COMMENT:
The drug interactions of oral contraceptives (OCs) are quite complex. They are both a victim to CYP3A4 inducers- leading to possible reduction of ethinyl estradiol concentration and pregnancy and to CYP3A inhibitors-- leading to increased adverse effects. The ethinyl estradiol component of OCs has been shown to be P450 cytochromal inhibitors of CYP2C9, CYP2C19, CYP2B6, intestinal CYP3A4 and CYP1A2. Melatonin, a substrate of CYP1A2, is a commonly used non-prescription hypnotic. This study shows that with co- administration of OCs and melatonin, the CMax of melatonin was increased 4-5 fold and that it is likely that melatonin's therapeutic index is wide since there was no increased sleepiness.

Although this DDI is likely of little clinical significance, it does remind clinicians to the possibility of more significant drug interactions with OCs combined with CYP1A2 substrates, such as clozapine, fluvoxamine, chlorpromazine, cyclobenzaprine, flutamide, ropinirole and others, some of which have had cases already reported in the literature. It is an exercise in rational prediction to assume that some women on OCs will have increased adverse effects with CYP1A2 substrates.

 ABSTRACT: J Clin Pharmacol. 2008 May 19. [Epub ahead of print] The Effect of Oral Contraceptives on the Pharmacokinetics of Melatonin in Healthy Subjects With CYP1A2 g.-163C>A Polymorphism Hilli J, Korhonen T, Turpeinen M, Hokkanen J, Mattila S, Laine K.

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 Cmax 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.