高效液相色谱法监测侵袭性真菌感染患者伏立康唑血药浓度及临床应用分析  

Determination of voriconazole in serum of patients with invasive fungal infection by HPLC and its clinical application

作　　者：高飞[1] 周丽娟 李敏 詹峰 李慧红 GAO Fei;ZHOU Li-juan;LI Min;ZHAN Feng;LI Hui-hong(Department of Nephrology,Sanmenxia Central Hospital,Henan Sanmenxia 472000,China;Translational Medicine Center,Zhengzhou Central Hospital Affiliated to Zhengzhou University,Henan Zhengzhou 450007,China)

机构地区：[1]三门峡市中心医院药学部,河南三门峡472000 [2]郑州大学附属郑州中心医院转化医学中心,河南郑州450007

出　　处：《中国医院药学杂志》2022年第1期7-13,共7页Chinese Journal of Hospital Pharmacy

基　　金：河南省医学科技攻关计划项目(编号:LHGJ20191056);河南省高等学校重点科研项目计划(编号:21B360010,20B350008)。

摘　　要：目的:建立高效液相色谱法(HPLC)测定人血清中伏立康唑的浓度,并对临床应用进行汇总分析,为临床用药提供参考。方法:以Merck Purospher STARLP RP-18 endcapped柱(250 mm×4.6 mm,5μm)为色谱柱,乙腈-水(53∶47)为流动相,流速1.0 mL·min^(-1),检测波长256 nm,柱温35℃。结果:伏立康唑在0.3174~21.16μg·mL^(-1)(R^(2)=0.9999,n=7)范围内与校正因子f(伏立康唑峰面积/尼莫地平峰面积)成良好的线性关系,定量限为0.8 ng,检测限为0.3 ng。伏立康唑平均提取回收率为98.03%,平均加样回收率为99.52%(RSD=0.83%,n=9)。296份血清样品的伏立康唑血药浓度测定结果准确可靠,平均血药谷浓度(C_(min))在性别及不同年龄段间均无显著差异(P>0.05);慢代谢型患者的平均C_(min)分别显著高于超快与快代谢型患者(P<0.05)和中间代谢型患者(P<0.05);平均C_(min)在CRP分层的3组间差异显著(P<0.01)。发生不良反应患者的平均C_(min)显著高于未发生者(P<0.01),根据C_(min)监测结果调整用药,调整后临床有效率显著高于调整前(P<0.01)。结论:该法操作简便、灵敏、准确,适用于伏立康唑治疗药物浓度监测,且CYP2C19基因表型和C-反应蛋白是影响患者C_(min)的危险因素,用以指导患者个体化用药。OBJECTIVE To establish an HPLC method for determination of voriconazole in serum and make a summary analysis of the clinical application,so as to provide reference for the clinical medication.METHODS An Merck Purospher STARLP RP-18 endcapped was used as the chromatographic column,and the mobile phase consisted of a mixture of acetonitrile-water(53∶47).The flow rate was 1.0 mL·min^(-1),the detective wavelength was 256 nm,and the column temperature was 35℃.RESULTS There was a good linear relationship between the concentration of voriconazole and correction factor(f,peak area value of voriconazole/peak area value of nimodipine)within the range of 0.3174-21.16μg·mL^(-1)(R^(2)=0.9999,n=7),the limit of quantification and the limit of detection was 0.8 ng and 0.3 ng,respectively.The average extraction recovery of voriconazole was 98.03%,and the average method recovery was 99.52%(RSD=0.83%,n=9).The determination results of voriconazole in 296 serum samples were accurate and reliable.The average blood trough concentration(C_(min))was not significantly different between male group and female groups,and among different age groups(P>0.05).The average C_(min) of the patients with slow metabolism was significantly higher than that of the patients with ultrafast metabolism(P<0.05)and the patients with intermediate metabolism(P<0.05).The average C_(min) was significantly different among the three groups with CRP stratification(P<0.01).The average C_(min) of the patients with adverse drug reactions(ADRs)was significant higher than that of those without ADRs(P<0.01).After adjusting the medication according to the C_(min) monitoring results,the clinical effective rate was significantly higher than that before adjustment(P<0.01).CONCLUSION The method is simple,sensitive and accurate,which can be used for the assay of voriconazole in serum.The CYP2C19 genotype and C-reactive protein(CRP)are the risk factors for C_(min).The study results can be used to guide drug individualized use in patients.

关 键 词：伏立康唑 高效液相色谱法 CYP2C19 C-反应蛋白 血药浓度 治疗药物监测 

分 类 号：R027.2[医药卫生]