Hormonal Effects on Tirilazad Clearance in Women: Assessment of the Role of CYP3A

• Published in: Journal of clinical pharmacology 1999-03, Vol.39 (3), p.260-267
• Main Authors: Fleishaker, Joseph C., Pearson, Laura K., Pearson, Paul G., Wienkers, Larry C., Hopkins, Nancy K., Peters, Gary R.
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Age Factors; Aged; Antioxidants - pharmacokinetics; Area Under Curve; Aryl Hydrocarbon Hydroxylases; Biological and medical sciences; Body Weight; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System - physiology; Drug Therapy, Combination; Estrogens - pharmacology; Estrogens - therapeutic use; Female; General pharmacology; Hormone Replacement Therapy; Humans; Medical sciences; Metabolic Clearance Rate; Midazolam - analogs & derivatives; Midazolam - blood; Midazolam - pharmacokinetics; Middle Aged; Miscellaneous; Oxidoreductases, N-Demethylating - physiology; Pharmacology. Drug treatments; Postmenopause - metabolism; Pregnatrienes - blood; Pregnatrienes - pharmacokinetics; Premenopause - metabolism; Progesterone - pharmacology; Progesterone - therapeutic use
• ISSN: 0091-2700; 1552-4604
• DOI: 10.1177/009127009903900309

This study assessed whether the previously reported difference in tirilazad clearance between pre‐ and postmenopausal women is reversed by hormone replacement and whether this observation can be explained by differences in CYP3A4 activity. Ten healthy women from each group were enrolled: premenopausal (ages 18–35), postmenopausal (ages 50–70), postmenopausal receiving estrogen, and postmenopausal women receiving estrogen and progestin. Volunteers received 0.0145 mg/kg midazolam and 3.0 mg/kg tirilazad mesylate intravenously on separate days. Plasma tirilazad and midazolam were measured by HPLC/dual mass spectrophotometry (MS/MS) assays. Tirilazad clearance was significantly higher in premenopausal women (0.51 ± 0.09 L/hr/kg) than in postmenopausal groups (0.34 ± 0.07, 0.32 ± 0.06, and 0.36 ± 0.08 L/hr/kg, respectively) (p = 0.0001). Midazolam clearance (0.64 ± 0.12 L/hr/kg) was significantly higher in premenopausal women compared to postmenopausal groups (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 clearance (r2 = 0.129, p = 0.02). Tirilazad clearance is faster in premenopausal women than in postmenopausal women, but the effect of menopause on clearance is not reversed by hormone replacement. Tirilazad clearance in these women is weakly related to midazolam clearance, a marker of CYP3A activity.