LC-MS/MS法测定缬更昔洛韦/更昔洛韦血浆浓度及在药动学研究中的应用  

Determination of valganciclovir and ganciclovir in plasma by liquid chromatographic-tandem mass spectrometry and its application in pharmacokinetic study

作　　者：胡珊珊[1] 翟晓慧 芮文斌[2] 安会敏[2] 邵琨[2] 周佩军[2] 陈冰[1] HU Shanshan;ZHAI Xiaohui;RUI Wenbin;AN Huimin;SHAO Kun;ZHOU Peijun;CHEN Bing(Department of Pharmacy,Shanghai Jiaotong University School of Medicine,Shanghai 200025,China;Organ Transplantion Center,Ruijin Hospital,Shanghai Jiaotong University School of Medicine,Shanghai 200025,China)

机构地区：[1]上海交通大学医学院附属瑞金医院药剂科,上海200025 [2]上海交通大学医学院附属瑞金医院器官移植中心,上海200025

出　　处：《中国临床药学杂志》2020年第1期6-12,共7页Chinese Journal of Clinical Pharmacy

基　　金：国家自然科学基金(编号81473275);上海交通大学医工交叉项目(编号YG2016MS60)

摘　　要：目的建立LC-MS/MS法同时测定人血浆中缬更昔洛韦(VGCV)和更昔洛韦(GCV)的浓度。研究中国肾移植患者服用VGCV后,VGCV和GCV在体内的药动学特征。方法50μL血浆加入含内标乙腈150μL沉淀,离心后取上清液进样。色谱柱为Agilent Eclipse Plus C(18)柱(50 mm×2.1 mm,3.5μm),流动相为甲醇-纯水(含2 mmol·L^-1甲酸铵/0.02%甲酸),采用梯度洗脱的方法,流速0.25 mL·min^-1。采用ESI正离子方式以多反应监测定量,检测离子对分别为m/z 355.3→152.1(VGCV)和m/z 256.4→152.1(GCV)。检测40例肾移植患者口服VGCV片达稳态后VGCV及GCV浓度,并计算药动学参数。结果VGCV在0.0048~0.95 mg·L^-1和GCV在0.048~9.6 mg·L^-1内线性良好(r>0.9999)。VGCV和GCV提取回收率分别为92.74%~97.83%和92.12%~102.12%,基质效应分别为106.97%~107.76%和102.45%~107.04%。VGCV的日内及日间RSD<15%。肾移植患者服用450 mg与900 mg VGCV后,GCV的AUC0→24h分别为(28.40±8.35)和(60.67±17.50)mg·h·L^-1,峰浓度ρ(max)分别为(4.24±1.07)和(8.64±1.65)mg·L^-1。结论本研究所建立的方法具有快速、准确、灵敏和专属性强等优点,适用于VGCV及GCV的药动学研究。AIM To establish an LC-MS/MS method for the determination of valganciclovir(VGCV)and ganciclovir(GCV)in human plasma and investigate the pharmacokinetic characteristics in Chinese renal-transplan-ted patients.METHODS A total of 150μL of acetontrile containing interal standard was added in 50μL plasma to precipitate protein.After centrifugation,the supernatant was eluted through Agilent Eclipse Plus C18 column(50 mm×2.1 mm,3.5μm)by methanol-water(contatining 2 mmol·L^-1 ammonium acetate and 0.02%methane acid)by a gradient assay,and the flow rate was set as 0.25 mL·min-1.Electrospray ionization(ESI)sources were applied and operated in the positive ion mode.Multiple reaction monitoring(MRM)mode with the transition of m/z 355.3→152.1(VGCV)and m/z 256.4→152.1(GCV)was used for quantification.Plasma concentration of VGCV and GCV of 40 renal-transplanted patients after administration of VGCV were determined and pharmacoki-netic parameters were calculated.RESULTS The method was proved to be linear in the range of 0.0048-0.95 mg·L^-1 for VGCV and 0.048-9.6 mg·L^-1 for GCV(r>0.9999).The extract recovery,matrix effect of VGCV and GCV were 92.74%-97.83%and 92.12%-102.12%,106.97%-107.76%and 102.45%-107.04%,respectively.The within-day and between-day variation of VGCV and GCV were all lower than 15%.The AUC0→24 of GCV in renal-transplanted patients after administration of single dose of 450 mg or 900 mg VGCV was(28.40±8.35)and(60.67±17.50)mg·h·L^-1,and theρmax was(4.24±1.07)and(8.64±1.65)mg·L^-1,re-spectively.CONCLUSION The method established is rapid,accurate,sensitive and specific,which is suitable for pharmacokinetic study of VGCV and GCV.

关 键 词：LC-MS/MS法 缬更昔洛韦 更昔洛韦 肾移植 药动学 

分 类 号：R969.1[医药卫生—药理学]