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

WANG Dunjian; JIAO Huiwen; QIAN Yi; XU Jianghao; XU Hao; SUN Luning; WANG Yongqing

doi:10.6039/j.issn.1001-0408.2022.18.16

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

更新时间：2023-02-22

- Establishment and application of a method for the determination of plasma protein binding rate of imatinib and its metabolite
- ZHONGGUO YAOFANG Vol. 33, Issue 18, Pages: 2256-2260(2022)
- 作者机构：
  
  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
- 作者简介：
- 基金信息：
- DOI：10.6039/j.issn.1001-0408.2022.18.16
  CLC： R969.1
- Published：30 September 2022，
  
  Received：15 February 2022，
  
  Revised：09 August 2022，
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王敦建,焦慧文,钱依等.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 ^Δ[J].中国药房,2022,33(18):2256-2260.

WANG Dunjian,JIAO Huiwen,QIAN Yi,et al.Establishment and application of a method for the determination of plasma protein binding rate of imatinib and its metabolite[J].ZHONGGUO YAOFANG,2022,33(18):2256-2260.
王敦建,焦慧文,钱依等.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 ^Δ[J].中国药房,2022,33(18):2256-2260. DOI： 10.6039/j.issn.1001-0408.2022.18.16.

WANG Dunjian,JIAO Huiwen,QIAN Yi,et al.Establishment and application of a method for the determination of plasma protein binding rate of imatinib and its metabolite[J].ZHONGGUO YAOFANG,2022,33(18):2256-2260. DOI： 10.6039/j.issn.1001-0408.2022.18.16.

摘要

目的

建立测定伊马替尼及其代谢物（

-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、4 000 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）%；

-去甲基伊马替尼在60、2 000 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（4 000 ng/mL）及其代谢物（2 000 ng/mL）与α1-酸性糖蛋白、球蛋白的血浆蛋白结合率显著提高（

＜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（

＞0.05）。空白血浆中，高浓度伊马替尼（4 000 ng/mL）及其代谢物（2 000 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（

＜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－0.298 5、－3.332 3（

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 （

-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

-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 （

＜0.05）， but there was no signifi-cant difference with albumin （

＞0.05）. In blank plasma， the protein binding rates of imatinib （4 000 ng/mL） at high concentration and its meta-bolites （2 000 ng/mL） were significantly lower than those of low （120， 60 ng/mL） and medium （750， 375 ng/mL） concentration （

＜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

＜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.

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

Keywords

N-desmethyl imatinibequilibrium dialysisliquid chromatography-tandem mass spectrometryplasma protein binding rate

references

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QIAN Y，SUN L N，LIU Y J，et al. Genetic polymorphisms and adverse events on unbound imatinib and its active metabolite concentration in patients with gastrointestinal stromal tumors[J]. Front Pharmacol，2019，10：854.

董馨蔚，蒋刚，马松涛，等. 二维液相色谱法同时测定人血浆中伊马替尼及其代谢产物浓度的方法学研究[J]. 肿瘤预防与治疗，2021，34（10）：918-925.

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