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Effect of an oral contraceptive preparation containing ethinylestradiol and gestodene on CYP3A4 activity as measured by midazolam 1′‐hydroxylation
Author(s) -
Palovaara Sanna,
Kivistö Kari T.,
Tapanainen Pasi,
Manninen Pekka,
Neuvonen Pertti J.,
Laine Kari
Publication year - 2000
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1046/j.1365-2125.2000.00271.x
Subject(s) - ethinylestradiol , gestodene , midazolam , placebo , pharmacokinetics , cmax , cyp3a4 , oral administration , hydroxylation , endocrinology , pharmacology , desogestrel , chemistry , medicine , population , cytochrome p450 , metabolism , sedation , biochemistry , family planning , alternative medicine , environmental health , pathology , research methodology , enzyme
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 C max , t max , t ½ 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 .