Menstrual cycle variability in midazolam pharmacokinetics

Activity of cytochrome P450 3A4 (CYP3A4), the most abundant human P450 isof orm and responsible for metabolizing approximately half of all therapeutic agents, has been speculated to vary during the menstrual cycle. This invest igation evaluated CYP3A4 activity during the menstrual cycle, using midazol am clearance as a metabolic probe. Midazolam (1 mg IV) was administered to nonsmoking, nonpregnant female volunteers (N = 11, age 26 +/- 5 years) with normal menstrual cycles on three separate occasions during the same cycle: days 2 (menstrual phase), 13 (estradiol peak), and 21 (progesterone peak). Venous plasma midazolam concentrations were determined by gas chromatograp hy-mass spectrometry. Midazolam clearance was determined by noncompartmenta l and compartmental analysis. Midazolam plasma disposition did not differ b etween phases of the menstrual cycle. There was no significant difference i n any measure of midazolam clearance. Noncompartmental clearances (mean +/- SD) were 7.36 +/- 2.73, 6.34 +/- 3.58, and 6.23 +/- 2.04 ml/kg/min, respec tively, on days 2, 13, and 21 of the menstrual cycle. These results suggest no difference in hepatic CYP3A4 activity on menstrual cycle days 2, 13, an d 21. Consideration of menstrual cycle variability in the metabolism of CYP 3A4 substrates does not appear indicated in the dosing or design of clinica l trials. Journal of Clinical Pharmacology 1999;39:275-280 (C) 1999 the Ame rican College of Clinical pharmacology.