Li Qingqing, Liu Ya-Nan, Wang Jing, Hu Yingying, Hu Jinyu, Xu Ren-Ai, Shao Liu, Chen Lianguo
The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.
Front Pharmacol. 2022 Jun 14;13:914733. doi: 10.3389/fphar.2022.914733. eCollection 2022.
Voxtalisib, is a specific, effective, and reversible dual inhibitor, which inhibits both pan-class I phosphoinositide 3-kinase (PI3K) and mechanistic target of rapamycin (mTOR). To date, voxtalisib has been studied in trials for melanoma, lymphoma, glioblastoma, breast cancer, and other cancers. In this study, a highly sensitive and rapid ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) technology was applied to the quantitative methodology and pharmacokinetic analysis of voxtalisib in rat plasma. After protein precipitation of the analyte by acetonitrile, the chromatographic separation was performed by gradient elution on an Acquity BEH C18 column (2.1 mm × 50 mm, 1.7 μm) with acetonitrile (solvent A) and 0.1% formic acid (solvent B) as the mobile phase. In the positive ion mode, the mass transfer detection of the analyte and IS was 270.91 > 242.98 and 572.30 > 246.10, respectively. In the concentration range of 1-2000 ng/ml, a good linear relationship of voxtalisib was successfully established by the UPLC-MS/MS technology, and the lower limit of quantification (LLOQ) of the analyte was identified as 1 ng/ml. Intra-day and inter-day precisions for voxtalisib were 7.5-18.7% and 13.0-16.6%, respectively, and the accuracies were in the ranges of -14.0-2.0% and -7.2-3.1%, respectively. The matrix effect, extraction recovery, carryover and stability of the analyte were all in compliance with the acceptance criteria of bioassays recommended by FDA. Finally, the pharmacokinetic profile of the analyte had been availably studied by the UPLC-MS/MS bio-analytical method after rats were treated by intragastric administration with voxtalisib (5 mg/kg). The results indicated that the UPLC-MS/MS technology can effectively and quickly quantify the analyte, and this method can also be used for the pharmacokinetic study of voxtalisib, which can provide reference for the optimization of clinical drug management in the later period.
沃克替尼是一种特异性、有效且可逆的双重抑制剂，它能同时抑制泛I类磷酸肌醇3激酶（PI3K）和雷帕霉素作用靶点（mTOR）。迄今为止，沃克替尼已在黑色素瘤、淋巴瘤、胶质母细胞瘤、乳腺癌及其他癌症的试验中进行了研究。在本研究中，一种高灵敏度、快速的超高效液相色谱串联质谱（UPLC-MS/MS）技术被应用于大鼠血浆中沃克替尼的定量分析方法及药代动力学分析。通过乙腈对分析物进行蛋白沉淀后，采用乙腈（溶剂A）和0.1%甲酸（溶剂B）作为流动相，在Acquity BEH C18柱（2.1 mm×50 mm，1.7μm）上进行梯度洗脱以实现色谱分离。在正离子模式下，分析物和内标的传质检测分别为270.91 > 242.98和572.30 > 246.10。在1 - 2000 ng/ml的浓度范围内，通过UPLC-MS/MS技术成功建立了沃克替尼良好的线性关系，分析物的定量下限（LLOQ）被确定为1 ng/ml。沃克替尼的日内和日间精密度分别为7.5 - 18.7%和13.0 - 16.6%，准确度分别在 - 14.0 - 2.0%和 - 7.2 - 3.
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