Pharmacokinetics of a novel antiangiogenic agent KR-31831 in rats

This study reports the absorption, dose-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 C1 (20.8-27.7ml/min/kg) and dose-normalized AUC (178.1-231 μg·min/ml based on the 5mg/kg dose) as a function of dose. However, V_ss 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 5-25mg/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 25mg/kg in rats. Orally administered KR-31831 could be eliminated mainly by the liver metabolic pathway.