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

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 C₁₈色谱柱（2.1 mm×100 mm，2.7 μm），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:AUC_0-8(12.165±3.345) ng·mL^-1·h,AUC_0-∞(12.900±3.800)ng·mL^-1·h,C_max(4.707±2.541)ng·mL^-1,t_max(0.577±0.251)h,t_1/2 (1.831±0.457)h,MRT(2.412±0.246)h,CL(16.925±5.281)L·h^-1,V_d(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.