Voxtalisib,是一个特定的,有效,和可逆双重抑制剂,抑制泛I类磷酸肌醇3激酶(PI3K)和雷帕霉素的机制靶标(mTOR)。迄今为止,voxtalisib已经在黑色素瘤的试验中进行了研究,淋巴瘤胶质母细胞瘤,乳腺癌,和其他癌症。在这项研究中,将高灵敏度、快速的超高效液相色谱-串联质谱(UPLC-MS/MS)技术应用于大鼠血浆中voxtalisib的定量方法学和药代动力学分析。用乙腈对分析物进行蛋白质沉淀后,色谱分离在AcquityBEHC18柱(2.1mm×50mm,1.7μm),以乙腈(溶剂A)和0.1%甲酸(溶剂B)为流动相。在正离子模式下,分析物和IS的传质检测分别为m/z270.91>242.98和m/z572.30>246.10。在1-2000ng/ml的浓度范围内,利用UPLC-MS/MS技术,并且分析物的定量下限(LLOQ)被鉴定为1ng/ml。voxtalisib的日内和日内精确度分别为7.5-18.7%和13.0-16.6%,分别,准确度在-14.0-2.0%和-7.2-3.1%之间,分别。矩阵效应,提取回收,分析物的残留和稳定性均符合FDA推荐的生物测定的验收标准。最后,在用voxtalisib(5mg/kg)对大鼠进行灌胃给药后,通过UPLC-MS/MS生物分析方法对分析物的药代动力学进行了有效研究。结果表明,UPLC-MS/MS技术能有效、快速地对分析物进行定量分析,该方法也可用于体素的药代动力学研究,为后期临床药物管理的优化提供参考。
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 m/z 270.91 > 242.98 and m/z 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.