title: Effect of endotoxin on tirilazad mesylate (U74006F) pharmacokinetic parameters in neonatal calves.
abstract: The pharmacokinetics of the 21-aminosteroid tirilazad mesylate (U74006F) were studied in both healthy and endotoxin-challenged neonatal calves. Group I calves received a 3-h intravenous (i.v.) infusion of sterile saline (250 ml) and tirilazad mesylate (1.5 mg/kg i.v.) 1 h after the start of the saline infusion. Group II calves received tirilazad mesylate 1 h after the start of a 3-h endotoxin (3.25 micrograms/kg) infusion. The data obtained indicate that tirilazad mesylate follows a biexponential equation in neonatal calves. The area-derived volume of distribution (Vdarea) was 9.68 +/- 0.759 l/kg in healthy calves and 6.53 +/- 1.20 l/kg in endotoxin-challenged calves (P < 0.05). Similarly, significant (P < 0.05) decreases in steady-state volume of distribution (Vdss) and central volume (Vc) were observed in endotoxin-challenged calves (5.32 +/- 0.979 l/kg and 1.68 +/- 0.189 l/kg, respectively) compared to healthy calves (7.58 +/- 0.834 l/kg and 2.43 +/- 0.452 l/kg, respectively). A and B were significantly larger in endotoxin-challenged calves than in healthy calves (P < 0.05). Rate constants and their associated half-lives, area under the curve and clearance were not significantly altered by endotoxin challenge. Serum thromboxane generation (ex vivo) was evaluated as a marker of the drug's physiologic activity. There was no significant difference in thromboxane generation during clotting of blood from healthy and endotoxemic calves treated with tirilazad mesylate.
authors.affiliation: Department of Surgical Sciences, University of Wisconsin School of Veterinary Medicine, Madison 53706.
authors.forename: M L
authors.initials: ML
authors.lastname: Rose
authors.forename: S D
authors.initials: SD
authors.lastname: Semrad
authors.forename: M L
authors.initials: ML
authors.lastname: Putnam
authors.forename: S A
authors.initials: SA
authors.lastname: Brown
mesh_terms: D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism*; D002417:Cattle; D002418:Cattle Diseases / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004731:Endotoxins; D005260:Female; D016166:Free Radical Scavengers; D008054:Lipid Peroxides / Q000037:antagonists & inhibitors*; D008297:Male; D011281:Pregnatrienes / Q000493:pharmacokinetics*; D013929:Thromboxane B2 / Q000097:blood; D014115:Toxemia / Q000378:metabolism / Q000662:veterinary*
chemical_list: D004731:Endotoxins; D016166:Free Radical Scavengers; D008054:Lipid Peroxides; D011281:Pregnatrienes; D013929:Thromboxane B2; C053355:tirilazad