INDUCTION OF TIRILAZAD CLEARANCE BY PHENYTOIN

Tirilazad is a membrane lipid peroxidation inhibitor being studied for the management of subarachnoid hemorrhage; phenytoin is used for seiz ure prophylaxis in the same disorder. The induction of tirilazad clear ance by phenytoin was assessed in 12 volunteers (6 male, 6 female). Su bjects received phenytoin orally every 8 h for 7 days (200 mg for nine doses and 100 mg for 13 doses) in one phase of a crossover study. In both study phases, 1.5 mg kg(-1) tirilazad mesylate was administered b y TV infusion every 6 h for 29 doses. Tirilazad mesylate and U-89678 ( an active metabolite) in plasma were quantified by HPLC. After the fin al dose, tirilazad clearance was increased by 91.8% in subjects receiv ing phenytoin + tirilazad versus tirilazad alone. AUC(0-6) for U-89678 after the last tirilazad dose was reduced by 93.1% by concomitant phe nytoin These effects were statistically significant. The time course o f induction was consistent with that of phenytoin's effect on the rati o of urinary 6 beta-hydroxycortisol to cortisol, a measure of hepatic CYP3A activity. The results show that phenytoin induces metabolism of tirilazad and U-89678 in healthy subjects and that, under these condit ions, tirilazad clearance approaches liver blood flow. (C) 1998 John W iley & Sons, Ltd.