Effect of fluoxetine pretreatment on plasma and tissue concentrations of desipramine in rats.

Because of clinical reports that fluoxetine co-administration has led to increased blood concentrations of desipramine and adverse clinical effects in depressed patients treated with desipramine, we investigated the effect of fluoxetine on desipramine metabolism by rat liver microsomes in vitro and on blood and brain concentrations of desipramine in rats treated with desipramine. Fluoxetine caused a concentration-dependent inhibition of the 2-hydroxylation and N-demethylation of desipramine in vitro. Fluoxetine increased blood and brain concentrations of desipramine and prolonged the half-life of desipramine in blood and brain in rats in vivo. The inhibition of desipramine metabolism by fluoxetine probably led to the increased blood levels of desipramine in the clinical cases and may have contributed to the acceleration of cortical beta adrenoreceptor downregulation reported in rats when desipramine and fluoxetine were co-administered.