Metabolic Interconversions and Binding of Imipramine, Imipramine-N-Oxide, and Desmethylimipramine in Rat Liver Slices

Abstract

1. Rat liver slices and microsomes were used to study metabolism, cellular transfer and binding of imipramine and imipramine-N-oxide (IPNO).

2. Imipramine permeates rapidly into slices and is avidly and strongly bound to microsomes. Concentrations in liver slice to incubation medium reach ratios of ten. The desmethylimipramine (DMI) formed shows even stronger binding than imipramine and little release into the cytosol occurs. IPNO is also formed from imipramine although part is reconverted to imipramine by extra-microsomal reductive enzymes. Both the capacity and strength of microsomal binding of IPNO are low, and the release of this metabolite into the medium is complete.

3. IPNO added to the medium also permeates into the liver cells, but more slowly than imipramine. This intracellular fraction is completely metabolized to imipramine and DMI. More DMI seems to be formed from IPNO by secondary microsomal metabolism of imipramine than by direct N-oxide demethylation. Again, imipramine and DMI are highly bound to the microsomes and released with difficulty. The characteristics of microsomal binding and release of IPNO are the same whether added exogenously or formed metabolically.

4. Time courses of the formation and disappearance of metabolites were measured in slices and homogenate as a function of temperature and NADPH-generating system added. Demethylation and N-oxidation of imipramine are higher in liver preparations from male than from female rats whereas the opposite holds for N-oxide reduction. Phenobarbital pretreatment increases demethylation and decreases N-oxidation of imipramine.