Pharmacokinetics of a novel antiangiogenic agent KR-31831 in rats

This study reports the absorption, close-linearity and pharmacokinetics of a novel antiangiogenic agent KR-31831 in rats after i.v and oral administration at doses of 5, 10 and 25 mg/kg on both occasions. Concentrations of KR-31831 were determined by a validated LC/MS/MS assay method. After i.v injection, plasma concentration-time profiles showed multi-compartmental characteristics, and there were no significant differences in Cl (20.8-27.7 ml/min/kg) and dose-normalized AUC (178.1-231 mug . min/ml based on the 5 mg/kg dose) as a function of dose. However, V,, was significantly increased at the 25 mg/kg dose (4931 ml/kg) compared with those (2288-2421 ml/kg) at lower doses. Subsequently, t(1/2) was increased from 143-159 min at the lower doses to 304 min at the 25 mg/kg dose. The altered V-SS was found to be a result of reduced plasma protein binding at relatively high concentrations. Following oral administration (doses 5-23 mg/kg), the absolute oral bioavailability ranged from 37.8% to 46.3%, and there were no significant alterations in dose-normalized AUC, T-max, C-max and t(1/2) as a function of dose. The extent of urinary excretion was low for both i.v (0.35%-0.54%) and oral (0.13%-0.33%) doses. Further discussions on the chemical and microsomal stability were included. In conclusion, dose-independent absorption kinetics were observed at oral doses from 5 to 25 mg/kg in rats. Orally administered KR-31831 could be eliminated mainly by the liver metabolic pathway. Copyright (C) 2004 John Wiley Sons, Ltd.