Zhan Jing, Ding Ya, Zou Benyan, Liao Hai, Jiang Wenqi, Li Su
State Key Laboratory of Oncology in Southern China, Sun Yat-sen University, Room 601, Building 1, No.651, Dongfengdong Road, Guangzhou, 510060, Guangdong, People's Republic of China.
Department of Clinical Trial Center, Cancer Center, Sun Yat-sen University, Guangzhou, 510060, Guangdong, People's Republic of China.
Eur J Drug Metab Pharmacokinet. 2018 Oct;43(5):555-564. doi: 10.1007/s13318-018-0468-8.
Puquitinib mesylate (XC-302) is a new multiple-target anticancer inhibitor, which directly suppresses the activity of phosphatidylinositol 3-kinase (PI3K). This study was aimed to develop a sensitive and specific liquid chromatography electrospray ionization tandem mass spectrometry (HPLC-ESI MS/MS) method for the quantification and pharmacokinetic investigation of plasma puquitinib in cancer patients.
The analytes of human plasma were prepared by liquid-liquid extraction using methyl-t-butyl ether (MTBE). The plasma analytes were separated by HPLC on Thermo ODS Hypersil column (2.1 × 150 mm; 3 μm) at 25 °C with 5 mmol/L ammonium acetate (A)-acetonitrile (B) (30:70, v/v) as the mobile phase.
The total run time was 3.5 min and the elution of puquitinib was at 1.38 min. The detection were analyzed by multiple reaction monitoring (MRM) mode with positive-ion electrospray ionization (ESI) interface using the respective [M + H] ions: m/z 318.2 → 261.1 for puquitinib and m/z 258.2 → 121.0 for the internal standard (etofesalamide). The optimized method provided a good linear relation over the concentration range of 1.00-500.00 ng/mL (r = 0.9944) for puquitinib. The intra-day and inter-day precision (relative standard deviation [RSD%]) were within 9.83%, and the intra-day and inter-day accuracy ranged from 91.05 to 103.26%. The lower limit of quantitation (LLOQ) was 1.00 ng/mL. The absolute extraction recovery was on an average of 50.43% for puquitinib and 49.3% for internal standard. In addition, the maximum plasma concentration (C) of puquitinib in dosage from 50 to 800 mg/m in the human study showed an increased linearly (57.1-1289.2 ng/mL), which displayed that the concentrations had reached effective levels.
The optimized method was successfully applied to the pharmacokinetic profile study in human cancer patient plasma after the oral administration of puquitinib.
甲磺酸普喹替尼（XC-302）是一种新型多靶点抗癌抑制剂，可直接抑制磷脂酰肌醇3激酶（PI3K）的活性。本研究旨在建立一种灵敏、特异的液相色谱-电喷雾电离串联质谱法（HPLC-ESI MS/MS），用于定量分析癌症患者血浆中的普喹替尼并进行药代动力学研究。
采用甲基叔丁基醚（MTBE）液液萃取法制备人血浆分析物。血浆分析物在Thermo ODS Hypersil柱（2.1×150 mm；3μm）上于25℃进行HPLC分离，以5 mmol/L醋酸铵（A）-乙腈（B）（30:70，v/v）作为流动相。
总运行时间为3.5分钟，普喹替尼在1.38分钟洗脱。采用多反应监测（MRM）模式，通过正离子电喷雾电离（ESI）接口，利用各自的[M + H]离子进行检测：普喹替尼为m/z 318.2→261.1，内标（依托法胺）为m/z 258.2→121.0。优化后的方法在1.00 - 500.00 ng/mL的浓度范围内为普喹替尼提供了良好的线性关系（r = 0.9944）。日内和日间精密度（相对标准偏差[RSD%]）均在9.83%以内，日内和日间准确度在91.05%至103.26%之间。定量下限（LLOQ）为1.00 ng/mL。普喹替尼的绝对提取回收率平均为50.43%，内标为49.3%。此外，在人体研究中，普喹替尼剂量为50至800 mg/m时的最大血浆浓度（C）呈线性增加（57.1 - 1289.2 ng/mL），表明浓度已达到有效水平。
优化后的方法成功应用于普喹替尼口服给药后人体癌症患者血浆药代动力学特征研究。
