7种抗肿瘤药物血药浓度测定方法建立及临床应用  

Determination method of plasma concentrations of 7 anti-tumor drugs and its application

作　　者：吕锦绣 颜楠 徐文俊 赵静 朱华 杭鹏洲 LYU Jinxiu;YAN Nan;XU Wenjun;ZHAO Jing;ZHU Hua;HANG Pengzhou(Dept.of Pharmacy,Northern Jiangsu People’s Hospital,Jiangsu Yangzhou 225001,China)

机构地区：[1]苏北人民医院药学部,江苏扬州225001

出　　处：《中国药房》2025年第4期475-481,共7页China Pharmacy

基　　金：苏北人民医院青年托举专项青年基金(No.SBQN22012);苏北人民医院院级扶持技术项目(No.FCJS202313)。

摘　　要：目的建立同时测定人血浆中7种抗肿瘤药物(伊立替康、卡培他滨、紫杉醇、多西他赛、他莫昔芬、来曲唑和甲氨蝶呤)血药浓度的方法并应用于临床。方法血浆样品以含0.1%甲酸的甲醇-乙腈混合液(1∶1,V/V)沉淀蛋白后,以各待测成分的氘代同位素为内标,采用液相色谱-串联质谱(LC-MS/MS)技术检测。以Agilent Eclipse Plus C18为色谱柱,以水(含0.1%甲酸和0.04%5 mmol/L甲酸铵)为流动相A相、乙腈(含0.1%甲酸)为流动相B相进行梯度洗脱,流速为0.6 mL/min,柱温为40℃,进样量为10μL,分析时间为5.5 min;采用电喷雾离子源在正、负离子模式下以多反应监测模式进行测定,用于定量分析的离子对分别为m/z587.1→167.1(伊立替康)、m/z 360.1→244.1(卡培他滨)、m/z 876.4→308.0(紫杉醇)、m/z 830.3→304.2(多西他赛)、m/z 372.1→129.1(他莫昔芬)、m/z 284.1→242.1(来曲唑)、m/z 455.0→308.0(甲氨蝶呤)。选择我院97例恶性肿瘤患者,采用上述方法测定其血浆中7种抗肿瘤药物的血药浓度。结果伊立替康、卡培他滨、紫杉醇、多西他赛、他莫昔芬、来曲唑和甲氨蝶呤的线性范围分别为2~1000 ng/mL(r=0.9943)、20~10000 ng/mL(r=0.9975)、2~1000 ng/mL(r=0.9979)、1~500 ng/mL(r=0.9958)、1~500 ng/mL(r=0.9952)、1~500 ng/mL(r=0.9964)、10~5000(r=0.9977);定量下限分别为2、20、2、1、1、1、10 ng/mL;批内精密度的RSD为0.08%~14.86%(n=6),批间精密度的RSD为1.51%~11.55%(n=3),准确度为89.17%~114.93%(n=6);基质效应为89.89%~119.74%(n=6);稳定性试验的RSD为1.98%~14.88%(n=6)。临床应用结果显示,伊立替康、卡培他滨、紫杉醇、多西他赛的平均血药浓度分别为704.09、909.40、36.45、150.43 ng/mL,变异系数分别为25.24%、62.65%、122.69%、92.27%。结论所建LC-MS/MS法操作简单、分析时间短,可用于恶性肿瘤患者体内7种常用抗肿瘤药物血药浓度的测定。OBJECTIVE To establish a method for simultaneous determination of 7 anti-tumor drugs(irinotecan,capecitabine,paclitaxel,docetaxel,tamoxifen,letrozole and methotrexate)in human plasma and apply it to the clinic.METHODS After precipitating with a methanol-acetonitrile mixture(1∶1,V/V)containing 0.1%formic acid,liquid chromatography-tandem mass spectrometry(LC-MS/MS)was used to determine the plasma concentration,using deuterium isotopes of each analyte as internal standards.The chromatography was performed on the Agilent Eclipse Plus C18 column with a gradient elution of water(containing 0.1%formic acid+0.04%5 mmol/L ammonium formate)as mobile phase A and acetonitrile(containing 0.1%formic acid)as mobile phase B.The flow rate was 0.6 mL/min,and the column temperature was set at 40℃.The sample size was 10μL,and the analysis lasted for 5.5 min.Electrospray ionization was used in positive and negative ion mode,and multiple reaction monitoring mode was used.The ion pairs used for quantitative analysis were m/z 587.1→167.1(irinotecan),m/z 360.1→244.1(capecitabine),m/z 876.4→308.0(paclitaxel),m/z 830.3→304.2(docetaxel),m/z 372.1→129.1(tamoxifen),m/z 284.1→242.1(letrozole),and m/z 455.0→308.0(methotrexate).A total of 97 patients with malignant tumors in our hospital were selected to measure the plasma concentrations of 7 anti-tumor drugs using the above method.RESULTS The linear ranges of irinotecan,capecitabine,paclitaxel,docetaxel,tamoxifen,letrozole and methotrexate were 2-1000 ng/mL(r=0.9943),20-10000 ng/mL(r=0.9975),2-1000 ng/mL(r=0.9979),1-500 ng/mL(r=0.9958),1-500 ng/mL(r=0.9952),1-500 ng/mL(r=0.9964),10-5000(r=0.9977),respectively.The quantitative lower limits were 2,20,2,1,1,1 and 10 ng/mL;RSDs of intra-assay precision were 0.08%-14.86%(n=6).RSDs of inter-batch precision were 1.51%-11.55%(n=3),and the accuracies were 89.17%-114.93%(n=6).The matrix effects ranged from 89.89%-119.74%(n=6).RSDs of the stability tests were 1.98%-14.88%(n=6).The results of clinical application showed,the average plas

关 键 词：抗肿瘤药物 治疗药物监测 血药浓度 液相色谱-串联质谱技术 

分 类 号：R917[医药卫生—药物分析学]