Effect of endotoxin on tirilazad mesylate (U74006F) pharmacokinetic parameters in neonatal calves

Rose, M.L., Semrad, S.D., Putnam, M.L., Brown, S.A. Effect of endotoxin on tirilazad mesylate (U74006F) pharmacokinetic parameters in neonatal calves.J. vet. Pharmacol. Therap. 16, 438–445.
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 g/kg) infusion. The data obtained indicate that tirilazad mesylate follows a biexponential equation in neonatal calves. The area-derived volume of distribution (V_darea) was 9.68 ± 0.759 1/kg in healthy calves and 6.53 ± 1.20 1/kg in endotoxin-challenged calves ( P < 0.05). Similarly, significant (P <0.05) decreases in steady-state volume of distribution (Vj_ss) and central volume (VJ were observed in endotoxin-challenged calves (5.32 ± 0.979 1/kg and 1.68 ± 0.189 1/kg, respectively) compared to healthy calves (7.58 ± 0.834 1/kg and 2.43 ± 0.452 1/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.