【摘要】：目的:建立LC-MS/MS法同時(shí)測定血漿中霉酚酸(MPA)及其代謝物MPAG與AcMPAG濃度,用于治療藥物監(jiān)測與藥動(dòng)學(xué)研究。方法:100μl血漿標(biāo)本加入300μl含內(nèi)標(biāo)吲哚美辛的乙腈沉淀,離心后取上清液進(jìn)樣。色譜柱為Agilent E-clipse XDB-C18柱(3.5μm,2.1 mm×100 mm),流動(dòng)相為2 mmol·L-1甲酸銨水溶液-甲醇,采用梯度洗脫的方法,流速0.3 ml·min-1。用多反應(yīng)監(jiān)測進(jìn)行定量,ESI負(fù)離子方式進(jìn)行檢測,用于定量分析的檢測離子分別為m/z319.1→274.9(MPA)、m/z495.3→174.4(MPAG與AcMPAG)與m/z 356.1→312.0(內(nèi)標(biāo)吲哚美辛)。24例肝移植患者,采用包括霉酚酸鈉腸溶片(EC-MPS)的三聯(lián)免疫抑制方案,測定服藥后MPA及其代謝物濃度并計(jì)算藥動(dòng)學(xué)參數(shù)。結(jié)果:MPA在0.10~50.5μg·ml-1,MPAG在1.13~4501μg·ml-,AcMPAG在0.11~22.4μg·ml-1范圍內(nèi)線性良好(r20.99)。MPA、MPAG、AcMPAG提取回收率為77.3%~92.6%;基質(zhì)效應(yīng)為76.0%~86.7%;回收率為94.2%~116.4%;日內(nèi)及日間變異均小于15%。24例肝移植患者用藥1周后MPA、MPAG、AcMPAG的主要藥動(dòng)學(xué)參數(shù)分別如下:峰濃度Cmax為(18.8±10.9),(154±118),(3.07±2.85)μg·ml-1;達(dá)峰時(shí)間Tmax為(3.82±2.66),(4.74±2.51),(4.51±2.72)h;曲線下面積AUC0-12為(45.2±20.3),(1 456±1 195),(18.3±16.2)μg·h·ml-1;消除半衰期t1/2為(3.21±2.56),(9.26±4.33),(5.57±5.76)h。結(jié)論:本研究所建立的方法快速準(zhǔn)確、靈敏、專屬性強(qiáng),適用于MPA及其代謝物的血藥濃度監(jiān)測和人體藥動(dòng)學(xué)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 鹵10.9), (154 鹵118), (3.07 鹵2.85) 渭 g ml-1;. The peak time (Tmax) was (3.82 鹵2.66), () 4.74 鹵2.51), (4.51 鹵2.72) h, and the area under the curve (AUC0-12) was (45.2 鹵20.3), (1 456 鹵1 195), (18.3 鹵16.2) 渭 g ml-1;. The elimination half life t 1 / 2 was (3.21 鹵2.56), (9.26 鹵4.33), (5.57 鹵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.
【作者單位】： 上海交通大學(xué)醫(yī)院附屬瑞金醫(yī)院藥劑科;
【基金】：國家自然科學(xué)基金(編號(hào):81473275) 上海市自然科學(xué)基金(編號(hào):12ZR1418900)
【分類號(hào)】：R969.1;O657.63

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