【作者】 刘飞；

【导师】 郭庆祥； 许毓；

【作者基本信息】 中国科学技术大学 ， 应用化学， 2008， 博士

【摘要】 质谱不仅能够提供大量可靠的样品结构信息和较高的检测灵敏度,也具有快速定性和定量的能力。复杂样品的快速分析一直是质谱学家追求的目标之一,是质谱技术发展的一个重要趋势。基于有机质谱快速、灵敏、准确以及能与其它检测手段联合应用于物质分析等特点,其应用范畴得到不断拓展。本研究应用离子阱质谱和三重四极杆质谱,结合高效液相色谱分离分析技术,探索、建立和发展了四种不同类型药物的分离检测技术和方法,主要包括:1、基于液相色谱——离子阱质谱联用分析技术,建立了人血浆中阿奇霉素的浓度测定方法。血浆样品的前处理采取简单的甲醇直接沉淀的方法,血浆中杂质峰不干扰样品的测定。线性范围为4.69～600ng/mL,回收率为87.41～99.97%。该方法已成功的应用于20个健康志愿者口服500mg阿奇霉素分散片的生物等效性研究。2、建立了一种快速灵敏的液相色谱——串联质谱联用检测人血浆中的曲克芦丁的方法,血浆样品的前处理采取高氯酸直接沉淀的方法,血浆中杂质峰不干扰样品的测定。由于曲克芦丁具有较强的极性,因此采用极性非常强的Fusion-RP柱进行色谱分离。定量下限为31.25pg/mL,日内、日间RSD均不大于12.28%,日内、日间RE在±12.8%之内。应用该法成功的测定了18个健康志愿者口服300mg曲克芦丁滴丸的生物等效性研究的血浆样品。3、采用液相色谱——串联质谱联用技术进行了人血浆中的左炔诺孕酮的检测方法研究,血浆样品的前处理采取乙酸乙酯提取的方法。实验表明,左炔诺孕酮在弱极性的C₁₈柱具有非常强的保留;用乙腈作流动相能显著降低背景噪声。线性范围为0.625～40ng/mL,回收率为84.77～90.88%。该方法已成功的应用于20个健康女性志愿者口服1.5mg左炔诺孕酮片的生物等效性研究。4、建立了口服给药后人血浆中的氢氯噻嗪和缬沙坦的快速液查色谱——串联质谱检测方法。采用同时检测,大大节约了成本,节省了时间。该方法准确、灵敏,已成功的应用于20个健康志愿者口服复方缬沙坦氢氯噻嗪片的生物等效性研究。更多还原

【Abstract】 Mass spectrometry（MS）could not only provide high sensitivity and reliable detection for various samples,but also offer much information about the structure and identity of analytes.Rapid analysis of complicated sample is always one of the goals of mass spectrometric scientists and an important development trendency of mass spectrometric technique.Based on its rapid,sensitive,accurate character and easy coupling with other analytical technique,the development of organic mass spectrometry shows the advantages in the widely applied area.In the present study, several applications were developed and validated for the determination of four different drug in human plasma by ion trap mass spectrometer or tri-quadrupole tandem mass spectrometer coupled with high-performance liquid chromatography.1.Based on LC/MS technique,a simple and rapid method for the quantification of azithromycin in human plasma is developed.Herein a simple sample preparation method of protein precipitation with methanol was employed.The calibration curves were linear over the concentration range 4.69-600ng/mL and the recovery ranged from 87.41 to 99.97%for the analyte.This method was applied to a biocquivalence study after administration of 500mg azithromycin to 20 healthy voluntecrs.2.A simple and sensitive LC-MS/MS method for the quantification of troxerutin in human plasma is developed and validated.Perchloric acid was employed for protein precipitation.Due to the high polarity,troxerutin could only achieve suitable retention on a Phenomenex Synergi Fusion RP column.The lower limit of quantification was 31.25pg/mL for the analyte,precision below 12.28%and relative error was not more than±12.8%.This method was applied to a bioequivalence study after an administra- tion of 300mg troxerutin to 18 healthy volunteers.3.A sensitive LC-MS/MS method for the determination of levonorgestrel in human plasma using liquid-liquid extraction（LLE）with ethyl acetate,was developed. It was found that levenorgestrel yielded strong retention on C₁₈column,and higher signal-to-noise ratio was observed using acetonitrile as the mobile phase than using methanol as the mobile phase.The proposed method was validated over the concentration range 0.625-40ng/mL and applied successfully to the analyses of samples obtained from a bioequivalence study.4.Simultaneous determination of hydrochlorothiazide and valsartan in human plasma by LC-MS/MS method was described,which was proved to be economical and efficient.The method was found to be suitable for application to a bioequivalence study after oral administration of dispersible tablet containing 12.5mg hydrochlorothiazide and 80mg valsartan to 20 healthy volunteers.更多还原