Pharmacokinetic correlation between in vitro hepatic microsomal enzyme kinetics and in vivo metabolism of imipramine and desipramine in rats.

A kinetic model capable of predicting the effect of the rate of intraportal imipramine infusion in rats on the steady-state concentrations of imipramine and its active metabolite, desipramine, was developed by using kinetic parameters obtained from in vitro studies. A nonlinear relationship was observed between steady-state concentrations of imipramine and desipramine (formed from imipramine) and the intraportal infusion rate of imipramine. Biliary and urinary excretion rates of both compounds were negligible compared with the corresponding infusion rate, and the free fractions of imipramine and desipramine in blood were constant over the concentration range used in this investigation. In vitro studies revealed that imipramine and desipramine 2-hydroxylations were mediated by a high-affinity and low-capacity (saturable) enzyme(s), while N-demethylation of imipramine (which formed desipramine) was mediated by a low-affinity and high-capacity (not saturable) enzyme(s). The adequate prediction of the steady-state concentrations of imipramine and desipramine by the proposed model was possible only after incorporating the mutual competitive inhibition between 2-hydroxylations of imipramine and desipramine, in addition to the incorporation of saturable kinetics of imipramine and desipramine 2-hydroxylations. Furthermore, the steady-state concentrations of desipramine were predicted to also be affected by the formation rate of desipramine, which increased nonlinearly with the increase in the rate of intraportal infusion of imipramine.