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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:XBrige TM C18(250 mm×4.6 mm,5μm);流动相:20 mmol·L-1NaH2PO4(用20%磷酸调至pH 3.0)-甲醇(45∶55);流速1.2 mL·min-1;检测波长304 nm;柱温45℃。血清样品经3 g·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0.312 5~50、3.125~500、0.156 3~25 mg·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在体内存在明显蓄积现象。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。
Abstract：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-1ZnSO4. The analytical column was XBrige TM C18( 250 mm ×4.6 mm,5 μm) and column temperature was kept at 45℃. The mobile phase was 20 mmol·L-1NaH2PO4buffer( pH 3. 0,adjusted with 20%phosphoric acid and methanol( 45∶ 55). The flow rate was 1. 2 mL·min-1and the detection wave length was 304nm. 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 and0. 156 3-25 mg·L-1respectively 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 metabolites. The concentration of them should be monitored routinely in clinical practice.
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基本信息:
DOI：10.19577/j.cnki.issn10074406.2014.01.003
中图分类号:R96
引用信息:
[1]陈红君,周蓉,干志彬,等.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[J].中国临床药学杂志,2014,23(01):14-19.DOI:10.19577/j.cnki.issn10074406.2014.01.003.
基金信息:
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)
2014-01-25
2014-01-25