液-质联用法同时测定人血浆中霉酚酸及其代谢物浓度及其在肝移植患者药动学研究中的应用

发布时间：2018-12-10 15:21

【摘要】：目的:建立LC-MS/MS法同时测定血浆中霉酚酸(MPA)及其代谢物MPAG与AcMPAG浓度,用于治疗药物监测与药动学研究。方法:100μl血浆标本加入300μl含内标吲哚美辛的乙腈沉淀,离心后取上清液进样。色谱柱为Agilent E-clipse XDB-C18柱(3.5μm,2.1 mm×100 mm),流动相为2 mmol·L-1甲酸铵水溶液-甲醇,采用梯度洗脱的方法,流速0.3 ml·min-1。用多反应监测进行定量,ESI负离子方式进行检测,用于定量分析的检测离子分别为m/z319.1→274.9(MPA)、m/z495.3→174.4(MPAG与AcMPAG)与m/z 356.1→312.0(内标吲哚美辛)。24例肝移植患者,采用包括霉酚酸钠肠溶片(EC-MPS)的三联免疫抑制方案,测定服药后MPA及其代谢物浓度并计算药动学参数。结果:MPA在0.10~50.5μg·ml-1,MPAG在1.13~4501μg·ml-,AcMPAG在0.11~22.4μg·ml-1范围内线性良好(r20.99)。MPA、MPAG、AcMPAG提取回收率为77.3%~92.6%;基质效应为76.0%~86.7%;回收率为94.2%~116.4%;日内及日间变异均小于15%。24例肝移植患者用药1周后MPA、MPAG、AcMPAG的主要药动学参数分别如下:峰浓度Cmax为(18.8±10.9),(154±118),(3.07±2.85)μg·ml-1;达峰时间Tmax为(3.82±2.66),(4.74±2.51),(4.51±2.72)h;曲线下面积AUC0-12为(45.2±20.3),(1 456±1 195),(18.3±16.2)μg·h·ml-1;消除半衰期t1/2为(3.21±2.56),(9.26±4.33),(5.57±5.76)h。结论:本研究所建立的方法快速准确、灵敏、专属性强,适用于MPA及其代谢物的血药浓度监测和人体药动学研究。
[Abstract]:Aim: to establish a LC-MS/MS method for simultaneous determination of mycophenolate mofetil (MPA) and its metabolites (MPAG and AcMPAG) in plasma for therapeutic drug monitoring and pharmacokinetic study. Methods: 100 渭 l plasma samples were added to 300 渭 l acetonitrile precipitates containing the internal standard indomethacin. The supernatant samples were collected after centrifugation. The chromatographic column consisted of Agilent E-clipse XDB-C18 column (3. 5 渭 m ~ 2. 1 mm 脳 100 mm), mobile phase: 2 mmol L-1 ammonium formate aqueous solution-methanol). Gradient elution was used at a flow rate of 0. 3 ml min-1.. Multireaction monitoring was used for quantitative analysis and ESI negative ion method was used for quantitative analysis. The detected ions for quantitative analysis were m/z319.1 + 274.9 (MPA),. M/z495.3 174.4 (MPAG and AcMPAG) and m / z 356.1 ~ 312.0 (internal standard indomethacin). 24 patients with liver transplantation were treated with triplex immunosuppressive regimen including mycophenolate sodium enteric-coated tablets (EC-MPS). MPA and its metabolites were measured and pharmacokinetic parameters were calculated. Results: MPA was linear in the range of 0.10 ~ 50.5 渭 g ml-1,MPAG and 1.13 ~ 4501 渭 g / ml-,AcMPAG in the range of 0.11 ~ 22.4 渭 g / ml-1 (r 20.99). The recovery of MPA,MPAG,AcMPAG was 77.3% and 92.6 渭 g / m ~ (-1). The matrix effect was 76.0 and the recovery rate was 94.2and 116.4, respectively. The main pharmacokinetic parameters of MPA,MPAG,AcMPAG in 24 patients with liver transplantation were as follows: the peak concentration of Cmax was (18.8 卤10.9), (154 卤118), (3.07 卤2.85) 渭 g ml-1;. The peak time (Tmax) was (3.82 卤2.66), () 4.74 卤2.51), (4.51 卤2.72) h, and the area under the curve (AUC0-12) was (45.2 卤20.3), (1 456 卤1 195), (18.3 卤16.2) 渭 g ml-1;. The elimination half life t 1 / 2 was (3.21 卤2.56), (9.26 卤4.33), (5.57 卤5.76 h). Conclusion: this method is rapid, accurate, sensitive and specific. It is suitable for the monitoring of MPA and its metabolites in blood and pharmacokinetics in human body.
【作者单位】：上海交通大学医院附属瑞金医院药剂科;
【基金】：国家自然科学基金(编号:81473275) 上海市自然科学基金(编号:12ZR1418900)
【分类号】：R969.1;O657.63

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