超高效液相色谱-串联质谱法测定血浆中伏立康唑的浓度及其在深部真菌感染患者伏立康唑血药浓度监测中的应用

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摘要目的采用超高效液相色谱-串联质谱法测定患者血浆中伏立康唑的浓度，并用于监测血药浓度。方法采用超高效液相色谱-串联质谱法进行测定。血浆样品以氟康唑为内标，经氢氧化钠碱化、乙酸乙酯萃取后进行分析。采用Acquity UPLCR BEH-C18 色谱柱（2.1 mm×50 mm，1.7 μm）分离，流动相为水（含0.1%甲酸及2 mmol/L 甲酸铵）-乙腈，梯度洗脱，流速为0.10 mL/min，柱温为40℃，进样量为1 μL，总分析时间为5.0 min；离子源为电喷雾离子源，采用正离子电离模式（ESI+），扫描方式为多离子反应监测模式（MRM）。结果血浆中伏立康唑浓度的线性范围为10～10 000 ng/mL（Y=1.303 93×10-3X+1.002 17，r=0.9992），定量下限为10 ng/mL；质控样品准确度为95.2%～104.8%；日内、日间RSD 均＜7%；方法回收率＞95%（RSD＜7%），提取回收率＞75%（RSD＜5%）。采用该法检测12例深部真菌感染患者体内伏立康唑的血药浓度为817.29～9054.24 ng/mL，有4例患者的血药浓度不在推荐治疗浓度范围内。结论该方法快速、灵敏、准确，专属性强，重复性好，适用于伏立康唑治疗药物监测。

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	葛欣
	刘妍妍
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关键词 ：伏立康唑, 超高效液相色谱-串联质谱法, 血药浓度, 治疗药物监测, 侵袭性真菌感染

Abstract：Objective To develop an ultra performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS)method for determination of Voriconazole in patients plasma and apply it to drug monitoring.Methods UPLC-MS/MS method was adopted.Using fluconazole as internal standard,the plasma samples were alkalized with sodium hydroxide and extracted with ethyl acetate and analyzed.The separation was achieved on an Acquity UPLCR BEH-C18 column(2.1 mm×50 mm,1.7 μm) and eluted with linear gradient using water (containing 0.1% formic acid and 2 mmol/L ammonium formate)-acetonitrile at flow rate of 0.10 mL/min.The injection volume was 1 μL and the column temperature was 40℃.The total time of the analysis was 5.0 min.Detection of the analytes was achieved using positive ion electrospray ionization (ESI+) in the multiple reaction monitoring (MRM) mode.Results The linear range of voriconazole was 10-10 000 ng/mL (Y=1.303 93×10-3X+1.002 17,r=0.9992),with the lower limit of quantitation of 10 ng/mL.The accuracy of quality control sample was 95.2%-104.8%.Intra-day and inter-day relative standard deviations were both ＜7%.Method recovery was ＞95% (RSD＜7%) and extraction recovery was ＞75% (RSD＜5%).The plasma concentrations of Voriconazole in 12 patients with invasive fungal infection determined by this method were 817.29-9054.24 ng/mL,and of those 4 patients′ plasma concentrations were outside the recommended treatment concentration range.Conclusion The established method is rapid,sensitive,accurate,specific and repeatable,and can be applied for the therapeutic drug monitoring of Voriconazole.

Key words： Voriconazole Ultra performance liquid chromatography-tandem mass spectrometry Plasma concentration Therapeutic drug monitoring Invasive fungal infection

作者简介: 葛欣（1984-），女，山东滕州人，博士，主管药师，研究方向：治疗药物监测

引用本文:

葛欣;刘妍妍;刘平. 超高效液相色谱-串联质谱法测定血浆中伏立康唑的浓度及其在深部真菌感染患者伏立康唑血药浓度监测中的应用[J]. 中国当代医药, 2021, 28(9): 26-30转42.
GE Xin;LIU Yan-yan;LIU Ping. Concentration determination of Voriconazole in patients plasma by ultra performance liquid chromatography-tandem mass spectrometry and its application in monitoring the plasma concentration of Voriconazole in patients with deep fungal infection. 中国当代医药, 2021, 28(9): 26-30转42.

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