Differential effects of fluvoxamine and other antidepressants on the biotransformation of melatonin

Melatonin, the predominant product of the pineal gland, is involved in the maintenance of diurnal rhythms. Nocturnal blood concentrations of melatonin have been shown to be enhanced by fluvoxamine, but not by other serotonin reuptake inhibitors. Because fluvoxamine is an inhibitor of several cytochrome P450 (CYP) enzymes, the authors studied the biotransformation of melatonin and the effects of fluvoxamine on the metabolism of melatonin in vitro using human liver microsomes and recombinant human CYP isoenzymes. Melatonin was found to be almost exclusively metabolized by CYP1A2 to 6-hydroxymelatonin and N-acetylserotonin with a minimal contribution of CYP2C19. Both reactions were potently inhibited by fluvoxamine, with a Ki of 0.02 microM for the formation of 6-hydroxymelatonin and 0.05 microM for the formation of N-acetylserotonin. Other than fluvoxamine, fluoxetine, paroxetine, citalopram, imipramine, and desipramine were also tested at 2 and 20 microM. Among the other antidepressants, only paroxetine was able to affect the metabolism of melatonin at supratherapeutic concentrations of 20 microM, which did not reach by far the magnitude of the inhibitory potency of fluvoxamine. The authors concluded that fluvoxamine is a potent inhibitor of melatonin degradation. Because this inhibitory action is also found in vivo, fluvoxamine might be used as an enhancer of melatonin, which might offer new therapeutic possibilities of fluvoxamine

Non-competitive inhibition of clomipramine N-demethylation by fluvoxamine

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 was N-demethylated and hydroxylated in vitro by microsomes to N-desmethyl-clomipramine, 8-hydroxyclomipramine, and 10-hydroxyclomipramine. Kinetic analyses revealed Km values of 6.2 microM for N-demethylation and 1.2 microM for 8-hydroxylation. Fluvoxamine was a non-competitive inhibitor for N-demethylation with mean Ki value of 6 microM. In the sera of patients treated with daily doses 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 clomipramine as monotherapy. Taken together, the data give evidence that fluvoxamine is a potent non-competitive inhibitor of N-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