PMID: 9533108Apr 9, 1998Paper

Induction of tirilazad clearance by phenytoin

Biopharmaceutics & Drug Disposition
J C FleishakerG R Peters

Abstract

Tirilazad is a membrane lipid peroxidation inhibitor being studied for the management of subarachnoid hemorrhage; phenytoin is used for seizure prophylaxis in the same disorder. The induction of tirilazad clearance by phenytoin was assessed in 12 volunteers (6 male, 6 female). Subjects 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 by i.v. infusion every 6 h for 29 doses. Tirilazad mesylate and U-89678 (an active metabolite) in plasma were quantified by HPLC. After the final dose, tirilazad clearance was increased by 91.8% in subjects receiving phenytoin + tirilazad versus tirilazad alone. AUC0-6 for U-89678 after the last tirilazad dose was reduced by 93.1% by concomitant phenytoin. These effects were statistically significant. The time course of induction was consistent with that of phenytoin's effect on the ratio 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 conditions, tirilazad clearance approaches liver blood flow.

Citations

Nov 30, 2000·Current Treatment Options in Neurology·P G Esce, S J Haines
Sep 1, 2001·Environmental Toxicology and Pharmacology·N A Coleman
Sep 29, 2001·British Journal of Anaesthesia·R J Kavanagh, P C Kam
Mar 22, 2003·Acta Anaesthesiologica Scandinavica·H PleymO Dale
Jan 26, 2000·Critical Care Nursing Quarterly·E C Seidl
Oct 3, 2006·Current Opinion in Anaesthesiology·D K Menon, A C Summors

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