title: 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.
authors.affiliation: Drug Metabolism and Bioanalysis Laboratory, College of Pharmacy, Wonkwang University, Iksan 570-749, Korea.
authors.forename: Sook J
authors.initials: SJ
authors.lastname: Kim
authors.forename: Hong I
authors.initials: HI
authors.lastname: Lee
authors.forename: Hye Y
authors.initials: HY
authors.lastname: Ji
authors.forename: Ya
authors.initials: Y
authors.lastname: Moon
authors.forename: In B
authors.initials: IB
authors.lastname: Paek
authors.forename: Sunkyung
authors.initials: S
authors.lastname: Lee
authors.forename: Kyu Y
authors.initials: KY
authors.lastname: Yi
authors.forename: Sun D
authors.initials: SD
authors.lastname: Yoo
authors.forename: Hye S
authors.initials: HS
authors.lastname: Lee
mesh_terms: D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D000818:Animals; D019540:Area Under Curve; D001578:Benzopyrans / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D007093:Imidazoles / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008571:Men; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D020533:Angiogenesis Inhibitors; D001578:Benzopyrans; D007093:Imidazoles; C503693:KR 31831