The Netherlands Cancer Institute, Division of Pharmacology, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands; Utrecht University, Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacology, Universiteitsweg 99, 3584 CG Utrecht, the Netherlands.
The Netherlands Cancer Institute, Division of Pharmacology, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
J Chromatogr B Analyt Technol Biomed Life Sci. 2021 Jun 1;1174:122718. doi: 10.1016/j.jchromb.2021.122718. Epub 2021 Apr 20.
Sotorasib is a KRAS inhibitor with promising anticancer activity in phase I clinical studies. This compound is currently under further clinical evaluation as monotherapy and combination therapy against solid tumors. In this study, a liquid chromatography-tandem mass spectrometric method to quantify sotorasib in mouse plasma and eight tissue-related matrices (brain, liver, spleen, kidney, small intestine, small intestine content, lung, and testis homogenates) was developed and validated. Protein precipitation using acetonitrile was utilized in 96-well format to extract sotorasib and erlotinib (internal standard) from mouse plasma and tissue homogenates. Separation of the analytes was performed on an Acquity UPLC® BEH C18 column by gradient elution of methanol and 0.1% formic acid in water at a flow rate of 0.6 ml/min. Sotorasib was detected by a triple quadrupole mass spectrometer with positive electrospray ionization in selected reaction monitoring mode. A linear calibration range of 2-2,000 ng/ml of sotorasib was achieved during the validation. Accuracy values were in the range of 90.7-111.4%, and precision values (intra- and interday) were between 1.7% and 9.2% for all tested levels in all investigated matrices. The method was successfully applied to investigate the plasma pharmacokinetics and tissue accumulation of sotorasib in female wild-type mice.
Sotorasib 是一种 KRAS 抑制剂，在 I 期临床研究中具有有前景的抗癌活性。该化合物目前正在作为单药和联合疗法用于治疗实体瘤的进一步临床评估。在这项研究中，开发并验证了一种用于定量检测小鼠血浆和 8 种组织相关基质（脑、肝、脾、肾、小肠、小肠内容物、肺和睾丸匀浆）中 sotorasib 的液相色谱-串联质谱法。采用 96 孔板格式，使用乙腈进行蛋白沉淀，从小鼠血浆和组织匀浆中提取 sotorasib 和厄洛替尼（内标）。采用 Acquity UPLC® BEH C18 柱，以甲醇和 0.1%甲酸水溶液为流动相，在 0.6 ml/min 的流速下进行梯度洗脱，对分析物进行分离。采用正电喷雾电离源和三重四极杆质谱仪，在选择反应监测模式下对 sotorasib 进行检测。在验证过程中，sotorasib 的线性校准范围为 2-2000ng/ml。在所有测试水平和所有研究的基质中，准确度值在 90.7-111.4%范围内，日内和日间精密度值（精度）在 1.7%-9.2%之间。该方法成功应用于研究雌性野生型小鼠中 sotorasib 的血浆药代动力学和组织蓄积情况。
