|
KMID : 0043320160390040492
|
|
Archives of Pharmacal Research
2016 Volume.39 No. 4 p.492 ~ p.498
|
|
|
Pharmacokinetic characterization of 2-(3-benzoyl)-4-hydroxy-1,1-dioxo-2H-1,2-benzothiazine-2-yl-1-phenylethanone, a novel 11β-hydroxysteroid dehydrogenase type 1 inhibitor in rats
|
|
Zheng Zhi
Seo Hye-Won
Kwak Hyun-Jung
Kim Ki-Young
Ahn Jin-Hee
Bae Myung-Ae
Song Jin-Sook
|
|
|
Abstract
|
|
|
|
11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is associated with metabolic syndromes such as type 2 diabetes mellitus and obesity. A new 11β-HSD1 inhibitor known as 2-(3-benzoyl)-4-hydroxy-1, 1-dioxo-2H-1, 2-benzothiazine-2-yl-1-phenylethanone (KR-66344) is being developed as a therapeutic agent for these metabolic diseases. The purpose of this study was to characterize the pharmacokinetics of KR-66344 to support further preclinical development. KR-66344 showed high liver microsomal stability with T1/2 values >3 h and high permeability with apparent permeability coefficients of 15.2?24.2 × 10?6 cm/s in Caco-2 cell monolayers. KR-66344 was also strongly bound to plasma proteins (>98 %). After intravenous dosing, KR-66344 exhibited low systemic clearance (0.27?0.37 L/h/kg) and a low to moderate volume of distribution at steady state (0.79?0.8 L/kg). The bioavailability and terminal half-lives of KR-66344 following oral administration were 25 % and 1.7?3.3 h, respectively. In addition, KR-66344 showed dose-independent pharmacokinetics at 0.5?10 mg/kg in intravenous and oral pharmacokinetic studies.
|
|
|
KEYWORD
|
|
|
11β-hydroxysteroid dehydrogenase type 1, Pharmacokinetics, Metabolic stability, Plasma protein binding, Caco-2 cell permeability
|
|
|
FullTexts / Linksout information
|
|
|
|
|
|
Listed journal information
|
|
  
|