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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 1k-hydroxylation of midazolam. Methods In this randomised, double-blind, cross-over trial nine healthy female subjects received either a combined OC (30 mg ethinylestradiol and 75 mg 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 1k-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 1k-hydroxymidazolam by 25% (95% CI 10% to 41%; P=0.01), compared with placebo. The metabolic ratio (AUC of 1k-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 signi®cant differences in the C max , t max , t K 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 1k-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.

HRT with estradiol and levonorgestrel significantly increased plasma tacrine concentrations. This interaction between tacrine and HRT involves reduced metabolic conversion of tacrine to its main metabolite 1-hydroxytacrine by CYP1A2 during the first-pass phase. The interaction may be clinically important with regard to both enhanced efficacy and increased likelihood of concentration-dependent adverse effects of tacrine in the long-term treatment of patients with Alzheimer's disease. Accordingly, smaller doses of tacrine may be appropriate when coadministered with HRT.

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The objective of these investigations was to determine the possible effects of the novel selective estrogen receptor modulator, ospemifene, on cytochrome P450 (CYP)-mediated drug metabolism. Ospemifene underwent testing for possible effects on CYP enzyme activity in human liver microsomes and in isolated human hepatocytes. Based on the results obtained in vitro, three Phase 1 crossover pharmacokinetic studies were conducted in healthy postmenopausal women to assess the in vivo effects of ospemifene on CYP-mediated drug metabolism. Ospemifene and its main metabolites 4-hydroxyospemifene and 4′-hydroxyospemifene weakly inhibited a number of CYPs (CYP2B6, CYP2C9, CYP2C19, CYP2C8, and CYP2D6) in vitro. However, only CYP2C9 activity was inhibited by 4-hydroxyospemifene at clinically relevant concentrations. Induction of CYPs by ospemifene in cultured human hepatocytes was 2.4-fold or less. The in vivo studies showed that ospemifene did not have significant effects on the areas under the plasma concentration-time curves of the tested CYP substrates warfarin (CYP2C9), bupropion (CYP2B6) and omeprazole (CYP2C19), demonstrating that pretreatment with ospemifene did not alter their metabolism. Therefore, the risk that ospemifene will affect the pharmacokinetics of drugs that are substrates for CYP enzymes is low.