【作者】 高俊；

【导师】 钟大放； 陈笑艳；

【作者基本信息】 沈阳药科大学 ， 药物分析学， 2007， 硕士

【摘要】 目的：拟建立两种专属、灵敏的LC／MS／MS法，分别测定人血浆中瑞舒伐他汀浓度和辛伐他汀浓度，并应用于瑞舒伐他汀临床药代动力学和辛伐他汀人体生物利用度及等效性研究。方法：测定人血浆中瑞舒伐他汀的浓度时，以氢氯噻嗪为内标，血浆样品经乙醚液—液萃取后，以甲醇-水（75∶25 v／v，1％氨水调pH至6）为流动相，采用Zorbax XDB C₁₈柱进行分离，通过（-）ESI源离子化，以多反应监测（MRM）方式进行检测。用于定量分析的离子反应分别为m／z 480→m／z 418（瑞舒伐他汀）和m／z 296→m／z 269（氢氯噻嗪）。测定人血浆中辛伐他汀时，200μL血浆样品经乙醚—二氯甲烷（3∶2，v／v）液—液萃取后，以乙腈-水-甲酸（55∶45∶0.25，v／v／v）为流动相，采用Zorbax SB C₁₈短柱分离，通过（+）ESI离子化，以选择反应监测（SRM）方式进行检测。用于定量分析的离子反应分别为m／z 441→m／z 325（辛伐他汀）和m／z 427→m／z 325（洛伐他汀）。结果：测定瑞舒伐他汀的线性范围为0.020-60.0 ng／mL，定量下限为0.020 ng／mL，日内、日间精密度（RSD％）小于8.5％，准确度（RE％）在-0.3～1.9％范围内。测定辛伐他汀的线性范围为0.05-100ng／mL，定量下限为0.05 ng／mL。日内、日间精密度（RSD％）小于7.9％，准确度（RE％）在-2.2～-0.6％范围内。已成功应用于瑞舒伐他汀和辛伐他汀的血浆浓度测定及临床药动学和人体生物利用度及等效性研究。结论：所建立的LC／MS／MS法专属、灵敏，可成功用于瑞舒伐他汀和辛伐他汀的血浆浓度测定以及临床药动学研究。更多还原

【Abstract】 Objective: Two rapid, sensitive and specific methods for quantitative analyses of two statins drugs in plasma will be developed and validated by liquid chromatography/tandem mass spectrometry in this thesis. The methods will be applied to pharmacokinetic studies.Method: Determination of rosuvastatin in human plasma by liquid chromatography-tandem mass spectrometry. Samples spiked with the analyte and internal standard, hydrochlorothiazide, were processed using liquid-liquid extraction. The extract was chromatographed on a Zorbax XDB C₁₈ column. The mobile phase consisted of methanol-water （75: 25, v/v, adjusted to pH 6 by 1% ammonia aqueous）, at a flow rate of 0.50 mL/min. An API4000 tandem mass spectrometer equipped with electrospray ionization source was used as detector and was operated in the negative ion mode. Multiple reaction monitoring （MRM） using the precursor product ion combinations of m/z 480→m/z 418 and m/z 296→m/z 269 were used to quantify rosuvastatin and hydrochlorothiazide, respectively. After simple liquid-liquid extraction, simvastatin and the internal standard lovastatin were chromatographed on a Zorbax SB C₁₈ column and detected by MS/MS with an electrospray ionization interface in a Thermo Finnigan TSQ Quantum Ultra tandem mass spectrometer. Selected reaction monitoring （SRM） using the precursor product ion combination of m/z 441→m/z 325 and m/z 427→m/z 325 was used to quantify simvastatin and the internal standard, respectively.Results: The linear calibration curves were obtained in the concentration range of 0.020-60.0 ng/mL for rosuvastatin. The intra- and inter-day relative standard deviation （RSD） across three validation runs over the entire concentration range was less than 8.5%. The accuracy was within -0.3 to 1.9%. The standard calibration curve for simvastatin was linear in the concentration range of 0.05-100 ng/mL in human plasma. The intra- and inter-run precisions were less than 7.9%, determined from QC samples for simvastain, and accuracy was within -2.2 to -0.6% in terms of relative error.Conclusion: The methods were successfully applied for the evaluation of the pharmacokinetics and bioequivalence ofrosuvastatin and simvastatin.更多还原