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

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 comb...

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Bibliographic Details
Published in:British journal of clinical pharmacology 2000-10, Vol.50 (4), p.333-337
Main Authors: Palovaara, Sanna, Kivistö, Kari T., Tapanainen, Pasi, Manninen, Pekka, Neuvonen, Pertti J., Laine, Kari
Format: Article
Language:English
Subjects:
Adult
Contraceptives, Oral, Hormonal - pharmacology
Cross-Over Studies
CYP3A4
Cytochrome P-450 CYP3A
Cytochrome P-450 Enzyme System - drug effects
Cytochrome P-450 Enzyme System - metabolism
Double-Blind Method
Drug Interaction
Estradiol Congeners - pharmacology
Ethinyl Estradiol - pharmacology
ethinylestradiol
Female
gestodene
Humans
Hydroxylation - drug effects
interaction
midazolam
Midazolam - metabolism
Mixed Function Oxygenases - drug effects
Mixed Function Oxygenases - metabolism
Norpregnenes - pharmacology
Progesterone Congeners - pharmacology
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Summary: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 µg ethinylestradiol and 75 µg 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, t½ 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.
ISSN:0306-5251
1365-2125
DOI:10.1046/j.1365-2125.2000.00271.x