NONCOMPETITIVE INHIBITION OF CLOMIPRAMINE N-DEMETHYLATION BY FLUVOXAMINE

The selective serotonin reuptake inhibitor fluvoxamine interferes with the metabolism of tricyclic antidepressants. The present investigatio n was set out to characterize these interactions in vitro using rat li ver microsomes and in vivo by analysing levels of clomipramine and met abolites in sera of depressed patients treated concomitantly with fluv oxamine and clomipramine. Clomipramine was N-demethylated and hydroxyl ated in vitro by microsomes to N-desmethylclomipramine, 8-hydroxyclomi pramine, and 10-hydroxyclomipramine. Kinetic analyses revealed K-m val ues of 6.2 mu M for N-demethylation and 1.2 mu M for 8-hydroxylation. Fluvoxamine was a non-competitive inhibitor for N-demethylation with m ean K-i value of 6 mu M. In the sera of patients treated with daily do ses of 150 mg clomipramine and varying doses of fluvoxamine, decrease in the formation of N-desmethylclomipramine and 8-hydroxyclomipramine were found in comparison to those in sera of patients receiving clomip ramine as monotherapy. Taken together, the data give evidence that flu voxamine is a potent non-competitive inhibitor of N-demethylation and to a minor extent of 8-hydroxylation of clomipramine. Because of the s pecies differences in the metabolism of xenobiotics between rodents an d humans, conclusions from animal studies on the clinical situation mu st be drawn cautiously. Nevertheless, the in vitro approach was helpfu l to understand drug interactions between clomipramine and fluvoxamine in psychiatric patients.