Effect of an oral contraceptive preparation containing ethinylestradiol and gestodene on CYP3A4 activity as measured by midazolam 1'-hydroxylation.
OBJECTIVE
To characterize the effect of an oral contraceptive (OC) containing ethinylestradiol and gestodene on the activity of CYP3A4 in vivo as measured by the 1'-hydroxylation of midazolam.


METHODS
In this randomised, double-blind, cross-over trial nine healthy female subjects received either a combined OC (30 microg ethinylestradiol and 75 microg gestodene) or placebo once daily for 10 days. On day 10, a single 7.5 mg dose of midazolam was given orally. Plasma concentrations of midazolam and 1'-hydroxymidazolam were determined up to 24 h and the effects of midazolam were measured with three psychomotor tests up to 8 h.


RESULTS
The combined OC increased the mean AUC of midazolam by 21% (95% CI 2% to 40%; P = 0.03) and decreased that of 1'-hydroxymidazolam by 25% (95% CI 10% to 41%; P = 0.01), compared with placebo. The metabolic ratio (AUC of 1'-hydroxymidazolam/AUC of midazolam) was 36% smaller (95% CI 19% to 53%; P = 0.01) in the OC phase than in the placebo phase. There were no significant differences in the Cmax, tmax, t(1/2) or effects of midazolam between the phases.


CONCLUSIONS
A combined OC preparation caused a modest reduction in the activity of CYP3A4, as measured by the 1'-hydroxylation of midazolam, and slightly increased the AUC of oral midazolam. This study suggests that, at the doses used, ethinylestradiol and gestodene have a relatively small effect on CYP3A4 activity in vivo.
Palovaara
S
S
Department of Pharmacology and Clinical Pharmacology, University of Turku, Turku, Finland.
Kivistö
K T
KT
Tapanainen
P
P
Manninen
P
P
Neuvonen
P J
PJ
Laine
K
K
D000328:Adult; D003278:Contraceptives, Oral, Hormonal / 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; D045166:Estradiol Congeners / Q000494:pharmacology; D004997:Ethinyl Estradiol / Q000494:pharmacology*; D005260:Female; D006801:Humans; D006900:Hydroxylation / Q000187:drug effects; D008874:Midazolam / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000187:drug effects / Q000378:metabolism*; D009652:Norpregnenes / Q000494:pharmacology*; D045167:Progesterone Congeners / Q000494:pharmacology
D003278:Contraceptives, Oral, Hormonal; D045166:Estradiol Congeners; D009652:Norpregnenes; D045167:Progesterone Congeners; C033273:Gestodene; D004997:Ethinyl Estradiol; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam