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The Effect of Oral Contraceptives on the Pharmacokinetics of Melatonin in Healthy Subjects With CYP1A2 g.-163C>A Polymorphism

From the Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland and Clinical Pharmacology, TYKSLAB, Health Care District of Southwest Finland (Dr Hilli, Dr Laine); SFINX Drug Interaction Unit, Turku University Hospital, Turku, Finland (Dr Korhonen); Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland and Novamass Analytical Ltd, Oulu, Finland (Dr Turpeinen); and Department of Chemistry, University of Oulu, Oulu, Finland (Mr Hokkanen, Dr Mattila).

The effect of oral contraceptives (OCs) on melatonin metabolism was studied in 29 subjects genotyped for CYP1A2 SNP g.-163C>A polymorphism. Plasma melatonin and 6-OH-melatonin concentrations were measured after a 6-mg dose of melatonin using a validated liquid chromatography/mass spectrometry method. The mean melatonin AUC and C_max values were 4- to 5-fold higher in OC users than in non-OC users (P < .0001), whereas the weight-adjusted clearance was significantly lower in OC users (P < .0001). No significant difference in melatonin pharmacokinetics between the genotypes and no additional effect by the genotype on the OC-induced increase in melatonin exposure were evident. Melatonin exposure had no significant effect on the subjects' state of alertness. In conclusion, a significant inhibitory effect of OCs on the CYP1A2-catalyzed melatonin metabolism was seen; thereby, OC use can alter CYP1A2-phenotyping results.

Key Words: YP1A2 polymorphism • SNP g.-163C>A • melatonin • oral contraceptives • ethinylestradiol

Address for reprints: Johanna Hilli, MD, PhD, Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Itäinen Pitkäkatu 4B, 3rd Floor, FIN-20520 Turku, Finland; e-mail: johanna.hilli{at}utu.fi.