房梦娜,李鹏艳,徐秋驰,姜琪坤,张天虹
FANG Mengna,LI Pengyan,XU Qiuchi,JIANG Qikun,ZHANG Tianhong

• 1:沈阳药科大学无涯创新学院

摘要(Abstract)：

目的 建立超高效液相色谱串联质谱法同时测定大鼠血浆中一甲基澳瑞他汀E(monomethyl auristatin E,MMAE)及其酶敏感性脂肪酸前药—一甲基澳瑞他汀E-缬氨酸-瓜氨酸-对氨基苄氧羰基-亚油酸(MMAE-valine-citrulline-PABC-linoleic acid, MMAE-V-C-LA)的质量浓度，并将该方法用于比较MMAE和MMAE-V-C-LA纳米粒在大鼠体内的药动学行为。方法 采用Phenomenex Kinetex~? XB-C_(18)(50 mm×2.1 mm, 2.6μm)色谱柱，甲醇-体积分数为0.1%甲酸溶液为流动相，采用梯度洗脱，流速为0.2 mL·min~(-1),采用电喷雾电离(ESI)源，正离子模式进行检测，采用沉淀蛋白法处理血浆样品，选择紫杉醇为内标。结果 大鼠血浆中MMAE及MMAE-V-C-LA的线性范围分别为5.000～2 000、10.00～10 000μg·L~(-1),最低定量下限分别为5.000μg·L~(-1)和10.00μg·L~(-1),日内、日间精密度的RSD在0.040%～14%内，准确度的RE在-1.3%～2.3%内，提取回收率在89.5%～95.7%内，内标归一化的基质因子在89.8%～97.7%内。结论 该方法准确可靠，符合生物样品测定要求，可用于MMAE和MMAE-V-C-LA纳米粒在大鼠体内的药动学研究。
Objective To establish an ultra-performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS) method for the simultaneous determination the mass concentration of monomethyl auristatin E and its prodrug-MMAE-valine-citrulline-PABC-linoleic acid(MMAE-V-C-LA) in rat plasma, and to compare the pharmacokinetic behavior of monomethyl auristatin E and MMAE-V-C-LA nanoparticles in rats.Methods The analysis was performed on a Phenomenex Kinetex~? XB-C_(18)(50 mm×2.1 mm, 2.6 μm) column with methanol-formic acid solution with a volume fraction of 0.1%as mobile phase using gradient elution at a flow rate of 0.2 mL·min~(-1) using electrospray ionization(ESI) source in positive ion mode.The plasma samples were treated by precipitation protein method with paclitaxel as internal standard.Results The linear range of plasma monomethyl auristatin E and its prodrug in rats was 5.000-2 000 μg·L~(-1) and 10.00-10 000 μg·L~(-1),respectively.Minimum quantitative limit were 5.000 μg·L~(-1),10.00 μg·L~(-1),respectively.The RSD of intra-day and inter-day precision were 0.040%-14%,the RE of accuracy was-1.3%-2.3%,the extraction recoveries were 89.5%-95.7%,the matrix factors normalized by internal standard were 89.8%-97.7%.Conclusion The method is accurate and reliable, and can be used for the pharmacokinetic study of MMAE and MMAE-V-C-LA nanoparticles in rats.

关键词(KeyWords)： 一甲基澳瑞他汀E;前药;纳米粒;超高效液相色谱串联质谱;药动学研究
monomethyl auristatin E;prodrug;nanoparticles;ultra performance liquid chromatography tandem mass spectrometry;pharmacokinetic studies

Abstract:

Keywords:

基金项目(Foundation):

作者(Author): 房梦娜,李鹏艳,徐秋驰,姜琪坤,张天虹
FANG Mengna,LI Pengyan,XU Qiuchi,JIANG Qikun,ZHANG Tianhong

DOI: 10.14066/j.cnki.cn21-1349/r.2021.0401

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