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KMID : 0043320110340122051
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Archives of Pharmacal Research
2011 Volume.34 No. 12 p.2051 ~ p.2058
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Dose-independent pharmacokinetics of a new peroxisome proliferator-activated receptor-γ agonist, KR-62980, in Sprague-Dawley rats and ICR mice
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Park Jong-Shik
Kim Min-Sun
Song Jin-Sook
Choi Sung-Heum
Lee Byung-Hoi
Woo Jae-chun
Ahn Jin-Hee
Bae Myung-Ae
Ahn Sung-Hoon
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Abstract
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The pharmacokinetics of a novel peroxisome proliferator-activated receptor-γ agonist, KR-62980, were characterized in vitro with respect to liver metabolic stability, cell permeability, and plasma protein binding and in vivo using Sprague-Dawley rats and ICR mice. The metabolic half-life of 0.1?10 μM KR-62980 was 11.5?15.2 min in rat liver microsomes and 25.8?28.8 min in human liver microsomes. KR-62980 showed high permeability across MDCK cell monolayers, with apparent permeability coefficients of 20.4 × 10?6 to 30.8 × 10?6 cm/sec. The plasma protein binding rate of KR-62980 was 89.4%, and most was bound to serum albumin. After intravenous administration of KR-62980 (2 mg/kg), the systemic clearance was 2.50 L/h/kg, and the volume of distribution at steady-state was 9.16 L/kg. The bioavailability after oral administration was approximately 60.9%. The dose-normalized AUC values were 0.50 ± 0.09, 0.41 ± 0.20, and 0.62 ± 0.08 h·μg/mL after oral administration of 2, 5, and 10 mg/kg KR-62980, respectively, showing no dose-dependency. The in vivo pharmacokinetic parameters in ICR mice were also dose independent. These data suggest that KR-62980 is not significantly dose dependent in rats or mice, although it may disappear rapidly from the systemic circulation via metabolism in the liver.
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KEYWORD
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KR-62980, Pharmacokinetics, Dose-dependency, Liver microsomal stability, Cell permeability, Plasma protein bindi
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