title: Fluvoxamine but not citalopram increases serum melatonin in healthy subjects-- an indication that cytochrome P450 CYP1A2 and CYP2C19 hydroxylate melatonin.
abstract: OBJECTIVE
  The nocturnal serum melatonin (MT) level increases after ingestion of fluvoxamine (FLU)-- a selective serotonin re-uptake inhibitor (SSRI) with antidepressive properties. The mechanism behind the MT increase is unknown. 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 MT levels differently, inasmuch as the ways they inhibit cytochrome P450 (CYP) enzymes in the liver differ markedly. FLU inhibits CYP1A2 potently, and to some extent also CYP2C19, whereas CIT is without such an effect. CYP enzymes are probably involved in the hepatic metabolism of MT. If FLU, but not CIT, inhibits liver enzymes involved in the metabolism of MT, different serum MT concentrations should probably ensue. The objective of this investigation 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, placebo was given, in experiment B 40 mg CIT and in experiment C 50 mg FLU. All doses were given orally at 1600 hours. Serum MT concentrations were determined at regular intervals between 1600 hours and noon next day (20 h). Plasma concentrations of CIT were measured repeatedly in experiment B, and plasma FLU concentrations in experiment C. MT areas under the curve representing the 20-h period (MT-AUC(0-20)) were compared in the three experiments, and differences were statistically evaluated.
  
  
  RESULTS
  FLU augmented the MT-AUC(0-20) by a factor of 2.8 compared with the 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 placebo. In contrast, CIT did not influence the MT excretion. A clear relationship was found between serum levels of MT and plasma concentrations of FLU.
  
  
  CONCLUSIONS
  The serum MT level increased markedly after ingestion of FLU but not after CIT. The exact mechanism behind this finding is unknown, but decreased hepatic metabolism of MT by either CYP1A2 or CYP2C19, or both, is probable. Although exogenous MT, causing high MT concentration in plasma, has sleep-promoting properties in man, it is at this stage unknown whether serum MT concentrations in the range found in this study have similar effects. This has to be given further attention in additional studies.
authors.affiliation: Karolinska Institutet, Department of Medicine, Stockholm Söder Hospital, Sweden. christer.v.bahr@medklin.sos.sll.se
authors.forename: C
authors.initials: C
authors.lastname: von Bahr
authors.forename: C
authors.initials: C
authors.lastname: Ursing
authors.forename: N
authors.initials: N
authors.lastname: Yasui
authors.forename: G
authors.initials: G
authors.lastname: Tybring
authors.forename: L
authors.initials: L
authors.lastname: Bertilsson
authors.forename: S
authors.initials: S
authors.lastname: Röjdmark
mesh_terms: D000284:Administration, Oral; D000328:Adult; D018687:Antidepressive Agents, Second-Generation / Q000097:blood / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases; D015283:Citalopram / Q000097:blood / Q000494:pharmacology*; D019388:Cytochrome P-450 CYP1A2 / Q000187:drug effects / Q000378:metabolism*; D065731:Cytochrome P-450 CYP2C19; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism*; D004311:Double-Blind Method; D005260:Female; D016666:Fluvoxamine / Q000097:blood / Q000494:pharmacology*; D006801:Humans; D006900:Hydroxylation / Q000187:drug effects; D008297:Male; D008550:Melatonin / Q000097:blood* / Q000652:urine; D006899:Mixed Function Oxygenases / Q000187:drug effects / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000097:blood / Q000494:pharmacology*
chemical_list: D018687:Antidepressive Agents, Second-Generation; D001189:Aryl Hydrocarbon Hydroxylases; D015283:Citalopram; D019388:Cytochrome P-450 CYP1A2; D065731:Cytochrome P-450 CYP2C19; D003577:Cytochrome P-450 Enzyme System; D016666:Fluvoxamine; D008550:Melatonin; D006899:Mixed Function Oxygenases; D017367:Selective Serotonin Reuptake Inhibitors; C045793:CYP2C19 protein, human