title: Determination of 2-(3-benzoyl)-4-hydroxy-1,1-dioxo-2H-1,2-benzothiazine-2-yl-1-phenylethanone by liquid chromatography-tandem mass spectrometry.
abstract: 2-(3-Benzoyl)-4-hydroxy-1,1-dioxo-2H-1,2-benzothiazine-2-yl-1-phenylethanone (KR-66344), a 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor, is newly developed for the control of type 2 diabetes mellitus (T2DM) and metabolic syndrome. A method for the determination of KR-66344 in rat plasma was developed by liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS-MS) to evaluate the pharmacokinetics of KR-66344. Plasma samples were processed by a liquid-liquid extraction method with ethyl acetate and introduced onto the LC-MS-MS system. The analyte and imipramine (internal standard) were analyzed by multiple reaction monitoring based on transitions at m/z 420.1 → 105.0 and 282.2 → 86.0, respectively. The calibration curve was linear (r = 0.9993) over the concentration range of 1.0-1,000 ng/mL. The mean recovery values for KR-66344 and imipramine were 83.8 and 86.2%, respectively. The mean inter-day and intra-day assay precision values were 3.9 and 2.4%, respectively. KR-66344 was stable under various handling and storage conditions. This developed method was applied to a pharmacokinetic study after the oral administration of KR-66344 in rats. The concentration of KR-66344 was readily measurable in rat plasma up to 24 h post-dose after an oral administration, suggesting that current assay is applicable to pharmacokinetic studies for KR-66344.
authors.affiliation: 1Drug Discovery Platform Technology Research Group, Korea Research Institute of Chemical Technology (KRICT), Yuseong-gu, Daejeon, 305-600, Korea.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Zheng
authors.forename: Jin Sook
authors.initials: JS
authors.lastname: Song
authors.forename: Byung Hoi
authors.initials: BH
authors.lastname: Lee
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Ahn
authors.forename: Jin-Hee
authors.initials: JH
authors.lastname: Ahn
authors.forename: JaeChun
authors.initials: J
authors.lastname: Woo
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Park
authors.forename: Dae Seok
authors.initials: DS
authors.lastname: Yoo
authors.forename: Myung Ae
authors.initials: MA
authors.lastname: Bae
mesh_terms: D042842:11-beta-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors; D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid / Q000592:standards; D003499:Cyclic S-Oxides / Q000008:administration & dosage / Q000302:isolation & purification* / Q000493:pharmacokinetics; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000302:isolation & purification* / Q000493:pharmacokinetics; D007099:Imipramine / Q000302:isolation & purification; D008297:Male; D017207:Rats, Sprague-Dawley; D012015:Reference Standards; D053719:Tandem Mass Spectrometry / Q000592:standards; D013843:Thiazines / Q000008:administration & dosage / Q000302:isolation & purification* / Q000493:pharmacokinetics
chemical_list: C558395:2-(3-benzoyl)-4-hydroxy-1,1-dioxo-2H-1,2-benzothiazine-2-yl-1-phenylethanone; D003499:Cyclic S-Oxides; D007004:Hypoglycemic Agents; D013843:Thiazines; D042842:11-beta-Hydroxysteroid Dehydrogenases; D007099:Imipramine