目的 建立同时测定吉非替尼、厄洛替尼、尼洛替尼和伊马替尼血药浓度的高效液相色谱串联质谱(HPLC-MS/MS)方法.方法 用乙腈沉淀蛋白法处理血浆样品,用Diamonsil C18色谱柱(150 mm × 4.6 mum,3.5 μm)进行色谱分离,流动相为0.1％甲酸水(A)-0.1％甲酸乙腈(B);梯度洗脱,流速为0.7 mL·min-1,柱温40℃,进样量3 μL.以安罗替尼为内标,用电喷雾电离源,采用正电离模式,以多反应监测的方式进行扫描.考察该方法的专属性、标准曲线、定量下限、精密度、准确度、回收率、基质效应和稳定性.测定20例慢性粒细胞白血病(CML)患者伊马替尼和厄洛替尼的谷浓度及3例非小细胞肺癌(NSCLC)患者吉非替尼和厄洛替尼的谷浓度.结果 4种药物的标准曲线分别为吉非替尼:y=2.536 ×10-3x+9.372 × 10-3(线性范围 20-2 000 ng·mL-1,R2=0.996 6),厄洛替尼:y=3.573 × 10-3x+7.406 × 10-3(线性范围 50～5 000 ng·mL-1,R2=0.994 9),尼洛替尼:y=1.945 × 10-3x+0.015 643(线性范围50～5 000 ng·mL-1,R2=0.990 6),伊马替尼:y=4.56 x 10-3x+0.010 451(线性范围 100～1 × 104 ng·mL-1,R2=0.996 3).日内、日间 RSD 均小于 10％,准确度在90％～110％,提取回收率为91.35％～98.93％(RSD＜10％),基质效应为91.64％～107.50％(RSD＜10％).测定23例患者血药浓度显示,尼洛替尼血药浓度范围在623.76～2 934.13 ng·mL-1,伊马替尼血药浓度范围在757.77～2 637.71 ng·mL-1,吉非替尼血药浓度范围为214.76～387.40 ng·mL-1,厄洛替尼血药浓度为569.57 ng·mL-1.结论 所建立HPLC-MS/MS方法简单、快速、灵敏度高、专属性好,可用于临床血药浓度监测.
Objective To establish a high performance liquid chromatography-tandem mass spectrometry(HPLC-MS/MS)for the simultaneous determination of gefitinib,erlotinib,nillotinib and imatinib plasma concentrations and analyze the results.Methods The plasma samples were treated with acetonitrile precipitation and separated by Diamonsil C18 column(150 mm ×4.6 mm,3.5 μm)with mobile phase of 0.1％formic acid water(A)-0.1％formic acid acetonitrile(B).The flow rate of gradient elution was 0.7 mL·min-1,and the column temperature was 40 ℃ and the injection volume was 3 μL.Using arotinib as the internal standard,the scanning was carried out by using electrospray ionization source in positive ionization mode with multi-reaction monitoring.The specificity,standard curve,lower limit of quantitation,precision,accuracy,recovery rate,matrix effect and stability of the method were investigated.The concentrations of imatinib and erlotinib in 20 patients with chronic myelogenous leukemia(CML)and gefitinib and erlotinib in 3 patients with non-small cell lung cancer were measured.Results The standard curves of the four drugs were as follows,gefitinib:y=2.536 × 10-3x+9.362 × 10-3(linear range 20-2 000 ng·mL-1,R2=0.996 6);erlotinib:y=3.575× 10-3x+7.406 × 10-3(linear range 50-5 000 ng·mL-1,R2=0.994 9);nilotinib:y=1.945 x 10-3x+0.015 643(linear range 50-5 000 ng·mL-1,R2=0.990 6);imatinib:y=4.56 x 10-3x+0.010 451(linear range 100～104 ng·mL-1,R2=0.9963).RSD of intra-day and inter-day were less than 10％,and the accuracy ranged from 90％to 110％,and the recovery rates were 91.35％to 98.93％(RSD＜10％);the matrix effect ranged from 91.64％to 107.50％(RSD＜10％).Determination of 23 patients showed that the blood concentration of nilotinib ranged from 623.76 to 2 934.13 ng·mL-1,and the blood concentration of imatinib ranged from 757.77 to 2 637.71 ng·mL-1,and the blood concentration of gefitinib ranged from 214.76 to 387.40 ng·mL-1.The serum concentration of erlotinib was 569.57 ng·mL-1.Conclusion The method of this research is simple,fast,sensitive and dedicated,which can be monitored by the concentration of clinical blood.
郑天伦;徐敬朴;韩竺杭;李文利;董维冲;张志清
河北医科大学第二医院药学部,河北石家庄 050000
药学
吉非替尼;厄洛替尼;尼洛替尼;伊马替尼;高效液相色谱串联质谱法
gefitinib;erlotinib;nilotinib;imatinib;high performance liquid chromatography-tandem mass spectrometry
《中国临床药理学杂志》 2024 (006)
899-903 / 5
10.13699/j.cnki.1001-6821.2024.06.024
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