title: Assessment of pharmacokinetics, bioavailability and protein binding of anacetrapib in rats by a simple high-performance liquid chromatography-tandem mass spectrometry method.
abstract: Anacetrapib is a potent and selective CETP inhibitor and is undergoing phase III clinical trials for the treatment of dyslipidemia. A simple and sensitive high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for the quantification of anacetrapib in rat plasma was developed and validated using an easily purchasable compound, chlorpropamide, as an internal standard (IS). A minimal volume of rat plasma sample (20 μL) was prepared by a single-step deproteinization procedure with 80 μL of acetonitrile. Chromatographic separation was performed using Kinetex C18column with a gradient mobile phase consisting of water and acetonitrile containing 0.1% formic acid at a flow rate of 0.3 mL/min. Mass spectrometric detection was performed using selected reaction monitoring modes at the mass/charge transitions m/z 638 → 283 for anacetrapib and m/z 277 → 175 for IS. The assay was validated to demonstrate the selectivity, linearity, precision, accuracy, recovery, matrix effect and stability. The lower limit of quantification was 5 ng/mL. This LC-MS/MS assay was successfully applied in the rat plasma protein binding and pharmacokinetic studies of anacetrapib. The fraction of unbound anacetrapib was determined to be low (ranging from 5.66 to 12.3%), and the absolute oral bioavailability of anacetrapib was 32.7%.
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea.
authors.forename: Sang-Bum
authors.initials: SB
authors.lastname: Kim
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea.
authors.forename: Ki Taek
authors.initials: KT
authors.lastname: Kim
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea.
authors.forename: Jeongmin
authors.initials: J
authors.lastname: Joo
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea.
authors.forename: Kyung-Ah
authors.initials: KA
authors.lastname: Seo
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea.
authors.forename: Hayoung
authors.initials: H
authors.lastname: Hwang
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea.
authors.forename: Soong-Hyun
authors.initials: SH
authors.lastname: Kim
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea.
authors.forename: Minsoo
authors.initials: M
authors.lastname: Song
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea.
authors.forename: Sungwoo
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Biotechnology, Dongseo University, Busan, 47011, Republic of Korea.
authors.forename: Alexander
authors.initials: A
authors.lastname: Jahn
authors.affiliation: College of Pharmacy, Kangwon National University, Gangwon, 24341, Republic of Korea.
authors.forename: Hyun-Jong
authors.initials: HJ
authors.lastname: Cho
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea.
authors.forename: Dae-Duk
authors.initials: DD
authors.lastname: Kim
authors.affiliation: College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam, 58554, Republic of Korea.
authors.forename: In-Soo
authors.initials: IS
authors.lastname: Yoon
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000097:blood* / Q000378:metabolism; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D057230:Limit of Detection; D008297:Male; D023303:Oxazolidinones / Q000097:blood* / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: D000924:Anticholesteremic Agents; D023303:Oxazolidinones; C530884:anacetrapib
keywords: HPLC-MS/MS; anacetrapib; pharmacokinetics; plasma protein binding; rat