Disposition of tirilazad (U74006F), a 21-aminosteroid, in the plasma, heart, brain, and liver of the rat.

Tirilazad mesylate (Freedox, Upjohn) is the first agent of a new class of compounds called lazaroids currently under clinical investigation for its potential beneficial effects following neurotrauma. Tirilazad's therapeutic effect is due to its ability to inhibit iron-dependent lipid peroxidation. This study was conducted in Sprague-Dawley rats to determine the basic pharmacokinetics and distribution of tirilazad into the brain, heart, and liver. Rats (N = 50) were killed in groups of five at 0, 10, 20, and 40 min, and at 1.5, 2, 3, 4, 6, and 8 hr after intravenous administration of 10 mg/kg of tirilazad mesylate. Tirilazad was assayed in plasma, heart, liver, and brain tissue by HPLC. Using the mean concentrations at each time point, pharmacokinetic parameters were estimated using standard noncompartmental techniques and statistical moment theory. Tirilazad was rapidly eliminated from the plasma with a half-life of 2.4 hr and clearance of 6.1 ml/min. The volume of distribution at steady-state was large, 4.8 liters/kg. The concentrations of tirilazad were highest in the liver and heart and lowest in the plasma and brain. Elimination from tissues paralleled elimination from plasma with half-lives of 1.9, 1.6, and 1.5 hr in the brain, heart, and liver, respectively. Tirilazad appears to be a highly extracted, hepatically eliminated drug, suggesting its clearance is dependent on liver blood flow, and alterations in plasma protein binding are unlikely to affect its clearance but may affect the fraction unbound.