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伊马替尼及其代谢物血浆蛋白结合率测定方法的建立及应用
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| 篇名： | 伊马替尼及其代谢物血浆蛋白结合率测定方法的建立及应用 |
| TITLE： | Establishment and application of a method for the determination of plasma protein binding rate of imatinib and its metabolite |
| 摘要： | 目的 建立测定伊马替尼及其代谢物（N-去甲基伊马替尼）血浆蛋白结合率的方法，并应用于胃肠道间质瘤（GIST）患者。方法以伊马替尼-d8为内标，采用甲醇沉淀蛋白处理样品，以平衡透析法结合液相色谱-串联质谱法测定，并同法检测GIST患者血浆中伊马替尼及其代谢物的游离浓度。结果伊马替尼在120、4000ng/mL浓度下，与白蛋白、α1-酸性糖蛋白、球蛋白的血浆蛋白结合率分别为（92.5±1.0）%和（91.7±0.4）%、（56.6±2.0）%和（62.6±2.6）%、（56.3±3.1）%和（68.0±8.6）%；N-去甲基伊马替尼在60、2000ng/mL浓度下，上述结合率分别为（90.6±3.5）%和（91.3±1.5）%、（54.1±5.1）%和（63.7±1.3）%、（56.2±7.6）%和（67.5±7.3）%。与低浓度伊马替尼（120ng/mL）及其代谢物（60ng/mL）比较，高浓度伊马替尼（4000ng/mL）及其代谢物（2000ng/mL）与α1-酸性糖蛋白、球蛋白的血浆蛋白结合率显著提高（P＜0.05），但与白蛋白的血浆蛋白结合率比较，差异无统计学意义（P＞0.05）。空白血浆中，高浓度伊马替尼（4000ng/mL）及其代谢物（2000ng/mL）的血浆蛋白结合率显著低于低（120、60ng/mL）、中（750、375ng/mL）浓度（P＜0.01）。GIST患者血浆中，伊马替尼及其代谢物的平均血浆蛋白结合率分别为（99.0±0.3）%、（99.2±0.3）%，伊马替尼及其代谢物的浓度与血浆蛋白结合率的相关系数分别为－0.2985、－3.3323（P均小于0.05）。结论成功建立了测定伊马替尼及其代谢物血浆蛋白结合率的方法；GIST患者伊马替尼及其代谢物的血浆蛋白结合率与药物浓度呈负相关。 |
| ABSTRACT： | OBJECTIVE To establish a method for the determination of plasma protein binding rate of imatinib and its metabolite（N-desmethyl imatinib ）and apply it to patients with gastrointestinal stromal tumor （GIST）.METHODS Using imatinib - d8 as the internal standard ，after being deproteinized methanol ，the sample was determined by equilibrium dialysis combined with liquid chromatography -tandem mass spectrometry . The free concentrations of imatinib and its metabolites in plasma of GIST patients were detected by the same method . RESULTS The protein binding rates of imatinib with albumin ，α1-acid glycoprotein and globulin at 120 ng/mL and 4 000 ng/mL were （92.5±1.0）% and（91.7±0.4）%，（56.6±2.0）% and（62.6±2.6）%，（56.3±3.1）% and （68.0±8.6）% ，respectively. The protein binding rates of N-desmethyl imatinib with albumin ，α1-acid glycoprotein and globulin at 60 ng/mL and 2 000 ng/mL were （90.6±3.5）% and（91.3±1.5）%，（54.1±5.1）% and（63.7±1.3）%，（56.2±7.6）% and（67.5±7.3）%，respectively. Compared with the low concentration group of imatinib （120 ng/mL）and its metabolite （60 ng/mL），the plasma protein binding rate of high concentration of imatinib （4 000 ng/mL）and its metabolite （2 000 ng/mL）with α1-acid glycoprotein and globulin was significantly increased （P＜ Δ基金项目 国家自然科学基金资助项目（No.81503160）；江苏省 0.05），but there was no signifi -cant difference with albumin 卫生健康发展研究中心 2021年度开放课题（No.JSHD2021004）；江苏 （P＞0.05）. In blank plasma ，the protein binding rates of imatinib（4 000 ng/mL）at high concentration and its metabolites（2 000 ng/mL）were significantly lower than those of low （120， 60 ng/mL） and medium （750， 375 ng/mL）concentration （P＜0.01）. Average protein binding rates of imatinib and its metabolite in plasma of GIST patients were （99.0±0.3）% and（99.2±0.3）%，respectively；the correlation coefficients between the concentrations of imatinib and its metabolites and the protein binding rates were －0.298 5 and －3.332 3，respectively（all P＜0.05）. CONCLUSIONS The method for determining the plasma protein binding rates of imatinib and its metabolites is successfully established . The plasma protein binding rates of imatinib and its metabolites in patients with GIST are negatively correlated with drug concentration . |
| 期刊： | 2022年第33卷第18期 |
| 作者： | 王敦建，焦慧文，钱依，徐江浩，徐皓，孙鲁宁，王永庆 |
| AUTHORS： | WANG Dunjian ，JIAO Huiwen ，QIAN Yi，XU Jianghao ，XU Hao，SUN Luning ，WANG Yongqing |
| 关键字： | 伊马替尼；N-去甲基伊马替尼；平衡透析法；液相色谱-串联质谱技术；血浆蛋白结合率 |
| KEYWORDS： | imatinib；N-desmethyl imatinib ；equilibrium dialysis ；liquid chromato graphy-tandem mass spectrometry ；plasma |
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