Venous irritation, pharmacokinetics, and tissue distribution of tirilazad in rats following intravenous administration of a novel supersaturated submicron lipid emulsion

Purpose. To compare the venous irritation, pharmacokinetics, and tissue dis tribution of tirilazad in rats after intravenous administration of a submic ron lipid emulsion with that of an aqueous solution. Methods. Venous irritation was determined by microscopic evaluation of inju ry to the lateral tail veins of rats. Pharmacokinetic parameters were deter mined by following plasma concentrations of drug. Tissue distribution of [C -14]-tirilazad was determined by quantitative whole body autoradiography. Results. Single dose injections of tirilazad as an emulsion at doses rangin g from 1.52 mg to 13.5 mg were non-irritating whereas the solution was irri tating at a dose of 1.3 mg. The pharmacokinetic parameters were not statist ically different between the emulsion and the solution (p > 0.2) at doses o f 6 mg/kg/day and 20 mg/kg/day. However, at 65 mg/kg/day dose, a higher AUC (0,6) (4-fold) and lower V-ss (18-fold) and CL(S-fold) were observed for th e lipid emulsion as compared to the solution (p < 0.05). Tissue distributio n showed higher initial concentrations (two fold or more) in most tissues f or the solution. These values, however, equilibrated by 4 h and AUC(0,4) di fferences were less than two fold in most tissues. Conclusions. Formulating tirilazad in the lipid emulsion significantly redu ces the venous irritation without changing the pharmacokinetics and tissue distribution at low doses.