Simultaneous quantification of donafenib, sorafenib, and their N-oxide metabolites in rat plasma using a HPLC-MS/MS method

化学 色谱法 索拉非尼 蛋白质沉淀 药代动力学 生物分析 分析物 高效液相色谱法 选择性反应监测 串联质谱法 代谢物 质谱法 药理学 肝细胞癌 生物化学 医学 生物 癌症研究
作者
Yutao Lou,Zhiyong Sun,Yitao Chai,Hui Qin,Qing Hu,Yujia Liu,Xiaowei Zheng,Ying Hu,Meihua Bao,Jinping Gu,Yiwen Zhang
出处
期刊:Journal of Chromatography B [Elsevier]
卷期号:1229: 123871-123871 被引量:3
标识
DOI:10.1016/j.jchromb.2023.123871
摘要

Donafenib and sorafenib are small molecule chemotherapy drugs for the management of hepatocellular carcinoma, with donafenib being a deuterated derivative of sorafenib. To date, a high liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method that quantify donafenib, sorafenib, and their main metabolites has not yet been developed. The objective of this study was to establish a HPLC-MS/MS method for the simultaneous detection of donafenib, donafenib-N-oxide, sorafenib, and sorafenib-N-oxide and for the pharmacokinetic studies in rat. The extraction of all analytes was achieved by simple protein precipitation utilizing acetonitrile. The Waters XBridge C18 column (2.1 × 100 mm, 3.5 µm) was selected, and the analytes could be efficiently separated and quantitated during a 2.8 min gradient elution procedure. The method was linear within the predefined quantification ranges and provided acceptable precision (%CV < 9.4%), reproducible extraction recovery (99.4%-111.5%), and low matrix effect (88.1%-98.6%). The hemolysis effect did not interfere with the quantification of all analytes, and similar results were obtained by changing the anticoagulant K2-EDTA to heparin or sodium citrate. Plasma pharmacokinetics revealed that the values of t1/2, Cmax, and AUC0-t of donafenib were 1.4-, 6.2-, and 3.1-fold higher than those of sorafenib, respectively. In conclusion, the proposed bioassay was successfully applied to pharmacokinetic studies in rat after administration of donafenib and sorafenib. Our work not only improves the bioanalytical method for determining the plasma concentrations of donafenib, sorafenib, and their N-oxide metabolites, but also provides a scientific reference for clinical pharmacokinetic studies.
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