同时测定吗替麦考酚酯在自身免疫性疾病患者血清中代谢物浓度的HPLC法及其应用  

Simultaneous determination of mycophenolate mofetil and its metabolits in Chinese patients with autoimmune disease by HPLC and method application

作　　者：陈红君[1] 周蓉[2] 干志彬[1] 余自成[1] 张芸[2] 唐原君[1] 沈杰[2] 

机构地区：[1]同济大学医学院附属杨浦医院临床药学与药理学研究室,上海200090 [2]同济大学医学院附属杨浦医院肾内科,上海200090

出　　处：《中国临床药学杂志》2014年第1期14-19,共6页Chinese Journal of Clinical Pharmacy

基　　金：上海市卫生局科研基金资助课题(编号2009219);同济大学附属杨浦医院"晨光计划"资助(编号Ye1201220)

摘　　要：目的建立可同时测定人血清中吗替麦考酚酯一级代谢物麦考酚酸（MPA）及其二级代谢物酚化葡萄糖醛麦考酚酸（MPAG）、酰基化MPAG（acyl．MPAG、AcMPAG）浓度的HPLC法，并将其应用于自身免疫性疾病患者给药后血药浓度测定及药动学研究。方法色谱柱：XBrigeTMC18（250mm×4．6mm，5μm）；流动相：20mmol·L-1 NaH2PO4（用20％磷酸渊至pH3．0）一甲醇（45：55）；流速1．2mL·min；检测波长304nm；柱温45℃。血清样品经3g·L-1ZnSO4的甲醇溶液处理后，取20μL，直接进样测定。测定10例自身免疫患者首次及稳态的血药浓度，并用3P87软件计算其药动学参数。结果MPA、MPAG、AcMPAG质量浓度分别在0．3125～50、3．125～500、0．1563～25mg·L-1时呈线性关系（r〉0．999），回收率及精密度均符合要求，检测方法成功应用于自身免疫性疾病患者血药浓度测定。研究结果显示患者个体间药动学参数差异较大，且MPAG在体内存在明硅莆积现象。结论同时测定人血清中MPA、MPAG、AcMPAG的HPLC法具有简便、准确、精密等优点。自身免疫患者同方案给药后，血药浓度及药动学个体间差异大，需要进行血药浓度监测，以制定个体化给药方案。AIM To establish a HPLC method for simultaneous determination of mycophenolic acid （MPA）, its phenol glucuronide metabolite （MPAG） and acyl-MPAG （AcMPAG） in Chinese patients with autoimmune disease, and to investigate the pharmacokinetics. METHODS The serum samples were treated with methanol containing 3 g L- 1 ZnSO4. The analytical column was XBrige TM C18（250 mm 4.6 ram,5 μm）and column temperature was kept at 45℃. The mobile phase was 20 mmol L-1 NaH2PO4 buffer （pH 3 .0, adjusted with 20% phosphoric acid and methanol （45： 55）. The flow rate was 1.2 mL min-1 and the detection wave length was 304 nm. The serum MPA, AcMPAG and MPAG concentrations in 10 patients with autoimmune disease were measured after the administration of a single dose and steady state. Pharmacokinetic parameters of MPA and MPAG were calculated with 3P87 software. RESULTS The assay was linear within the range of 0.312 5 -50, 3.125 -500 and 0.156 $ -25 mg＂ L-1 respectively for MPA, MPAG and AcMPAG （r 〉 0.999） and the precision and recoveries were good. It had been used successfully to determine clinical samples. However, a larger variability of pharmacokinetic parameters existed in patients with autoimmune disease and the accumulation for MPAG was detected after repetitive mycophenolate mofetil administration. CONCLUSION The method described is simple, accurate and precise, and can be useful in pharmacokinetic studies or TDM of MPA and its metabo- lites. The concentration of them should be monitored routinely in clinical practice.

关 键 词：吗替麦考酚酯 代谢物 HPLC法 血清浓度 自身免疫疾病 药动学 

分 类 号：R96[医药卫生—药理学]