Induction of ethinylestradiol and levonorgestrel metabolism by oxcarbazepine in healthy women.
OBJECTIVE
To evaluate the effect of oxcarbazepine (OCBZ) on the pharmacokinetic profile of steroid oral contraceptives.


METHODS
Twenty-two healthy women aged 18-44 years were recruited, and 16 of them completed the study. By using a randomized double-blind crossover design, each woman was studied in two different menstrual cycles, during which placebo or OCBZ (maintenance dosage, 1,200 mg/day) was given in randomized sequence for 26 consecutive days with a washout of at least one cycle in between. A steroid oral contraceptive containing 50 microg ethinylestradiol (EE) and 250 microg levonorgestrel (LN) was taken for the first 21 days of each cycle. Plasma concentrations of EE and LN were measured by gas chromatography-mass spectrometry in samples collected at regular intervals on days 21-23 of each cycle.


RESULTS
Compared with placebo, areas under the plasma concentration curves (AUC(0-24h, geometric means) decreased by 47% for both EE (from 1,677 to 886 pg.h/ml; p < 0.01) and LN (from 137 to 73 ng.h/ml; p < 0.01), during OCBZ treatment. Peak plasma EE concentrations decreased from 180 pg/ml during the placebo cycle to 117 pg/ml during the OCBZ cycle (p < 0.01), whereas peak plasma LN concentrations decreased from 10.2 to 7.7 ng/ml (p < 0.01). The half-lives of EE and LN also decreased from 13.6 to 7.9 h (p < 0.01) and from 28.8 to 15.8 h, respectively (p < 0.01).


CONCLUSIONS
OCBZ reduces plasma concentrations of the estrogen and progestagen components of steroid oral contraceptives, presumably by stimulating their CYP3A-mediated metabolism in the liver or gastrointestinal tract or both. Because this may lead to a decreased efficacy of the contraceptive pill, women treated with OCBZ should receive preferentially a high-dosage contraceptive and should be monitored for signs of reduced hormonal cover.
Fattore
C
C
Clinical Pharmacology Unit, University of Pavia, Italy.
Cipolla
G
G
Gatti
G
G
Limido
G L
GL
Sturm
Y
Y
Bernasconi
C
C
Perucca
E
E
D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases; D002220:Carbamazepine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism; D004311:Double-Blind Method; D004790:Enzyme Induction / Q000187:drug effects; D004997:Ethinyl Estradiol / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D005260:Female; D006207:Half-Life; D006801:Humans; D016912:Levonorgestrel / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D000078330:Oxcarbazepine; D010089:Oxidoreductases, N-Demethylating / Q000187:drug effects / Q000378:metabolism; D010919:Placebos
D000927:Anticonvulsants; D010919:Placebos; D002220:Carbamazepine; D004997:Ethinyl Estradiol; D016912:Levonorgestrel; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D000078330:Oxcarbazepine