caa a22 4500 477057519 CHVBK 20180405111350.0 cr unu---uuuuu 170330e19960401xx s 000 0 eng 10.1007/s002280050082 doi (NATIONALLICENCE)springer-10.1007/s002280050082 Gender does not affect the degree of induction of tirilazad clearance by phenobarbital [Elektronische Daten] [J. C. Fleishaker, L. K. Pearson, G. R. Peters] Abstract.: Objective: Tirilazad mesylate is a membrane lipid peroxidation inhibitor being evaluated for the treatment of patients with subarachnoid haemorrhage (SAH); phenobarbital may be administered to these patients for seizure prophylaxis. Therefore, the effect of phenobarbital on tirilazad 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 phases. Tirilazad mesylate and U-89678 (an active metabolite) in plasma were quantified by HPLC. Results: Phenobarbital had no effect on the first dose pharmacokinetics of tirilazad or U-89678. After the final dose, clearance for tirilazad was increased 25% in males and 29% in females receiving phenobarbital + tirilazad versus tirilazad mesylate alone. These differences were statistically significant, and the degree of induction was not significantly different between genders. AUC0-6 for U-89678 after the last tirilazad mesylate dose was reduced 51% in males and 69% in females. The decreases were statistically significant, and there was no gender by treatment interaction. Conclusion: The results show that phenobarbital induces metabolism of tirilazad and U-89678 similarly in both men and women. Lower levels of tirilazad and U-89678 in SAH patients receiving phenobarbital may adversely impact clinical response. Springer-Verlag Berlin Heidelberg, 1996 Key words Tirilazad nationallicence Phenobarbital nationallicence pharmacokinetics nationallicence gender effect nationallicence aminosteroid nationallicence antioxidant nationallicence inducer nationallicence cytochrome P-450 nationallicence Fleishaker J. C. Clinical Pharmacokinetics and Clinical Research Units 7215-24-2, The Upjohn Company, Kalamazoo, MI 49007, USA, US aut Pearson L. K. Clinical Pharmacokinetics and Clinical Research Units 7215-24-2, The Upjohn Company, Kalamazoo, MI 49007, USA, US aut Peters G. R. Clinical Pharmacokinetics and Clinical Research Units 7215-24-2, The Upjohn Company, Kalamazoo, MI 49007, USA, US aut https://doi.org/10.1007/s002280050082 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s002280050082 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Fleishaker J. C. Clinical Pharmacokinetics and Clinical Research Units 7215-24-2, The Upjohn Company, Kalamazoo, MI 49007, USA, US aut NATIONALLICENCE 700 1- Pearson L. K. Clinical Pharmacokinetics and Clinical Research Units 7215-24-2, The Upjohn Company, Kalamazoo, MI 49007, USA, US aut NATIONALLICENCE 700 1- Peters G. R. Clinical Pharmacokinetics and Clinical Research Units 7215-24-2, The Upjohn Company, Kalamazoo, MI 49007, USA, US aut Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer