Ziritaxestat is a first‐in‐class autotoxin inhibitor. The purpose of this study was to develop a liquid chromatography/electrospray ionization tandem mass spectrometric (LC–MS/MS) method for the determination of ziritaxestat in rat plasma. The plasma sample was deproteinated using acetonitrile and then separated on an Acquity BEH C₁₈ column with water containing 0.1% formic acid and acetonitrile as mobile phase, which was delivered at 0.4 ml/min. Ziritaxestat and the internal standard (crizotinib) were quantitatively monitored with precursor‐to‐product transitions of m/z 589.3 > 262.2 and m/z 450.1 > 260.2, respectively. The total running time was 2.5 min. The method showed excellent linearity over the concentration range 0.5–2000 ng/ml, with correlation coefficient >0.9987. The extraction recovery was >82.09% and the matrix effect was not significant. Inter‐ and intra‐day precisions (RSD) were <11.20% and accuracies were in the range of −8.50–7.45%. Ziritaxestat was demonstrated to be stable in rat plasma under the tested conditions. The validated LC–MS/MS method was successfully applied to study the pharmacokinetic profiles of ziritaxestat in rat plasma after intravenous and oral administration. Pharmacokinetic results demonstrated that ziritaxestat displayed a short half‐life (~3 h) and low bioavailability (20.52%).

中文翻译：

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LC-MS / MS法测定大鼠血浆中齐拉他司他的含量及其药代动力学研究。

Ziritaxestat是一流的自毒素抑制剂。这项研究的目的是开发一种液相色谱/电喷雾串联质谱法（LC-MS / MS），用于测定大鼠血浆中的齐立他司他。使用乙腈对血浆样品进行脱蛋白处理，然后在Acquity BEH C ₁₈色谱柱上以0.1％甲酸和乙腈为流动相的水进行分离，并以0.4 ml / min的速度进行输送。使用m / z 589.3> 262.2和m / z的前体到产品的转变对Ziritaxestat和内标（crizotinib）进行了定量监测450.1> 260.2。总运行时间为2.5分钟。该方法在0.5-2000 ng / ml的浓度范围内显示出极好的线性，相关系数> 0.9987。提取回收率> 82.09％，基质效应不明显。日间和日内精度（RSD）<11.20％，准确度在−8.50–7.45％范围内。齐立他司他在测试条件下在大鼠血浆中稳定。经过验证的LC-MS / MS方法已成功地用于研究Ziritaxestat在静脉和口服给药后在大鼠血浆中的药代动力学特征。药代动力学结果表明，齐立他司他的半衰期短（〜3小时）且生物利用度低（20.52％）。