats demonstrated that N-demethylation activities of imipramine and of 2-hydroxyimipramine, which showed a large sex difference (male greater than female) in young rats, decreased markedly only in old male rats, while 2-hydroxylation activities of imipramine and desipramine, with no sex difference at any age, did not show a marked alteration in either sex. These data strongly suggest that the hydroxylation pathways of imipramine and desipramine and the demethylation pathways of imipramine and 2-hydroxyimipramine are each sharing the same species of cytochrome P-450. The in vivo metabolic inhibition between imipramine and desipramine was examined by simultaneous intraportal infusion of imipramine (25 nmol/min) and desipramine (175 nmol/min). The steady-state concentration of imipramine after simultaneous infusion was increased twofold over that after infusion of imipramine alone, without any change in the free fraction in blood.