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 cytochr ome P450 (CYP) enzymes, the authors studied the biotransformation of melato nin and the effects of fluvoxamine on the metabolism of melatonin in vitro using human liver microsomes and recombinant human CW isoenzymes. Melatonin was found to be almost exclusively metabolized by CYP1A2 to 6-hydroxymelat onin and N-acetylserotonin with a minimal contribution of CYP2C19. Both rea ctions were potently inhibited by fluvoxamine, with a K-i of 0.02 muM for t he formation of 6-hydroxymelatonin and 0.05 muM for the formation of N-acet ylserotonin. Other than fluvoxamine, fluoxetine, paroxetine, citalopram, im ipramine, and desipramine were also tested at 2 and 20 muM. Among the other antidepressants, only paroxetine was able to affect the metabolism of mela tonin at supratherapeutic concentrations of 20 muM, which did not reach by far the magnitude of the inhibitory potency of fluvoxamine. The authors con cluded that fluvoxamine is a potent inhibitor of melatonin degradation. Bec ause this inhibitory action is also found in vivo, fluvoxamine might be use d as an enhancer of melatonin, which might offer new therapeutic possibilit ies of fluvoxamine.