Effect of an oral contraceptive preparation containing ethinylestradiol and gestodene on CYP3A4 activity as measured by midazolam 1'-hydroxylation

Br J Clin Pharmacol. 2000 Oct;50(4):333-7. doi: 10.1046/j.1365-2125.2000.00271.x.


Aims: 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.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Contraceptives, Oral, Hormonal / pharmacology*
  • Cross-Over Studies
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / drug effects
  • Cytochrome P-450 Enzyme System / metabolism*
  • Double-Blind Method
  • Estradiol Congeners / pharmacology
  • Ethinyl Estradiol / pharmacology*
  • Female
  • Humans
  • Hydroxylation / drug effects
  • Midazolam / metabolism*
  • Mixed Function Oxygenases / drug effects
  • Mixed Function Oxygenases / metabolism*
  • Norpregnenes / pharmacology*
  • Progesterone Congeners / pharmacology


  • Contraceptives, Oral, Hormonal
  • Estradiol Congeners
  • Norpregnenes
  • Progesterone Congeners
  • Gestodene
  • Ethinyl Estradiol
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Midazolam