Dose-independent pharmacokinetics of a new peroxisome proliferator-activated receptor-γ agonist, KR-62980, in Sprague-Dawley rats and ICR mice.
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.
Drug Discovery Platform Technology Team, Korea Research Institute of Chemical Technology, Daejeon, 305-343, Korea.
Jong-Shik
JS
Park
Min-Sun
MS
Kim
Jin Sook
JS
Song
Sung Heum
SH
Choi
Byung Hoi
BH
Lee
Jaechun
J
Woo
Jin Hee
JH
Ahn
Myung Ae
MA
Bae
Sung-Hoon
SH
Ahn
D000818:Animals; D002460:Cell Line; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007192:Indenes / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008862:Microsomes, Liver / Q000378:metabolism*; D009025:Morpholines / Q000493:pharmacokinetics*; D047495:PPAR gamma / Q000819:agonists*; D051381:Rats; D017207:Rats, Sprague-Dawley
C513115:1-(methylimino-N-oxy)-6-(2-morpholinoethoxy)-3-phenyl-1H-indene-2-carboxylic acid ethyl ester; D007192:Indenes; D009025:Morpholines; D047495:PPAR gamma