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目的:建立高效液相色谱-质谱联用(HPLC-MS/MS)测定人血浆中卢非酰胺浓度的方法。方法:40名健康受试者随机分成4组,分别单剂量口服给药卢非酰胺片200,400,800,1 200 mg。血浆样品经乙腈沉淀蛋白提取分离,色谱柱为Ultimate?AQ-C18(100 mm×2.1 mm,5μm,Welch Material Inc.);流动相为乙腈-5 mmol·L~(-1)乙酸胺水溶液(含0.1%甲酸)=32∶68;流速为0.30 mL·min~(-1);内标为埃索美拉唑。采用电喷雾离子源,以多反应监测(MRM)方式进行正离子检测。结果:卢非酰胺的血浆浓度在40~5 000 ng·mL~(-1)范围内线性良好,定量下限为40 ng·mL~(-1),日内精密度(RSD)均≤8.20%,日间精密度(RSD)均≤6.35%,提取回收率为91.94%~96.48%。卢非酰胺呈非线性药动学特征,单剂量空腹口服给药卢非酰胺片200,400,800,1 200 mg后,Cmax分别为1 803.50±528.06,2 485.00±562.71,3 710.00±965.50和4 158.00±1 181.91μg·L~(-1)。AUC0–t分别为34 522.13±9 525.00,56 138.53±18 021.98,88 848.53±23 348.14和107 058.03±34 420.08μg·h·L~(-1)。结论:该法操作简单,灵敏,准确,重复性好,适用于卢非酰胺片临床药动学研究。从药动学研究可知,卢非酰胺在中国健康受试者中呈非线性药动学特征。
OBJECTIVE: To establish a method for the determination of rfamide in human plasma by high performance liquid chromatography-mass spectrometry (HPLC-MS / MS). Methods: Forty healthy volunteers were randomly divided into 4 groups: oral administration of Lufidemide tablets 200, 400, 800 and 1 200 mg respectively. The plasma samples were separated by acetonitrile-precipitated protein. The column was Ultimate® AQ-C18 (100 mm × 2.1 mm, 5 μm, Welch Material Inc.). The mobile phase was acetonitrile-5 mmol·L -1 aqueous solution of acetate Containing 0.1% formic acid) = 32:68; the flow rate was 0.30 mL · min -1; the internal standard was esomeprazole. Electrospray ionization was used to conduct positive ion detection in multiple reaction monitoring (MRM) mode. RESULTS: The plasma concentrations of Lufamide were linear within the range of 40-5 000 ng · mL -1 with a lower limit of quantitation of 40 ng · mL -1. The intra-day precision (RSD) was ≤8.20% Daytime precision (RSD) were ≤6.35%, extraction recovery was 91.94% ~ 96.48%. Lufamide showed a nonlinear pharmacokinetic profile. Cmax was 1803.50 ± 528.06, 2 485.00 ± 562.71, 3 710.00 ± 965.50 and 4 158.00 ± 1 after oral administration of Lufamide tablets at 200, 400, 800 and 1 200 mg respectively 181.91μg · L -1. AUC0-t were 34 522.13 ± 9 525.00, 56 138.53 ± 18 021.98, 88 848.53 ± 23 348.14 and 107 058.03 ± 34 420.08 μg · h · L -1, respectively. Conclusion: The method is simple, sensitive, accurate and reproducible. It is suitable for the clinical pharmacokinetics of ralfinamide tablets. From the pharmacokinetic study shows that, the non-linear pharmacokinetics of rofamide in Chinese healthy subjects.