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  

Establishment and application of a method for the determination of plasma protein binding rate of imatinib and its metabolite

作　　者：王敦建 焦慧文 钱依 徐江浩[3] 徐皓[3] 孙鲁宁 王永庆 WANG Dunjian;JIAO Huiwen;QIAN Yi;XU Jianghao;XU Hao;SUN Luning;WANG Yongqing(School of Pharmacy,Xuzhou Medical University,Jiangsu Xuzhou 221004,China;Research Division of Clinical Pharmacology,the First Affiliated Hospital of Nanjing Medical University,Nanjing 210029,China;Dept.of General Surgery,the First Affiliated Hospital of Nanjing Medical University,Nanjing 210029,China)

机构地区：[1]徐州医科大学药学院,江苏徐州221004 [2]南京医科大学第一附属医院临床药理研究室,南京210029 [3]南京医科大学第一附属医院普外科,南京210029

出　　处：《中国药房》2022年第18期2256-2260,共5页China Pharmacy

基　　金：国家自然科学基金资助项目(No.81503160);江苏省卫生健康发展研究中心2021年度开放课题(No.JSHD2021004);江苏省人民医院优秀中青年人才支持计划项目。

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、4000 ng/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、2000 ng/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(120 ng/mL)及其代谢物(60 ng/mL)比较,高浓度伊马替尼(4000 ng/mL)及其代谢物(2000 ng/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(4000 ng/mL)及其代谢物(2000 ng/mL)的血浆蛋白结合率显著低于低(120、60 ng/mL)、中(750、375 ng/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。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 imatinibd8 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 4000 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 2000 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(4000 ng/mL)and its metabolite(2000 ng/mL)withα1-acid glycoprotein and globulin was significantly increased(P<0.05),but there was no signifi-cant difference with albumin(P>0.05).In blank plasma,the protein binding rates of imatinib(4000 ng/mL)at high concentration and its metabolites(2000 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-0.2985 and-3.3323,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 neg

关 键 词：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 

分 类 号：R969.1[医药卫生—药理学]