Qiang Yongzai, Zhang Xiaohui
Department of Pharmacy, The Affiliated Hospital of Inner Mongolia Medical University, Hohot, Inner Mongolia, China.
Biomed Chromatogr. 2019 Mar;33(3):e4441. doi: 10.1002/bmc.4441. Epub 2018 Dec 17.
TAK-875 is a selective partial agonist of human GPR40 receptor, which was unexpectedly terminated at phase III clinical trials owing to its severe hepatotoxicity. The purpose of this study was to investigate the pharmacokinetics of TAK-875 and its toxic metabolite TAK-875-acylglucuronide in rat plasma by liquid chromatography tandem mass spectrometry (LC-MS/MS). Plasma samples were extracted with ethyl acetate and chromatographic separations were achieved on a C column with water and acetonitrile containing 0.05% ammonium hydroxide as mobile phase. The sample was detected in selected reaction monitoring mode with precursor-to-product ion transitions being m/z 523.2 → 148.1, m/z 699.3 → 113.1 and m/z 425.2 → 113.1 for TAK-875, TAK-875-acylglucuronide and IS, respectively. The assay showed good linearity over the tested concentration ranges (r > 0.9993), with the LLOQ being 0.5 ng/mL for both analytes. The extraction recovery was >78.45% and no obvious matrix effect was detected. The highly sensitive LC-MS/MS method has been further applied for the pharmacokinetic study of TAK-875 and its toxic metabolite TAK-875-acylglucuronide in rat plasma. Pharmacokinetics results revealed that oral bioavailability of TAK-875 was 86.85%. The in vivo exposures of TAK-875-acylglucuronide in terms of AUC were 17.54 and 22.29% of that of TAK-875 after intravenous and oral administration, respectively.
TAK-875是一种人GPR40受体的选择性部分激动剂，由于其严重的肝毒性，该药物在III期临床试验中意外终止。本研究的目的是通过液相色谱串联质谱法（LC-MS/MS）研究TAK-875及其毒性代谢产物TAK-875-酰基葡萄糖醛酸在大鼠血浆中的药代动力学。血浆样品用乙酸乙酯萃取，在C柱上进行色谱分离，流动相为含0.05%氢氧化铵的水和乙腈。采用选择反应监测模式检测样品，TAK-875、TAK-875-酰基葡萄糖醛酸和内标（IS）的母离子到子离子的跃迁分别为m/z 523.2→148.1、m/z 699.3→113.1和m/z 425.2→113.1。该分析方法在测试浓度范围内显示出良好的线性（r＞0.9993），两种分析物的最低定量限（LLOQ）均为0.5 ng/mL。萃取回收率＞78.45%，未检测到明显的基质效应。这种高灵敏度的LC-MS/MS方法已进一步应用于TAK-875及其毒性代谢产物TAK-875-酰基葡萄糖醛酸在大鼠血浆中的药代动力学研究。药代动力学结果显示，TAK-875的口服生物利用度为86.85%。静脉注射和口服给药后，TAK-875-酰基葡萄糖醛酸的AUC体内暴露量分别为TAK-875的17.54%和22.29%。
