化学
色谱法
伊曲康唑
泊沙康唑
生物分析
氟康唑
三级四极质谱仪
药代动力学
串联质谱法
高效液相色谱法
治疗药物监测
分析物
药理学
质谱法
选择性反应监测
抗真菌
医学
皮肤病科
作者
Lu Shi,Zheli Jiang,Bowen Zhang,Congrong Tang,Ren-ai Xu
标识
DOI:10.1016/j.jpba.2020.113386
摘要
Pexidartinib was approved in the USA for targeted therapy of adult patients with symptomatic tenosynovial giant cell tumour (TGCT) by the FDA. The purpose of our study was to develop and establish a quick assay based on ultra performance liquid chromatography tandem mass spectrometry (UPLC–MS/MS) for the measurement of pexidartinib concentrations in plasma and to survey whether antifungal drugs (isavuconazole, posaconazole, fluconazole and itraconazole) could change the pharmacokinetic parameters of pexidartinib in rats. After the quick protein crash with acetonitrile, the chromatographic separation of pexidartinib and upadacitinib (used as the internal standard in this study, IS) were conducted on an Acquity BEH C18 (2.1 × 50 mm, 1.7 μm) column, and the detection of the analyte was also accomplished with a Xevo TQ-S triple quadrupole tandem mass spectrometer in the positive ion electro-spray ionization (ESI) interface. The assay showed good linearity in the range of 1−7000 ng/mL. The accuracy and precision were all within the acceptable limits in the bioanalytical method, and the results of recovery, matrix effect, stability, and carry-over were also met the requirements. The application of the validated UPLC–MS/MS bioanalytical method was further successfully involved in the drug-drug interactions study from rats. It was found that fluconazole and itraconazole significantly increased the concentration of pexidartinib and had the inhibitory effect on the metabolism of pexidartinib, while not isavuconazole and posaconazole. Thus, more attention should be paid to the concurrent use of pexidartinib with fluconazole or itraconazole to reduce the risk of unexpected clinical outcomes.
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