GENDER DOES NOT AFFECT THE DEGREE OF INDUCTION OF TIRILAZAD CLEARANCEBY PHENOBARBITAL

Objective: Tirilazad mesylate is a membrane lipid peroxidation inhibit or being evaluated for the treatment of patients with subarachnoid hae morrhage (SAH); phenobarbital may be administered to these patients fo r seizure prophylaxis. Therefore, the effect of phenobarbital on tiril azad mesylate pharmacokinetics was assessed in 15 healthy volunteers ( 7M, 8F). Methods: Subjects received 100 mg phenobarbital orally daily for 8 days in one phase of a two-way crossover study. In both phases, 1.5 mg . kg(-1) tirilazad mesylate was administered (as a 10 minute IV infusion) every 6 hours for 29 doses. Three weeks separated study pha ses. Tirilazad mesylate and U-89678 (an active metabolite) in plasma w ere quantified by HPLC. Results: Phenobarbital had no effect on the fi rst dose pharmacokinetics of tirilazad or U-89678. After the final dos e, clearance for tirilazad was increased 25% in males and 29% in femal es receiving phenobarbital + tirilazad versus tirilazad mesylate alone . These differences were statistically significant, and the degree of induction was not significantly different between genders. AUC(0-6) fo r U-89678 after the last tirilazad mesylate dose was reduced 51% in ma les and 69% in females. The decreases were statistically significant, and there was no gender by treatment interaction. Conclusion: The resu lts show that phenobarbital induces metabolism of tirilazad and U-8967 8 similarly in both men and women. Lower levels of tirilazad and U-896 78 in SAH patients receiving phenobarbital may adversely impact clinic al response.