LC-MS/MS测定裸鼠血浆中抗肿瘤化合物C17的分析方法及其在药物动力学研究中的应用  

LC-MS/MS method for the determination of an anti-tumor compound C17 in nude mice plasma and its application to a pharmacokinetic study

作　　者：姚庆宇 冯瑶瑶 严晓雪 陈国术[2] 周田彦 YAO Qing-yu;FENG Yao-yao;YAN Xiao-xue;CHEN Guo-shu;ZHOU Tian-yan(Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System,School of Pharmaceutical Sciences,Health Science Center,Peking University,Beijing 100191,China;School of Chemistry and Chemical Engineering,Guangzhou University,Guangzhou 510006,China)

机构地区：[1]北京大学医学部药学院,分子药剂学与新药递送系统北京市重点实验室,北京100191 [2]广州大学化学化工学院,广东广州510006

出　　处：《药学学报》2023年第8期2448-2453,共6页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(82073919);北京市自然科学基金资助项目(7192100)。

摘　　要：C17是一种具有抗肿瘤干细胞作用的可口服的抗肿瘤化合物。本研究首先建立了测定裸鼠血浆中C17的LC-MS/MS分析方法,该方法以普萘洛尔作为内标物,采用甲醇沉淀蛋白法对血浆样品进行处理。采用Intersil C8-3色谱柱(100 mm×2.1 mm,3μm)进行色谱分离,以0.1%的甲酸水溶液和90%异丙醇与10%乙腈的混合溶液为流动相进行梯度洗脱。采用API 4000 Q-TRAP三重四级杆质谱的多反应监测扫描模式进行检测,正离子模式下C17和内标物的离子对质核比分别为439.3/247.1和260.2/116.2。标准曲线的线性范围为5~800 ng·mL^(-1)(r>0.995),方法的日内/日间精密度和准确性分别在7.42%~13.22%和−8.99%~8.81%间,所建方法稳定、灵敏且简单易行。之后,使用该方法测定裸鼠C17单次灌胃给药50 mg·kg^(-1)剂量下的血药浓度,并采用非线性混合效应模型(NONMEM)进行PK建模分析。C17灌胃给药后出现两个互相分离的吸收峰,采用带有两个一级速率顺序吸收过程的二室模型对其PK行为进行描述,为研究C17在裸鼠的体内过程和暴露打下基础。所有动物实验均严格遵循北京大学生物医学伦理委员会的规定。C17 is an orally available anti-tumor compound inhibiting cancer stem cell(CSC).In this study,a stable,sensitive and simple liquid chromatography-tandem mass spectrometry(LC-MS/MS)method was established and validated,and was further applied to a pharmacokinetic study in nude mice receiving C17 by gavage.Using propranolol as the internal standard,the plasma samples were pre-treated by precipitation with methanol and analyzed on an Intersil C8-3 column(100 mm×2.1 mm,3μm),and gradient elution was performed with a mobile phase consisting of 0.1%formic acid aqueous and solution mixed up by 90%isopropanol and 10%acetonitrile.The analyte was detected by a triple quadrupole tandem mass spectrometer,and multiple reaction monitoring was employed to select C17 at m/z 439.3/247.1 and propranolol at m/z 260.2/116.2 in the positive ion mode.The calibration curves were linear(r>0.995)over the range of 5-800 ng·mL^(-1).The intra-and inter-day precisions and accuracies were 7.42%-13.22%and-8.99%-8.81%respectively.The method was successfully applied to a PK study in nude mice administered with a single oral dose of 50 mg·kg^(-1) C17,and the PK data were analyzed with non-linear mixed effect model(NONMEM).Two separated absorption peaks were found in the PK curve of C17,and a two-compartment model with two sequential first-order absorption rate was utilized to describe the PK properties of C17,and the model could provide insights into the physiological process and exposure of C17 in nude mice.All animal experiments were in strict accordance with the regulations of the Biomedical Ethics Committee of Peking University.

关 键 词：液相色谱-串联质谱 裸鼠 药物动力学 非线性混合效应模型 

分 类 号：R917[医药卫生—药物分析学]