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首页> 外文期刊>The Southeast Asian journal of tropical medicine and public health >Development and validation of a liquid chromatography-mass spectrometry method for the simultaneous quantification of artesunate and dihydroartemisinin in human plasma.
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Development and validation of a liquid chromatography-mass spectrometry method for the simultaneous quantification of artesunate and dihydroartemisinin in human plasma.

机译：液相色谱-质谱联用技术在人血浆中青蒿琥酯和双氢青蒿素同时定量的开发和验证。

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摘要

The present study describes the development and validation of a simple, sensitive, and specific liquid chromatography-mass spectrometry (LC-MS) analytical method used for the co-quantification of artesunate (ARS) and its active metabolite, dihydroartemisinin (DHA), in human plasma, using artemisinin (ARN) as an internal standard. The liquid-liquid extraction of samples was carried out using dichloromethane and tert.-methyl butyl ether (at a ratio of 8:2 v/v) and then evaporated to dryness by a stream of nitrogen gas at room temperature. Chromatographic separation and mass analysis were performed on the Agilent 1100 Series Liquid Chromatography/Mass Spectrometer Detector Trap system, using electrospray ionization as an interface. The stationary phase was an Elipse XDB-C18 column. The mobile phase contained acetonitrile and 0.003 M glacial acetic acid at a ratio of 62:38 (v/v) delivered at a flow rate of 0.5 ml per minute. Positive ion mode was selected to detect extracted ions at m/z 407 and 261 for ARS, at m/z 307 and 261 for DHA, and at m/z 305 for ARN. The retention times for alpha-DHA, ARS, beta-DHA, and ARN were 6.6, 8.0, 9.2, and 10.8 minutes, respectively, and the total chromatography run time was 12 minutes. The limit of detection (LOD) was 2 ng/ml while the limit of quantification (LOQ) was 10 ng/ml for both ARS and DHA. In order to address any complications caused by the spontaneous non-catalytic breakdown of ARS to DHA, two calibration curves were prepared separately for both analytes. These graphs were found to be linear over the range of 10 to 3,200 ng/ml (r2 > 0.99). The recoveries at concentrations of 100, 200, 400, and 800 ng/ml were 108, 106, 91, and 89%, respectively, for ARS and were 112, 95, 80, and 86%, respectively, for DHA. For ARN, the recoveries were 119, 119, and 90% for concentrations of 200, 400, and 800 ng/ml, respectively. ARS working solutions were not stable after two months of storage at 4 degrees C or after 21 days at room temperature. This newly developed LC-MS method was then applied for measuring of ARS and DHA concentrations in a healthy volunteer having received oral ARS at 200 mg once daily for 5 consecutive days. There was no decline in ARS concentration after repeated doses and the C(ss-max-average) for DHA was found to be 703 +/- 94 ng/ml at t(ss-max) of 2 h.
机译：本研究描述了一种简单，灵敏，特异的液相色谱-质谱（LC-MS）分析方法的开发和验证，该方法用于青蒿琥酯（ARS）及其活性代谢物二氢青蒿素（DHA）的共定量。人血浆，使用青蒿素（ARN）作为内标。使用二氯甲烷和叔甲基丁基醚（比例为8：2 v / v）进行液-液萃取，然后在室温下用氮气流蒸发至干。色谱分离和质量分析是在Agilent 1100系列液相色谱/质谱仪检测器捕集阱系统上进行的，使用电喷雾电离作为界面。固定相为Elipse XDB-C18色谱柱。流动相包含乙腈和0.003 M冰醋酸，比例为62:38（v / v），流速为每分钟0.5 ml。选择正离子模式可检测出对于ARS在m / z 407和261，对于DHA在m / z 307和261，对于ARN在m / z 305提取的离子。 α-DHA，ARS，β-DHA和ARN的保留时间分别为6.6、8.0、9.2和10.8分钟，总色谱运行时间为12分钟。 ARS和DHA的检出限（LOD）为2 ng / ml，定量限（LOQ）为10 ng / ml。为了解决由ARS自发地非催化分解为DHA引起的任何并发症，分别为两种分析物准备了两条校准曲线。发现这些图在10到3200 ng / ml的范围内是线性的（r2> 0.99）。在100、200、400和800 ng / ml的浓度下，ARS的回收率分别为108％，106％，91％和89％，DHA的回收率分别为112％，95％，80％和86％。对于ARN，浓度分别为200、400和800 ng / ml时，回收率分别为119％，119％和90％。在4摄氏度下存放两个月或在室温下存放21天后，ARS工作溶液不稳定。然后将这种新开发的LC-MS方法应用于健康志愿者中，该志愿者连续5天每天接受一次200 mg口服ARS的健康志愿者中的ARS和DHA浓度测量。重复给药后，ARS浓度没有下降，在2小时的t（ss-max）下，DHA的C（ss-max-平均值）为703 +/- 94 ng / ml。

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