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.
RCT Entities:
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.
Authors: Margit Fröhlich; Jürgen Burhenne; Meret Martin-Facklam; Johanna Weiss; Michael von Wolff; Thomas Strowitzki; Ingeborg Walter-Sack; Walter E Haefeli Journal: Br J Clin Pharmacol Date: 2004-03 Impact factor: 4.335