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 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.
Fleishaker
J C
JC
Clinical Pharmacokinetics Unit, Pharmacia and Upjohn, Inc, Kalamazoo, MI 49007, USA. joseph.c.fleishaker@am.pnu.com
Pearson
L K
LK
Peters
G R
GR
D000328:Adult; D000927:Anticonvulsants / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D000975:Antioxidants / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001259:Ataxia / Q000139:chemically induced; D018592:Cross-Over Studies; D004244:Dizziness / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000031:analogs & derivatives / Q000652:urine; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D009043:Motor Activity / Q000187:drug effects; D009759:Nystagmus, Pathologic / Q000139:chemically induced; D010672:Phenytoin / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D010744:Phosphoric Monoester Hydrolases / Q000097:blood / Q000187:drug effects; D011281:Pregnatrienes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D012894:Sleep Stages / Q000187:drug effects; D013997:Time Factors; D005723:gamma-Glutamyltransferase / Q000097:blood / Q000187:drug effects
D000927:Anticonvulsants; D000975:Antioxidants; D011281:Pregnatrienes; C087053:U 89678; C001380:6 beta-hydroxycortisol; D010672:Phenytoin; D005723:gamma-Glutamyltransferase; D010744:Phosphoric Monoester Hydrolases; D006854:Hydrocortisone; C053355:tirilazad