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 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.

Comparison of the pharmacokinetics of tirilazad mesylate in healthy volunteers and stable subjects with mild liver cirrhosis.

OBJECTIVE: The pharmacokinetics of tirilazad mesylate and an active reduced metabolite, U89678, were studied in 7 volunteers with mild cirrhosis of the liver, and seven age, sex, weight and smoking status matched healthy normal volunteers. Subjects received a single intravenous infusion of 2.0 mg.kg-1 tirilazad mesylate over 10 min. RESULTS: Mean tirilazad AUCzero-infinity was 8.83 mumol h.l-1 and 18.6 mumol h.l-1 in healthy volunteers and cirrhotic subjects, respectively. Mean tirilazad clearance in cirrhotics (12.7 l.h-1) was approximately 2.1 fold lower than in healthy volunteers (27.8 l.h-1). The differences were statistically significant. Mean U-89678 AUCzero-infinity in cirrhotic subjects (3.88 mumol h.l-1) was 2.5 fold higher than in healthy controls (1.53 mumol h.l-1), but the difference was marginally significant. CONCLUSION: These results indicate that clearance of both tirilazad mesylate and U89678 is decreased in subjects with hepatic impairment. This observation may be attributed either to decreases in liver blood flow and/or intrinsic clearance. The results of this study thus suggest that increased monitoring and or a reduction in tirilazad dosing may be necessary in patients with hepatic impairment.

The lack of effect of smoking on the pharmacokinetics and pharmacodynamics of adinazolam and N-demethyladinazolam.

The pharmacokinetics and pharmacodynamics of adinazolam and N-demethyladinazolam (NDMAD) were evaluated in twelve healthy non-smokers (NS) and twelve smokers (S, > or = 20 cigarettes/day) following a single 60 mg dose of adinazolam mesylate sustained-release tablets in an open-label, parallel-group design. Venous blood samples were collected for up to 36 h following drug administration and assayed for adinazolam and NDMAD by HPLC. Urine samples were also collected and assayed for NDMAD by HPLC. Psychomotor performance was measured using the Neurobehavioral Evaluation System. No significant differences were observed in adinazolam oral clearance (51.8 +/- 25.8 versus 48.2 +/- 14.01 h-1) or peak adinazolam plasma concentrations (Cmax) (93.3 +/- 31.8 versus 90.4 +/- 18.0 ng ml-1) between groups. NDMAD AUC (2541 +/- 457 versus 2798 +/- 447 ng h ml-1) and Cmax (173 +/- 30.3 versus 175 +/- 26.9 ng ml-1) did not differ significantly between groups. NDMAD renal clearance was significantly lower in smokers than non-smokers (8.7 +/- 0.7 versus 10.7 +/- 2.71 h-1; p < 0.05), but the clinical significance of this observation is unclear. Marginally significant differences were seen between groups in the symbol-digit substitution and digit span (forward) tasks. The results suggest that smoking has little effect on adinazolam and NDMAD pharmacokinetics or psychomotor effects but that smoking may slightly decrease renal clearance of NDMAD.

Extent and variability of the first-pass elimination of adinazolam mesylate in healthy male volunteers.

The pharmacokinetics of adinazolam and N-desmethyladinazolam (NDMAD) were studied in 14 healthy male volunteers who received 15 mg adinazolam mesylate orally as a solution and 5 mg adinazolam mesylate intravenously in a crossover design. Two weeks prior to the crossover study, each subject received 5 mg/kg indocyanine green (ICG) as an intravenous bolus injection to estimate liver blood flow. The absolute bioavailability (F), calculated as the dose-corrected ratio of oral to iv adinazolam area under the curve (AUC) values, was found to be 39%. NDMAD AUC values were similar following oral and iv administration, and adinazolam mean absorption time was approximately 0.77 hr. Thus, adinazolam is completely and rapidly absorbed after oral administration in man; the incomplete bioavailability is due to first-pass metabolism. Mean liver blood flow, adinazolam systemic clearance, blood/plasma ratio, and extraction ratio were 1189 ml/min, 498 ml/min, 0.70, and 0.57, respectively. The extraction ratio agrees with that calculated as 1-F (0.62), suggesting that the liver is primarily responsible for first-pass metabolism of adinazolam. The unbound fraction of adinazolam in plasma was 0.31 (range, 0.25-0.36); adinazolam free intrinsic clearance (a reflection of metabolic capacity) was 4285 ml/min (range, 2168-6312 ml/min). These results suggest that the majority of the variability in adinazolam plasma concentrations following oral administration is due to the variability in the metabolic capacity of the liver for adinazolam, rather than variability in plasma protein binding.