LC-MS/MS法测定血浆中马来酸甲麦角新碱及其人体药代动力学研究  

Determination of methylergonovine maleate in plasma emd its pharmacokinetic research by LC-MS/MS

作　　者：赵恒利[1,2] 李岩 方增军[1] 高彦慧[2] 王海生[1] ZHAO Heng-li1,3, LI Yan2, FANG Zeng-jun1, GAO Yan-hui3, WANG Hai-sneng 1(1. The Second Hospital of Shandong University, Jinan 250033, China; 2. Huaiyin Municipal Center for Disease Control and Prevention, Jinan 250000, China; 3. Pharmaeeutics College of Shandong University, Jinan 250012, China)

机构地区：[1]山东大学第二医院临床药理部,济南250033 [2]山东大学药学院,济南250012 [3]山东省济南市槐荫区疾病预防控制中心,济南250000

出　　处：《药物分析杂志》2018年第3期393-398,共6页Chinese Journal of Pharmaceutical Analysis

基　　金：山东大学第二医院青年基金项目资助(Y2013010075)

摘　　要：目的:建立LC-MS/MS法测定人血浆中甲麦角新碱浓度,对肌注0.2 mg马来酸甲麦角新碱注射液后药动学进行研究。方法:以文拉法辛为内标,血浆以NaOH碱化后经乙酸乙酯液液萃取浓缩后进行LC-MS/MS分析。采用高效液相色谱分离系统,色谱柱为CAPCELL CORE C_(18)色谱柱(2.1 mm×100 mm,2.7μm),流动相为甲醇(0.05%乙酸)-水(5 mmol·L^(-1)乙酸铵,0.05%乙酸)(65∶35);采用质谱检测法,多反应监测(MRM)方式监测m/z 340.2→m/z 208.1(甲麦角新碱)和m/z 278.3→m/z 215.1(内标文拉法辛)。结果:建立的LC-MS/MS法在0.025~10 ng·mL^(-1)范围内甲麦角新碱色谱响应与浓度相关性良好,定量限为0.025 ng·mL^(-1),日内、间精密度RSD均小于7%,准确度在96.7%~112.4%,方法稳定性较好。16名受试者单次肌注0.2 mg马来酸甲麦角新碱注射液后AUC_(0-8)为(12.165±3.345)ng·mL^(-1)·h,AUC_(0-∞)为(12.900±3.800)ng·mL^(-1)·h,C_(max)为(4.707±2.541)ng·mL^(-1),t_(max)为(0.577±0.251)h,t_(1/2)为(1.831±0.457)h,MRT为(2.412±0.246)h,CL为(16.925±5.281)L·h^(-1),V_d为(43.183±14.041)L。结论:该法灵敏准确,简便易行,适用于低剂量甲麦角新碱血药浓度的测定及其药代动力学研究。研究结果显示马来酸甲麦角新碱注射液肌注后吸收较快,0.5 h左右达峰;部分受试者用药后发生恶心、呕吐及头痛等不良事件,但程度均为轻微。Objective： To develop an LC-MS/MS method for the determination of the concentration of methylergonovine in human plasma and to study its pharmacokinetic parameters after 0.2 mg intramuscular injection of methylergonovine maleate injection.Methods： Venlafaxine was used as an internal standard, plasma was alkalified by NaOH and extracted by ethyl acetate,and then was analyzed by LC-MS/MS.A high performance liquid phase system was used.The mobile phase consisted of CAPCELL CORE C18 column（2.1 mm×100 mm,2.7 μm） with methanol （0.05% acetic acid） -water （5 mmol·L-1 ammonium acetate,0.05% acetic acid） （65：35）.m/z 340.2→m/z 208.1 （methylergonovine） and m/z 278.3→m/z 215.1 （internal standard venlafaxine） were monitored by mass spectrometry and multiple reaction monitoring （MRM）.Results： The established LC-MS/MS method showed a good correlation with concentration in the range of 0.025-10 ng·mL-1,the limit of quantification was 0.025 ng·mL-1,and RSD of precision was less than 7%,the accuracy was between 96.7%-112.4%,the method had better stability.Mean pharmacokinetic parameters for methylergonovine in 16 volunteers after a single dose of 0.2 mg methylergonovine maleate injection were as follows：AUC0-8（12.165±3.345） ng·mL-1·h,AUC0-∞（12.900±3.800）ng·mL-1·h,Cmax（4.707±2.541）ng·mL-1,tmax（0.577±0.251）h,t1/2 （1.831±0.457）h,MRT（2.412±0.246）h,CL（16.925±5.281）L·h-1,Vd（43.183±14.041）L.Conclusion： The established LC-MS/MS method is simple,sensitive and accurate,which is suitable for the pharmacokinetic study of low dose methylergonovine in human plasma.The results showed that methylergine maleate injection intramuscularly absorbed faster,0.5 h reached peak;Some slight adverse events happened in the study,including nausea,vomiting and headache.

关 键 词：甲麦角新碱 文拉法辛 生物样品 人血浆测定 药代动力学 液相色谱 质谱 

分 类 号：R917[医药卫生—药物分析学]