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目的建立灵敏、快速的液相色谱-串联质谱法测定人血浆中非布司他的浓度并应用于其药动学研究。方法血浆样品采用乙酸乙酯进行液-液萃取法处理后,以API3000 HPLC-MS/MS进行分析。采用SHISEIDO,CAPCELL PAK C18(2.0 mm×50mm,5μm)色谱柱;0.1%甲酸水溶液-乙腈(含0.1%甲酸)(15∶85)为流动相;流速0.25 m L·min-1等度洗脱。以电喷雾离子源(ESI)在正离子电离模式下进行检测,多离子反应监测(MRM)模式定量测定。12名健康受试者单剂量口服非布司他片40、80 mg,多剂量口服非布司他片40 mg后采集血浆样品,以HPLC-MS/MS测定非布司他浓度,计算药动学参数并进行统计分析。结果本方法的线性范围为10.02~8 020 ng·m L-1,定量下限为10.02 ng·m L-1,日内、日间精密度均小于12.40%,准确度在85.75%~105.91%之间,萃取回收率约为87%,稳定性考察结果良好,单个样品分析时间仅2 min。结果显示,在考察剂量范围内,非布司他在健康中国人体内的药动学过程呈现线性动力学特征,多剂量服用时无蓄积现象,在不同性别人群体内药动学过程无显著性差异。结论本方法灵敏、快速、专属性强,适用于人血浆中非布司他的测定及非布司他的临床药动学研究。
Objective To establish a sensitive and rapid liquid chromatography-tandem mass spectrometry (HPLC-MS / MS) method for the determination of febuxostat in human plasma and its application in pharmacokinetics. Methods Plasma samples were analyzed by HPLC-MS / MS with ethyl acetate after liquid-liquid extraction. The mobile phase was consisted of SHISEIDO, CAPCELL PAK C18 (2.0 mm × 50 mm, 5 μm) column, 0.1% formic acid in water and acetonitrile with 0.1% formic acid (15:85) . Electrospray ionization (ESI) was performed in positive ionization mode and quantitatively in multi-ion reaction monitoring (MRM) mode. Twelve healthy subjects were given a single dose of oral febuxostat 40,80 mg, plasma samples were taken after multiple doses of oral febuxostat 40 mg, febuxostat concentration was determined by HPLC-MS / MS, and pharmacokinetic Learning parameters and statistical analysis. Results The linear range of this method was 10.02 ~ 8 020 ng · m L-1 with the lower limit of quantitation of 10.02 ng · m L-1. The intra-day and inter-day precision were less than 12.40% and the accuracy was between 85.75% and 105.91% , The recovery rate of extraction was about 87%. The result of stability study was good. The analysis time of single sample was only 2 min. The results showed that the pharmacokinetics of febuxostat showed a linear kinetic characteristic in healthy Chinese during the investigation of dose range, no accumulation in multi-dose administration, and no significant difference in pharmacokinetics among different sex groups . Conclusion The method is sensitive, rapid and specific. It is suitable for the determination of febuxostat in human plasma and the clinical pharmacokinetics of febuxostat.