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 C18 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 AUC0-t were 17.54 and 22.29% of that of TAK-875 after intravenous and oral administration, respectively.

中文翻译：

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TAK-875及其毒性代谢产物TAK-875-酰基葡糖醛酸在液相色谱串联质谱中的药代动力学。

TAK-875是人GPR40受体的选择性部分激动剂，由于其严重的肝毒性而在III期临床试验中意外终止。这项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，并在C18色谱柱上进行色谱分离，水和乙腈中含有0.05％的氢氧化铵作为流动相。对于TAK-875，TAK-875-酰基葡糖醛酸和IS，在选定的反应监测模式下检测到的样品的前体-产物离子跃迁为m / z 523.2→148.1，m / z 699.3→113.1和m / z 425.2→113.1 ， 分别。该测定在测试浓度范围内表现出良好的线性（r> 0.9993），两种分析物的LLOQ为0.5 ng / mL。提取回收率> 78.45％，未发现明显的基质效应。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-酰基葡糖醛酸在大鼠血浆中的药代动力学研究。药代动力学结果表明，TAK-875的口服生物利用度为86.85％。静脉内和口服给药后，TAK-875-酰基葡糖醛酸对AUC0-t的体内暴露分别为TAK-875的17.54％和22.29％。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-酰基葡糖醛酸在大鼠血浆中的药代动力学研究。药代动力学结果表明，TAK-875的口服生物利用度为86.85％。静脉内和口服给药后，TAK-875-酰基葡糖醛酸对AUC0-t的体内暴露分别为TAK-875的17.54％和22.29％。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-酰基葡糖醛酸在大鼠血浆中的药代动力学研究。药代动力学结果表明，TAK-875的口服生物利用度为86.85％。静脉内和口服给药后，TAK-875-酰基葡糖醛酸对AUC0-t的体内暴露分别为TAK-875的17.54％和22.29％。