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目的:建立LC-MS-MS法测定人血浆中肉桂酸的浓度,研究单剂量和多剂量静脉滴注脉络宁注射液后肉桂酸在健康人体内的药动学。方法:血浆样品以酸化的乙酸乙酯-乙醚(1∶3)萃取;ZOBAX SB C18色谱柱(4.6 mm×150 mm,5μm)分离,柱温为30℃,流动相为甲醇-水(2 mmol.L-1醋酸铵)(45∶55),流速为500μL.min-1;电喷雾离子源,多反应监测。检测离子:肉桂酸,[M-H]-,m/z146.8/103.1;替硝唑(内标),[M-H]-,m/z245.6/126.0。10名受试者单、多次剂量静脉滴注脉络宁注射液后,采用LC-MS-MS法测定血浆中肉桂酸浓度,DASver1.0软件对药-时曲线进行拟合,并计算药动学参数。结果:肉桂酸在0.50～400μg.L-1呈现良好线性,最低定量限为0.50μg.L-1,日内、日间精密度均小于10%。受试者给药后,肉桂酸药时曲线符合二房室模型。单、多次剂量主要药动学参数分别为Cmax(μg.L-1):115.73±44.31,113.79±25.61;T1/2β(h):0.41±0.087,0.52±0.132;V(L.kg-1):0.519±0.134,0.651±0.322;CL(L.kg-1.h-1):0.899±0.295,0.830±0.222;AUC0～t(μg.L-1.h-1):158.64±56.019,166.49±46.788。结论:该法准确、灵敏、专属。单剂量和多剂量给药后肉桂酸主要药动学参数经统计学分析无显著差异;多剂量给药后,肉桂酸体内无蓄积现象,体内过程不受性别差异的影响;其在受试者体内的药动学存在明显个体差异。
OBJECTIVE: To establish a LC-MS-MS method for the determination of cinnamic acid in human plasma and study the pharmacokinetics of cinnamic acid in healthy volunteers after intravenous infusion of single and multiple doses of Mailuoning injection. Methods: The plasma samples were extracted with acidified ethyl acetate-diethyl ether (1: 3) and separated on a ZOBAX SB C18 column (4.6 mm × 150 mm, 5 μm). The column temperature was 30 ℃ and the mobile phase was methanol- .L-1 ammonium acetate) (45:55) at a flow rate of 500 μL · min -1; electrospray ionization source, multiple reaction monitoring. Detection of ions: cinnamic acid, [MH] -, m / z 146.8 / 103.1; tinidazole (internal standard), [MH] -, m / z 245.6 / 126.0.10 subjects single and multiple doses After intravenous injection of Mailuoning injection, the concentration of cinnamic acid in plasma was determined by LC-MS-MS. The drug-time curve was fitted by DASver 1.0 software and the pharmacokinetic parameters were calculated. Results: Cinnamic acid showed a good linearity at 0.50-400μg.L-1 with the lowest limit of quantitation of 0.50μg.L-1. The intra-day and inter-day precision were less than 10%. After administration of the subject, the cinnamic acid drug profile conformed to the two-compartment model. The main pharmacokinetic parameters of single and multiple doses were Cmax (μg.L-1): 115.73 ± 44.31,113.79 ± 25.61; T1 / 2β (h): 0.41 ± 0.087,0.52 ± 0.132; V (L.kg- 1): 0.519 ± 0.134, 0.651 ± 0.322; CL (L.kg-1.h-1): 0.899 ± 0.295, 0.830 ± 0.222; AUC0- t (μg.L- 1.h-1): 158.64 ± 56.019 , 166.49 ± 46.788. Conclusion: This method is accurate, sensitive and exclusive. After single-dose and multi-dose administration, the main pharmacokinetic parameters of cinnamic acid had no significant difference after statistical analysis. After multi-dose administration, there was no accumulation of cinnamic acid in vivo, and the in vivo process was not affected by gender differences. There are significant individual differences in pharmacokinetics in vivo.