LC-MS/MS assay for the determination of a novel anti-fibrotic candidate mefunidone in monkey plasma and its application to a pharmacokinetics study
LC-MS/MS assay for the determination of a novel anti-fibrotic candidate mefunidone in monkey plasma and its application to a pharmacokinetics study
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LC-MS/MS 测定猴血浆中新型抗纤维化候选药物甲夫尼酮及其在药代动力学研究中的应用
DOI：
10.1002/dta.2588
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发表时间：
2019
影响因子：
2.9
通讯作者：
Cheng Zeneng
中科院分区：
文献类型：
--
作者：
Han Xuhua;Wen Zhou;Fan Zhihong;Ma Yuehui;Wang Lei;Cheng Zeneng
甲呋尼酮 (MFD) 是一种有前途的抗纤维化候选分子，其抗纤维化活性比吡非尼酮 (PFD) 更强。然而，目前尚无关于 MFD 定量方法或其药代动力学研究的报告。在本研究中，开发了一种高效可靠的液相色谱-串联质谱（LC-MS/MS）方法来测定猴血浆中的MFD。该测定方法经过验证并应用于猴子的药代动力学研究。该测定的定量下限为0.1 μg·mL−1，在0.1和60 μg·mL−1之间获得线性校准曲线，R2> 0.99。日内和日间精密度的评估变异系数为1.5%~5.8%，而平均准确度范围为91.7%~106.9%。使用该测定法获得了可忽略的基质效应和良好的回收率，MFD 和内标 (IS) 的平均提取回收率分别在 85.5%–124.8% 和 84.1%–94.0% 的范围内。 MFD和IS的绝对基体效应精度分别为1.2-3.0%和1.2-7.3%。样品在所有实验条件下都是稳定的。在猴子中观察到 MFD 的线性药代动力学，在 10–90 mg·kg−1 范围内，MFD 暴露量随着 MFD 剂量的增加而成比例增加。观察到 MFD 从体内中度消除，t1/2 为 5-7 h，多次给药期间 MFD 消除率稳定。总之，该方法为血浆中 MFD 的定量提供了可靠的分析方法，并成功应用于猴子的药代动力学研究。
Mefunidone (MFD) is a promising anti‐fibrotic candidate molecule with greater anti‐fibrotic activity than pirfenidone (PFD). However, there has been no report on the methodology used for the quantification of MFD or on any investigation of its pharmacokinetics. In this study, an efficient and reliable liquid chromatography–tandem mass spectrometry (LC–MS/MS) method was developed to assay MFD in monkey plasma. This assay method was validated and applied to a pharmacokinetics study in monkeys. The lower limit of quantification of this assay was 0.1 μg·mL−1, and the linear calibration curve was acquired with R2> 0.99 between 0.1 and 60 μg·mL−1. The intra‐day and inter‐day precision were evaluated with coefficient of variations of 1.5%–5.8%, whereas the mean accuracy ranged from 91.7% to 106.9%. A negligible matrix effect and good recovery were obtained using this assay, with average extraction recoveries of MFD and the internal standard (IS) in the range of 85.5%–124.8% and 84.1%–94.0%, respectively. The precision of the absolute matrix effect of MFD and the IS was 1.2–3.0% and 1.2–7.3%, respectively. The samples were stable under all experimental conditions. Linear pharmacokinetics were observed for MFD in monkeys, where the exposures of MFD increased proportionally with increasing MFD doses at the range of 10–90 mg·kg−1. Moderate elimination of MFD from the body was observed, with t1/2of 5–7 h, and the elimination rate of MFD was stable during multiple dosing. In conclusion, this method provides an reliable analytical approach for quantification of MFD in plasma and was successfully applied to a pharmacokinetics study in monkeys.