Assessment of pharmacokinetics, bioavailability and protein binding of anacetrapib in rats by a simple high-performance liquid chromatography-tandem mass spectrometry method

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• 作者：Sang-Bum Kim ; Ki Taek Kim ; Jeongmin Joo ; Kyung-Ah Seo ; Hayoung Hwang ; Soong-Hyun Kim ; Minsoo Song ; Sungwoo Lee ; Alexander Jahn ; Hyun-Jong Cho ; Dae-Duk Kim and In-Soo Yoon
• 刊名：Biomedical Chromatography
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：31
• 期：2
• 全文大小：840K
• ISSN：1099-0801

文摘

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 C₁₈ column 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%.