【作者】 关心；

【导师】 陈笑艳； 钟大放；

【作者基本信息】 沈阳药科大学 ， 药物分析学， 2006， 硕士

【摘要】 目的：分别建立测定人血浆中的缬沙坦和米氮平的快速、灵敏的液相色谱-串联质谱法，并应用于药物动力学研究以及制剂人体生物利用度和生物等效性研究。方法：50μL含缬沙坦的血浆样品加入内标坎地沙坦，经液—液萃取处理后，以甲醇-5mmol/L乙酸铵（80：20，v/v）为流动相，采用Zorbax SB-C₁₈柱分离；50μL含米氮平的血浆样品加入内标苯海拉明，经沉淀蛋白处理后，以乙腈-水-甲酸（80：20：0.2，v/v/v）为流动相，采用Zorbax SB-C₈柱分离。分别通过电喷雾离子化四极杆串联质谱，以选择反应监测（SRM）方式进行正离子检测，用于监测定量的离子反应分别为m/z436→m/z207，235，291（缬沙坦）和m/z 441→m/z 263（内标）；m/z 266→m/z 195（米氮平）和m/z 256→m/z 167（内标）。药动学参数采用非室模型计算。结果：缬沙坦和米氮平测定方法的线性范围分别为4.0～8000ng/mL和0.18～144.0ng/mL。日内、日间精密度均小于15％，准确度在±15％以内。每个样品测试时间均少于3.6min。应用上述方法研究比较了健康受试者分别单剂量口服缬沙坦160mg以及米氮平30mg后的药物动力学特点，分别进行了两种药物不同制剂的人体生物利用度和生物等效性研究。结论：本文所建立的两种定量方法选择性强，灵敏度高，操作简便，血浆用量少，分别适用于缬沙坦以及米氮平制剂的生物等效性评价及临床药动学研究。更多还原

【Abstract】 Objective: To develop two sensitive and specific LC/MS/MS methods for respective determination of valsartan and mirtazapine in human plasma and to study the bioequivalences of different formulations containing valsartan and mirtazapine and clinical investigations of their pharmacokinetics, respectively. Method: For determination of the plasma concentration of valsartan, an aliquot of 50-μL plasma was treated by liquid-liquid extraction, then the analytes of interest were analyzed on a Zorbax SB-C₁₈ column with the mobile phase consisted of methanol-5 mmol/L ammonium acetate （80: 20, v/v）. For determination of the plasma concentration of mirtazapine, an aliquot of 50-μL plasma was treated by precipitation. The analytes of interest were separated on a Zorbax SB-C₈ column with the mobile phase consisting of acetonitrile-water-formic acid （80: 20: 0.2, v/v/v）. A Thermo Finnigan TSQ Ultra tandem mass spectrometer equipped with electrospray ionization source was used as detector and was operated in the positive ion mode. Selected reaction monitoring （SRM） using the precursor → product ion combination of m/z 436 → m/z 207,235,291 and m/z 441→m/z 263 was used to respectively quantify valsartan and candesartan, m/z 266 → m/z 195 and m/z 256→ m/z 167 was used to respectively quantify mirtazapine and diphenhydramine. Results: The linear calibration curves were obtained in the concentration range of 4.0-8000 ng/mL and 0.18-144.0 ng/mL for valsartan and mirtazapine, respectively. The intra- and inter-day relative standard deviation （RSD） across three validation runs over the entire concentration range was less than 15%. Accuracy determined at three QC concentrations was within ± 15% as terms of relative error （RE）. Each plasma sample was chromatographed within 3.6 min. Conclusion: The methods were sensitive and convenient, and proved to be suitable for bioequivalence evaluations of different formulations containing valsartan and mirtazapine, respectively.更多还原