Non-competitive inhibition of clomipramineN-demethylation by fluvoxamine

Abstract

The selective serotonin reuptake inhibitor fluvoxamine interferes with the metabolism of tricyclic antidepressants. The present investigation was set out to characterize these interactions in vitro using rat liver microsomes and in vivo by analysing levels of clomipramine and metabolites in sera of depressed patients treated concomitantly with fluvoxamine and clomipramine. Clomipramine wasN-demethylated and hydroxylated in vitro by microsomes toN-desmethylclomipramine, 8-hydroxyclomipramine, and 10-hydroxyclomipramine. Kinetic analyses revealed K_m values of 6.2 µM forN-demethylation and 1.2 µM for 8-hydroxylation. Fluvoxamine was a non-competitive inhibitor forN-demethylation with mean K_i value of 6 µM. In the sera of patients treated with daily doses of 150 mg clomipramine and varying doses of fluvoxamine, decrease in the formation ofN-desmethylclomipramine and 8-hydroxyclomipramine were found in comparison to those in sera of patients receiving clomipramine as monotherapy. Taken together, the data give evidence that fluvoxamine is a potent non-competitive inhibitor ofN-demethylation and to a minor extent of 8-hydroxylation of clomipramine. Because of the species differences in the metabolism of xenobiotics between rodents and humans, conclusions from animal studies on the clinical situation must be drawn cautiously. Nevertheless, the in vitro approach was helpful to understand drug interactions between clomipramine and fluvoxamine in psychiatric patients.