白芷的化学成分及其药动学研究

【作者】 黄玉伟；

【导师】 毕开顺； 陈晓辉；

【作者基本信息】 沈阳药科大学 ， 药物分析学， 2007， 硕士

【摘要】 白芷为伞形科植物白芷Angelica dahurica（Fisch.ex Hoffm.）Benth.et Hook.f.或杭白芷Angelica dahurica（Fisch.ex Hoffm.）Benth.et Hook.f.var.formosana（Boiss.）Shan et Yuan的干燥根，现作为常用中药收载于《中国药典》2005年版一部。本文以白芷为研究对象对香豆素类化合物进行了提取工艺研究；并对单体化合物的分离、纯化方法进行了考察，对得到的化合物利用波谱技术进行了结构确认；并对主要活性成分欧前胡素在大鼠体内的药物动力学行为进行了研究，为白芷的进一步开发利用和质量控制提供了科学依据。本研究采用正交实验设计优化了白芷药材化学成分提取工艺条件，以欧前胡素的含量为评价指标，对影响白芷中香豆素类化合物提取的因素进行研究，确定白芷的最佳提取工艺为5倍量的95％的乙醇提取3次，每次3小时。采用液-液萃取、反复硅胶柱色谱、ODS开放柱层析和重结晶等分离、纯化的方法，从白芷95％乙醇提取物中分离得到了3种香豆素类化合物，经理化和波谱数据分析鉴定了它们的结构，分别为佛手柑内酯（bergapten）、欧前胡素（imperatorin）和Cnidilin。该工艺操作简便，制备的对照品纯度高，数量大，为白芷的质量控制方法和药动学研究提供了一定的物质基础。建立了测定大鼠血浆中欧前胡素含量的反相高效液相色谱分析方法，以布洛芬为内标，采用C₁₈色谱柱（150mm×4.6mm，5μm），甲醇-水（72：28v/v，磷酸调pH 4.0）为流动相，流速1.0mL·min^-1，检测波长300nm，柱温为30℃。欧前胡素在0.025～2.500μg·mL^-1范围内线性关系良好，定量下限为0.025μg·mL^-1，日内精密度和日间精密度均小于11.0％。采用本法测定大鼠灌胃白芷95％乙醇提取物后血浆中欧前胡素的血药浓度一时间曲线，用DAS2.0计算其药物动力学参数，结果表明欧前胡素在大鼠体内呈二室模型分布，主要药动学参数为：t_max（h）0.7084±0.102，C_max(μg·mL^-1)2.17±0.588，t_1/2α（h）0.562±0.639，t_1/2β（h）4.698±1.741，AUC_0→t(μg·h·mL^-1)6.984±3.570，AUC_0→∞(μg·h·mL^-1)7.230±3.695。该法灵敏度高，重复性良好，简单易行，可作为大鼠血浆中欧前胡素的检测及其体内药物动力学研究，为白芷及其制剂的基础研究提供依据。更多还原

【Abstract】 Radix Angelica dahurica, the dried root of Angelica dahurica(Fisch,ex Hoffm.)Benth.et Hook.f.var.formosana(Boiss.)Shan et Yuan, is used as a Traditional Chinese Medicines and listed in the Chinese Pharmacopoeia with the name of " baizhi". Investigations indicated it has many clinic effects, such as analgesic and anti-inflammatory and so on, and imperatorin is the main biologically active chemical component.In this study, we studied on the process for extracting coumarins compounds from Radix Angelica dahurica by orthogonal experiments. Using the weight of imperatorin which was extracted from Radix Angelica dahurica as the investigation index, study on the factors that effect the extraction, through this way to optimize the conditions for the extraction of Angelica dahurica. Results show that the optimum conditions for the extraction of Angelica dahurica is ABC. That is, adding five times of 95 % alcohol, refluxing and extracting for 3 h, totally extracting 3 times.Three of the coumarins have been isolated and purified from Radix Angelica dahurica with gel column、ODS column and so on. Their structures were identified with H-NMR, and they are Imperatorin、Bergapten、Cnidilin. This experiment developed a much more simple、economic and safe method to extract reference substances from Radix Angelica dahurica.A rapid and sensitive liquid chromatography method has been developed to determine imperatorin in rat plasma. Imperatorin and Brufen (an internal standard) were extracted from plasma using protein precipitation with acetonitrile, they were separated on a C column.Oral administration of Radix Angelica dahurica extract to rats at a dose of 2g/kg, the concentrations of imperatorin in rat plasma were determined by a reversed-phase high-performance liquid chromatography, and the pharmacokinetic parameters were estimated by the DAS2．0 computer program.The Results show that the concentration-time profiles was fitted with an open two compartment model system. The main pharmacokinetic parameters were t 0．708(?)0．102, C, ((?)g(?)mL) 2．170(?)0．588, t(h) 0．562(?)0．639, t (h) 4．698(?)1．741, AUC ((?)g(?)h(?)mL) 6．984(?)3．570, AUC((?)g(?)h(?)mL) 7．230(?)3．695。This HPLC method is appropriate for the determination and pharmacokinetic study of imperatorin in rat plasma after administrating the Radix Angelicae dahuricae extract.更多还原