The metabolism of imipramine and its metabolites by rat liver microsomes

The metabolic pathways of imipramine and its metabolites by rat liver microsomes have been studied with the aim to obtain a comprehensive picture of the metabolism of imipramine and further insight into the action of the microsomal drug-metabolizing enzyme system. Paper- and thin-layer chromatography was used for detection and determination of metabolites; demethylation was additionally determined by formaldehyde assay. Imipramine is extensively metabolized and in addition to the known major metabolites, desmethylimipramine and 2-hydroxy-imipramine, all ten hitherto described metabolites of imipramine were found to be formed in the rat, nine of them in vitro. Time course-studies and the separate investigation of the metabolism of imipramine metabolites allow conclusions as to the sequence of metabolite formation, and primary, secondary and tertiary metabolites of imipramine can be distinguished. A total of sixteen metabolic pathways were detected: demethylations, aromatic hydroxylations, side chain dealkylations, N-oxidation, N-oxide reduction and conjugations. Based on these results an attempt was made to establish a comprehensive scheme of the metabolism of imipramine in the rat and to estimate relative conversion rates for the metabolic pathways.