Pharmacokinetics of a novel antiangiogenic agent KR‐31831 in rats

Abstract

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.

Characterization of cytochrome P450 enzymes and P-glycoprotein involved in the metabolism and transport of a new anti-angiogenic agent KR-31831

“…The apical to basolateral P app value for KR-31831 was 11.7 Â 10 À6 cm/s, suggesting that KR-31831 may still be effectively absorbed in the intestinal tract. These results support the possibility that the low oral bioavailability of KR-31831 in rats [Kim et al, 2005a] may be more dependent on presystemic metabolism in the liver than on lack of absorption.…”

“…Although KR-31831 p.o. was almost completely absorbed in rats, the bioavailability was modest (36-46%), indicating considerable first-pass (liver, stomach, and intestine) metabolism in rats [Kim et al, 2004[Kim et al, , 2005a. In rats, KR-31831 was metabolized to N-(4-chlorophenyl)-N-(1H-imidazol-2-ylmethyl) amine by N-dealkylation and (2R,3R,4S)-6-amino-4-[N-(4-chlorophenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3-hydroxy-2-hydroxymethyl-3,4-dihydro-2-methyl-2H-1-benzopyran by the reduction of acetal group to hydroxymethyl group and 6-acetyl-KR-31831 by Nacetylation [Kim et al, 2005b].…”

Evaluation of Antiangiogenic Effects of a New Synthetic Candidate Drug KR-31831 on Xenografted Ovarian Carcinoma Using Dynamic Contrast Enhanced MRI

“…KR-31831 has been reported to suppress endothelial cell proliferation, tube formation, invasion, and migration in vitro (14, 15, 17). Also, KR-31831 inhibits vessel formation in the mouse Matrigel plug assay in vivo (15-17).…”

“…KR-31831 has been reported to suppress endothelial cell proliferation, tube formation, invasion, and migration in vitro (14, 15, 17). Also, KR-31831 inhibits vessel formation in the mouse Matrigel plug assay in vivo (15-17). Although the specific mechanisms underlying the anti-angiogenic effects of this new synthetic agent are not fully understood, the inhibitory mechanism of KR-31831 on tumor angiogenesis, especially on the VEGF-signaling pathway in human umbilical vein endothelial cells (HUVECs), has been thoroughly studied.…”

“…KR-31831 down-regulates VEGF-induced tumor formation and proliferation of HUVECs by inhibiting intracellular Ca 2+ release and phosphorylation of extracellular regulated kinase 1/2 (Erk1/2). Moreover, the expression of VEGF receptor 2 (VEGFR2 [also known as Flk-1 or KDR]) was also reduced by the treatment of KR-31831 (16, 17). …”