Fluvoxamine but not citalopram increases serum melatonin in healthy subjects - an indication that cytochrome P-450 CYP1A2 and CYP2C19 hydroxylate melatonin

Objective: The nocturnal serum melatonin (MT) level increases after ingesti on of fluvoxamine (FLU) - a selective serotonin re-uptake inhibitor (SSRI) with antidepressive properties. The mechanism behind the MT increase is unk nown. Citalopram (CIT) is another SSRI. It is not known whether CIT affects the serum MT level. It may well be that these two compounds affect serum M T levels differently, inasmuch as the ways they inhibit cytochrome P-450 (C YP) enzymes in the liver differ markedly. FLU inhibits CYP1A2 potently, and to some extent also CYP2C19, whereas CIT is without such an effect. CYP en zymes are probably involved in the hepatic metabolism of MT. If FLU, but no t CIT, inhibits liver enzymes involved in the metabolism of MT, different s erum MT concentrations should probably ensue. The objective of this investi gation was to test this hypothesis. Methods: Seven healthy subjects participated in three different experiments , which were performed in random order 6-8 days apart. In experiment A, pla cebo was given, in experiment B 40 mg CIT and in experiment C 50 mg FLU. Al l doses were given orally at 1600 hours. Serum MT concentrations were deter mined at regular intervals between 1600 hours and noon next day (20 h). Pla sma concentrations of CIT were measured repeatedly in experiment B, and pla sma FLU concentrations in experiment C. MT areas under the curve representi ng the 20-h period (MT-AUC(0-20)) were compared in the three experiments, a nd differences were statistically evaluated. Results: FLU augmented the MT-AUC(0-20) by a factor of 2.8 compared with th e effect of placebo (P < 0.01), whereas CIT was without significant effect. More MT was excreted in the urine after ingestion of FLU than after placeb o. In contrast, CIT did not influence the MT excretion. A clear relationshi p was found between serum levels of MT and plasma concentrations of FLU. Conclusion: The serum MT level increased markedly after ingestion of FLU bu t not after CIT. The exact mechanism behind this finding is unknown, but de creased hepatic metabolism of MT by either CYP1A2 or CYP2C19, or both, is p robable. Although exogenous MT, causing high MT concentration in plasma, ha s sleep-promoting properties in man, it is at this stage unknown whether se rum MT concentrations in the range found in this study have similar effects . This has to be given further attention in additional studies.