化学
蛋白质沉淀
色谱法
丙戊酸
分析物
药物警戒
抗惊厥药
治疗药物监测
药理学
药品
癫痫
医学
生物
神经科学
作者
Weijun Wang,Zhao Yue-Tao,Hao-Ran Dai,Yuanyuan Zhang,Jie Wang,Hongli Guo,Xiaowen Ding,Feng Chen
标识
DOI:10.1016/j.jpba.2023.115538
摘要
Valproic acid (VPA) is a well-documented contributor to liver injury, which is likely caused by the formation of its toxic metabolites. Monitoring VPA and its metabolites is very meaningful for the pharmacovigilance, but the availability of a powerful assay is a prerequisite. In this study, for the first time, a sensitive and specific LC-MS/MS method was developed and validated to simultaneously quantify the concentrations of VPA and its six pestering isomer metabolites (3-OH-VPA, 4-OH-VPA, 5-OH-VPA, 2-PGA, VPA-G, and 2-ene-VPA) in human plasma, using 5-OH-VPA-d7 and VPA-d6 as the internal standards (ISs). We also figured out another tricky problem that the concentrations of the parent drug and the metabolites vary widely. Of note, after protein precipitation and dilution with acetonitrile (ACN) and 50% ACN successively, the analytes and the ISs were successfully separated on a Kinetex C18 column. Intriguingly, sacrificing its signal intensity by elevated collision energy of VPA finally achieved the simultaneous determination. As expected, the method showed great linearity (r > 0.998) over the concentration ranges for all analytes. The inter-day and intra-day accuracy and precision were both acceptable. The method was successfully applied in 127 children with epilepsy. This novel assay will support the VPA-associated pharmacovigilance in the future.
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