Hormonal effects on tirilazad clearance in women: Assessment of the role of CYP3A

This study assessed whether the previously reported difference in tirilazad clearance between pre- and postmenopausal women is reversed by hormone rep lacement and whether this observation can be explained by differences in CY P3A4 activity. Ten healthy women from each group were enrolled: premenopaus al (ages 18-35), postmenopausal (ages 50-70), postmenopausal receiving estr ogen, and postmenopausal women receiving estrogen and progestin. Volunteers received 0.0245 mg/kg midazolam and 3.0 mg/kg tirilazad mesylate intraveno usly on separate days, plasma tirilazad and midazolam were measured by HPLC /dual mass spectrophotometry (MS/MS) assays. Tirilazad clearance was signif icantly higher in premenopausal women (0.51 +/- 0.09 L/hr/kg) than in postm enopausal groups (0.34 +/- 0.07, 0.32 +/- 0.06, and 0.36 +/- 0.08 L/hr/kg r espectively) (p = 0.0001). Midazolam clearance (0.64 +/- 0.12 L/hr/kg) was significantly higher in premenopausal women compared to postmenopausal grou ps (0.47 +/- 0.11, 0.49 +/- 0.11, and 0.53 +/- 0.19 L/hr/kg, respectively) (p = 0.037). Tirilazad clearance was weakly correlated with midazolam clear ance (r(2) = 0.129, P = 0.02). Tirilazad clearance is faster in premenopaus al women than in postmenopausal women, but the effect of menopause on clear ance is not reversed by hormone replacement. Tirilazad clearance in these w omen is weakly related to midazolam clearance, a marker of CYP3A activity. Journal of Clinical Pharmacology, 1999;39:260-267 (C) 1999 the American Col lege of Clinical Pharmacology.