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 Cl (20.8-27.7 ml/min/kg) and dose-normalized AUC (178.1-231 microg x min/ml based on the 5 mg/kg dose) as a function of dose. However, Vss was significantly increased at the 25 mg/kg dose (4931 ml/kg) compared with those (2288-2421 ml/kg) at lower doses. Subsequently, t1/2 was increased from 143-159 min at the lower doses to 304 min at the 25 mg/kg dose. The altered VSS was found to be a result of reduced plasma protein binding at relatively high concentrations. Following oral administration (doses 5-25 mg/kg), the absolute oral bioavailability ranged from 37.8% to 46.3%, and there were no significant alterations in dose-normalized AUC, Tmax, Cmax and t1/2 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.

Pharmacokinetic scaling of SJ-8029, a novel anticancer agent possessing microtubule and topoisomerase inhibiting activities, by species-invariant time methods.

This study examined the pharmacokinetic disposition of SJ-8029, a novel anticancer agent possessing microtubule and topoisomerase inhibiting activities, in mice, rats, rabbits and dogs after i.v. administration. The serum concentration-time curves of SJ-8029 were best described by tri-exponential equations in all these animal species. The mean Cl, V(ss) and t(1/2) were 0.3 l/h, 0.1 l and 63.2 min in mice, 1.5 l/h, 1.6 l and 247.7 min in rats, 13.8 l/h, 39.6 l and 245.9 min in rabbits, and 29.2 l/h, 44.6 l and 117.4 min in dogs, respectively. Based on animal data, the pharmacokinetics of SJ-8029 were predicted in humans using simple allometry and also by several species-invariant time transformations using kallynochron, apolysichron and dienetichron times. The human pharmacokinetic parameters of Cl, V(ss) and t(1/2) predicted by the simple allometry and various species-invariant time methods were 50.4-145.0 l/h, 369.0-579.8 l and 242.0-1448.3 min, respectively. These preliminary parameter values may be useful in designing early pharmacokinetic studies of SJ-8029 in humans.