3种二线抗结核药物血药浓度测定及其影响因素  

Determination of plasma concentration of three second-line anti-tuberculous drugs and their influencing factors

作　　者：雷倩 赵嫄 王皓 党丽云 吕小会 周俊 LEI Qian;ZHAO Yuan;WANG Hao;DANG Li-yun;LÜ Xiao-hui;ZHOU Jun(Department of Pharmacy,Xi’an Chest Hospital,Xi’an 710061,China)

机构地区：[1]西安市胸科医院药剂科,西安710061

出　　处：《药物分析杂志》2020年第8期1405-1412,共8页Chinese Journal of Pharmaceutical Analysis

基　　金：陕西省科技计划自然科学基础研究项目(2017JQ8016)。

摘　　要：目的:研究3种二线抗结核药血药浓度的测定方法及其影响因素,探索其与结核菌转阴相关性,为合理用药提供参考。方法:对257例结核病患者服用莫西沙星(123例)、利奈唑胺(80例)、氯法齐明(54例)后2 h的血药浓度进行监测。样品用乙腈提纯,采用高效液相-质谱联用法测定。色谱条件:Shimadzu ODS-C18色谱柱(100 mm×2.0 mm,2.2μm),以0.1%甲酸-10 mmol·mL^-1甲酸铵-水溶液(A)和50%甲醇-50%乙腈-0.1%甲酸溶液(B)作为流动相,进行梯度洗脱。质谱条件:正离子模式下的电喷雾(ESI)离子源,喷雾电压5 kV,离子源温度500℃,MRM模式。并采集相关的人口学特征、实验室数据,对相关性和影响因素进行回顾性分析。结果:该方法日内、日间的准确度、精密度(RSD均小于13.2%)、线性(r均高于0.9970)、回收率和稳定性都在可接受范围内。男性(χ^2=-4.565,P=0.033)、30~49岁(χ^2=11.918,P=0.003)、内生肌酐清除率较低(t=2.352,P=0.020)、复治患者(χ^2=6.276,P=0.012)、吸烟史(χ^2=5.826,P=0.016)、耐多药(χ^2=8.162,P=0.004)和利奈唑胺2 h血药浓度偏低(t=2.033,P=0.046)是结核菌培养转阴时间更长的相关因素。莫西沙星组中女性的血药浓度更高(P=0.044),血清白蛋白和血药浓度之间有负相关性(P=0.035);利奈唑胺组中,单位给药剂量越大,血药浓度越高(P<0.001),而内生肌酐清除率和血药浓度之间有负相关性(P=0.024);氯法齐明2 h血药浓度没有明显的影响因素。结论:本方法可以同时、方便、快捷地测出3种二线抗结核药的血药浓度。利奈唑胺的2 h血药浓度偏低与结核菌培养转阴时间长有关,应关注其单位给药剂量和肌酐清除率,从而实现个体化给药。Objective:To study the method of monitoring plasma concentration of three second-line antituberculosis drugs and its influencing factors,and to explore its correlation with conversion of mycobacterium tuberculosis,so as to provide reference for rational using of drugs. Methods:The plasma levels of moxifloxacin(n=123),linezolid(n=80),and clofazimine(n=54)were determined for 257 hospitalized patients. The sample was purified by acetonitrile and estimated by high-pressure liquid chromatography-tandem mass spectrometry. The chromatographic condition:Shimadzu ODS-C18(100 mm×2.0 mm,2.2 μm) column,0.1% formic acid-10 mmol·mL^-1 ammonium formate-water(A)and 50% methanol-50% acetonitrile-0.1% formic acid(B)as mobile phase for gradient el ution. The mass condition: ESI in positive mode,spray of 5 kV,ESI temperature of 500 ℃,MRM detect mode. At the same time,collected the relevant demographic characteristics and laboratory data,to retrospectively analyze the relevance and influencing factors. Results:Intra-and inter-day accuracy,RSD<13.2%,linearity(r>0.997 0),recovery and stability were acceptable. Male(χ^2=-4.565,P=0.033),30~49 years old(χ^2=11.918,P=0.003),lower creatinine clearance(t=2.352,P=0.020),retreatment history(χ^2=6.276,P=0.012),smoker(χ^2=5.826,P=0.016),multidrug resistance(χ^2=8.162,P=0.004)and lower 2 h plasma concentration of linezolid(t=2.033,P=0.046)were the related factors of longer conversion time of mycobacterium tuberculosis. Female in the moxifloxacin group got higher plasma concentration(P=0.044),and the correlation between serum albumin and plasma concentration was negative(P=0.035). In the linezolid group,the higher dosage was related to the higher plasma concentration(P<0.001),while there was a negative correlation between creatinine clearance and plasma concentration(P=0.024). No significant influence factor was found about clofazimine 2 h plasma concentration. Conclusion:The method can simultaneously,conveniently and quickly measure the plasma concentration of three second-line anti-tub

关 键 词：结核分枝杆菌 耐药 血药浓度监测 二线抗结核药 莫西沙星 利奈唑胺 氯法齐明 高效液相色谱-质谱联用法 

分 类 号：R917[医药卫生—药物分析学]