Effect of Gender and Menopausal Status on the Pharmacokinetics of Tirilazad Mesylate in Healthy Subjects.

The pharmacokinetics of tirilazad were assessed in men ages 40--60 years, women <40 years of age, premenopausal women ages 40--60, and postmenopausal ages 40--60. Eight subjects in each group received single 3.0 mg kg(minus sign1) intravenous infusions of tirilazad mesylate over 10 min. Plasma concentrations of tirilazad and U-89678, an active metabolite, were measured by high-performance liquid chromatography. Tirilazad administration was well tolerated in all groups. Mean tirilazad clearance was 59.6% higher in young women compared to the middle-aged men (35.6 plus minus 8.04 L h(minus sign1) vs. 22.3 plus minus 8.40 L h(minus sign1)). Mean tirilazad clearance in middle-aged women was 30.7% higher than in middle-aged men. Mean clearance in postmenopausal women (26.1 plus minus 4.21 L h(minus sign1)) was not significantly different than that in middle-aged men, but clearance corrected for body weight was significantly different between the men and postmenopausal women. Clearance in premenopausal middle-aged women (32.2 plus minus 7.60 L h(minus sign1)) was not significantly different from that in young women and was 44% greater than that in middle-aged men. Mean AUC(0minus signinfty infinity) and C(max) values for U-89678 were significantly higher in men than in all of the female groups. Among the women, values for U-89678 AUC(0minus signinfty infinity) were lowest in young women (467 plus minus 345 ng h ml(minus sign1), 8.8% of male value) and highest in postmenopausal women (1565 plus minus 1382 ng h ml(minus sign1), 29.4% of male value). The absolute values for U-89678 AUC(0minus signinfty infinity) must be interpreted with caution, as limited assay sensitivity and low plasma concentrations in the latter portion of the concentration-time profile in women precluded accurate determination of the terminal half-life and AUC(0minus signinfty infinity). Regardless, these results show that women, particularly premenopausal women, have lower concentrations of U-89678, an active metabolite of tirilazad, than are achieved in men. The gender differences in tirilazad and U-89678 pharmacokinetics are of sufficient magnitude that they may impact the clinical response of male and female patients to tirilazad treatment.