Development of a rapid and sensitive UPLC–MS/MS assay for simultaneous quantitation of Vorolanib and its metabolite in human plasma and application to a pharmacokinetics study
Development of a rapid and sensitive UPLC–MS/MS assay for simultaneous quantitation of Vorolanib and its metabolite in human plasma and application to a pharmacokinetics study
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开发快速、灵敏的 UPLC-MS/MS 检测方法，用于同时定量人血浆中的 Vorolanib 及其代谢物，并应用于药代动力学研究
DOI：
10.1016/j.jpba.2021.114034
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发表时间：
2021
影响因子：
3.4
通讯作者：
Hongyun Wang
中科院分区：
文献类型：
--
作者：
Xin Zheng;Huitao Gao;Yanbao Zhang;Xinge Cui;Ranran Jia;Junli Xue;Wenbo Tang;Yang Wang;Hua Li;Xuefei Chen;Hongyun Wang
Vorolanib是一种口服酪氨酸激酶抑制剂，靶向血管内皮生长因子受体（VEGFR）和血小板衍生生长因子受体（PDGFR）。开发并充分验证了一种灵敏度和特异性的LC-MS/MS测定法，用于同时定量人血浆中的伏罗拉尼及其主要代谢产物X297。K2-EDTA血浆样品经乙腈蛋白沉淀（PP）提取后，在C18反相柱上进行梯度洗脱分离。以多反应监测模式（MRM）操作SCIEX 5500 QTRAP®质谱仪系统，并使用正电喷雾电离（ESI）检测所有组分。结果成功证明，该方法在伏罗拉尼（1.00−1000 ng/mL）和X297（0.500−500 ng/mL）浓度范围内具有令人满意的线性、灵敏度和选择性。在本研究中，在伏罗拉尼和X297检测通道中观察到两个浓度相关峰，推测为伏罗拉尼和X297的异构体。为了规范样品预处理过程，评价了灯光和pH值对异构体再转化的影响。结果表明，处理过程中样品暴露于灯光不会导致异构体转化。首次建立了一种用于高通量定量人血浆中伏罗拉尼和X297的耐用且特异性的超高效液相色谱串联质谱（UPLC-MS/MS）测定法，并按照生物分析验证指南进行了验证。该方法已成功应用于中国晚期实体瘤患者伏罗拉尼片的药代动力学评价。
Vorolanib is an oral tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR). A sensitive and specific LC–MS/MS assay was developed and fully validated for simultaneous quantification of vorolanib and its main metabolite X297 in human plasma. The two analytes were extracted from K2-EDTA plasma samples by protein precipitation (PP) with acetonitrile, and chromatographically separated on a C18 reverse-phase column using a gradient elution. A SCIEX 5500 QTRAP® mass spectrometer system was operated in multiple-reaction monitoring mode (MRM) and all components were detected using positive electrospray ionization (ESI). The results successfully demonstrated that the method had satisfactory linearity, sensitivity, and selectivity in the concentration ranges of vorolanib (1.00−1000 ng/mL) and X297 (0.500−500 ng/mL).In this study, two concentration related peaks in the vorolanib and X297 detection channels were observed, which were speculated to be isomers of vorolanib and X297. In order to standardize the sample pretreatment process, the effect of lamp light and pH on the isomer reconversion was evaluated. The results indicated, that the exposure of samples to lamp light during the handling procedures, did not cause the conversion of the isomers. For the first time a robust and specific ultra-performance liquid chromatography tandem mass spectrometry (UPLC–MS/MS) assay for the high-throughput quantification of vorolanib and X297 in human plasma was established and validated following bioanalytical validation guidelines. The proposed method was successfully applied to clinical trials evaluating the pharmacokinetics of vorolanib tablets in Chinese advanced solid tumor patients.