高效液相二极管阵列检测法测定人血浆中伏立康唑和<i>N-</i>氧化伏立康唑浓度及其对儿童白血病的用药指导

doi:10.11669/cpj.2019.14.009

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摘要目的建立同时测定伏立康唑及其主要代谢物N-氧化伏立康唑血药浓度方法,并用于监测2~12岁儿童白血病中伏立康唑和N-氧化伏立康唑的血药浓度。方法采用Agilent ZORBAX SB-C₁₈柱(4.6 mm×250 mm,5 μm),流动相为乙腈、甲醇与醋酸铵缓冲液(10 mmol·L^-1,用醋酸调节pH值至3.0)=27∶23∶50,流速为1 mL·min^-1,波长为262 nm。以卡马西平为内标,样品处理采用乙酸乙酯液液萃取。结果伏立康唑和N-氧化伏立康唑的血浆浓度在0.1~8.0 μg·mL^-1内呈良好的线性,定量下限均为0.1 μg·mL^-1,批内、批间精密度(RSD)均在3%~10%以内。准确度和方法回收率均符合要求。此次监测29例儿童白血病患者,共100个血样。伏立康唑浓度、N-氧化伏立康唑及N-氧化伏立康唑与伏立康唑的比值中位数值分别为0.87 μg·mL^-1 (IQR,0.32~1.65 μg·mL^-1)、1.15 μg·mL^-1(IQR,0.55~1.67 μg·mL^-1)和1.10 (IQR,0.66~1.22)。伏立康唑浓度与N-氧化伏立康唑浓度存在相关性(r=0.603 1, P<0.000 1)。结论本方法操作简单、准确、专属性高,满足临床同时监测伏立康唑和N-氧化伏立康唑浓度,可用于伏立康唑药动学研究及临床上治疗药物监测。

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	罗兴献
	黄琳
	李泰锋
	胡蕾
	刘雪梅
	薛学财
	张海英
	陈月
	冯婉玉

关键词 ：伏立康唑, N-氧化伏立康唑, 高效液相二极管阵列检测, 儿童白血病, 治疗药物监测

Abstract：OBJECTIVE To establish a method for simultaneous determination of voriconazole and its main metabolite N-oxidized voriconazole in blood, and monitor the levels of voriconazole and N-oxidized voriconazole in leukemia children aged 2-12 years. METHODS Agilent ZORBAX SB-C₁₈ column (4.6 mm×250 mm,5 μm) was used, and the mobile phase was acetonitrile, methanol and ammonium acetate buffer (10 mmol·L^-1, pH adjusted with acetic acid to 3.0)=27∶23∶50, the flow rate was 1 mL·min^-1, and the wavelength was set at 262 nm. The sample was extracted with ethyl acetate.Carbamazepine was used as the internal standard. RESULTS The calibration curves of voriconazole and N-oxidized voriconazole were linear in the range of 0.1-8.0 μg·mL^-1, the lower limit of quantitation was 0.1 μg·mL^-1, and the intra-assay and inter-assay precision RSDs were between 2% and 10%. The accuracy, method recovery and stability all met the requirements.Twenty-nine patients were monitored with a total of 100 blood samples.The medians (IQRs) of voriconazole concentration, N-oxidized voriconazole concentration, and ratio of N-oxidized voriconazole to voriconazole were 0.87 μg·mL^-1 (0.32-1.65 μg·mL^-1) and 1.15 μg·mL^-1 (0.55-1.67 μg·mL^-1) and 1.10(0.66-1.22), respectively. There was a correlation relationship between the concentrations of voriconazole and N-oxidized voriconazole (r=0.603 1, P<0.000 1). CONCLUSION The method is simple, accurate, highly specific, and can simultaneously monitor the concentrations of voriconazole and N-oxidized voriconazole, thus can be used for the pharmacokinetic research of voriconazole and clinical drug monitoring.

Key words： voriconazole N-oxidized voriconazole HPLC-PDA childhood leukemia therapeutic drug monitoring

收稿日期: 2018-11-06

R917

通讯作者: 冯婉玉,女,博士,主任药师研究方向:个体化给药和临床药理学研究 Tel:(010)88325525 E-mail:renminyaojike@sina.com

作者简介: 罗兴献,男,硕士,药师研究方向:临床药学

引用本文:

罗兴献, 黄琳, 李泰锋, 胡蕾, 刘雪梅, 薛学财, 张海英, 陈月, 冯婉玉. 高效液相二极管阵列检测法测定人血浆中伏立康唑和N-氧化伏立康唑浓度及其对儿童白血病的用药指导[J]. 中国药学杂志, 2019, 54(14): 1169-1175. LUO Xing-xian, HUANG Lin, LI Tai-feng, HU Lei, LIU Xue-mei, XUE Xue-cai, ZHANG Hai-ying, CHEN Yue, FENG Wan-yu. High Performance Liquid Chromatography Coupling with Photo-diode Array Detector Method for Monitoring Voriconazole and Its Main Metabolite N-oxidized Voriconazole and Its Application to Medication Guidance for Childhood Leukemia. Chinese Pharmaceutical Journal, 2019, 54(14): 1169-1175.

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http://journal11.magtechjournal.com/Jwk_zgyxzz/CN/10.11669/cpj.2019.14.009 或 http://journal11.magtechjournal.com/Jwk_zgyxzz/CN/Y2019/V54/I14/1169

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