原儿茶酸冰片酯的设计、合成及代谢研究

【作者】 申旭霁；

【导师】 郑晓晖；

【作者基本信息】 西北大学 ， 中药学， 2012， 博士

【摘要】 中药作为中医临床治疗疾病的主要手段,通过几千年的实践积累了丰富的有关中药配伍应用的经验和理论。以中药为源泉的创新药物开发必须在中医药理论指导下进行才会有更广阔的发展空间。因此,本文以“君-使”药对理论为着眼点,以治疗血瘀证的君药丹参、广枣等药材中广泛存在的原儿茶酸和使药冰片为原料,设计合成了全新化合物原儿茶酸冰片酯。运用代谢组学等手段对其药物动力学、体内组织分布及代谢产物的变化进行深入研究。发现原儿茶酸冰片酯可以针对血瘀证的病因,增强机体的统血、行血的能力,从而产生活血化瘀的作用。本文所提出的创新药物开发思路可以开发出具有临床意义的创新药物,并可为以中药及天然产物为基础的创新药物开发提供有益的借鉴与模式。全文共分五章,主要研究内容如下：1.以原儿茶酸和冰片为原料,设计并通过多种方法合成了原儿茶酸冰片酯。2.采用平衡透析结合高效液相色谱法测定原儿茶酸冰片酯与大鼠血浆蛋白结合率。发现在实验浓度范围内,原儿茶酸冰片酯与大鼠血浆蛋白的结合率较高。3.建立了大鼠血浆及组织中原儿茶酸冰片酯的高效液相色谱-飞行时间质谱测定方法,并运用该方法对原儿茶酸冰片酯在正常及模型大鼠体内的药代动力学过程及组织分布特征进行研究。发现原儿茶酸冰片酯在正常及模型大鼠体内的药代动力学过程符合三室开放模型,作用持久；原儿茶酸冰片酯在正常及模型大鼠体内组织分布特征分别为c脾>c心>c肺>c脑>c肾>c肝和c脾>c心>c肝>c肺>c脑>c肾,该方法可用于原儿茶酸冰片酯的非临床和临床动力学研究。在研究原儿茶酸冰片酯体内代谢过程时发现了其甲基化产物,并鉴定其结构为香草酸冰片酯。4.以香草酸和冰片为原料,运用直接酯化法合成了香草酸冰片酯。5.建立了大鼠血浆及组织中香草酸冰片酯的高效液相色谱-飞行时间质谱测定方法,并运用该方法对香草酸冰片酯在正常及模型大鼠体内的药代动力学过程及组织分布特征进行研究。发现香草酸冰片酯在正常及模型大鼠体内的药代动力学过程符合一室开放模型,半衰期长；在正常及模型大鼠体内组织分布特征分别为c肺>c心>c肾>c脾>c肝>c脑和c心>c肾>c脾>c肺>c肝>c脑,该方法可用于香草酸冰片酯的非临床和临床动力学研究。更多还原

【Abstract】 Traditional Chinese medicine, a Chinese clinical treatment of disease mainly means, through the thousands of years of practice has accumulated rich experience of Chinese crude drug compatibility on application and theory. Chinese medicines as a source of innovative drug development, must be under the guidance of the theory of Chinese medicine, it would have the broader space for development. Therefore, based on the jun-shi compatible herbs theory, the author synthesized a new compounds, bornyl protocatechuate, and used metabolism and other means depth to investigative its pharmacokinetics, in vivo tissue distribution and metabolite changes. The author found bornyl protocatechuate could against the origin of blood stasis, consequently enhance the ability of the body to controlling blood circulation, resulting in promoting blood circulation and eliminating stasis. This paper proposed the new drug development idea can be developed a new drug clinical significance, and can in traditional Chinese medicine and natural products for the innovation of the foundation offer beneficial reference for the drug development and mode. This dissertation consist of five chapters, the main contents are as follows:1. The author design and synthesized bornyl protocatechuate, protocatechuic acid and borneol as raw materials.2. The author use the balanced dialysis combined with HPLC method for the determination of bornyl protocatechuate with rats plasma protein binding rate. Found in the experimental concentration range, the bornyl protocatechuater and rats plasma protein binding rate is higher.3. A novel high performance liquid chromatography/time-of-flight mass spectrometry method to determinate the bornyl protocatechuate in rat (or stasis rat) plasma and tissue was established, and applied it in its pharmacokinetic study and tissue distribution after intravenous injection bornyl protocatechuate. The statistical results indicated that the plasma concentration-time course of bornyl protocatechuate in rat (or stasis rat) confirmed to a3-compartment open model, and lasting effect, and the its tissue distribution was of c spleen>c heart＞c lung＞c brain＞c kidney>c liver (or c spleen＞c heart＞c liver＞c lung＞c brain＞c kidney), demonstrating that the method can be applied in studying the clinical and non-clinical pharmacokinetic of bornyl protocatechuate. The author found a methylated product of bornyl protocatechuate in vivo metabolic process, and identified the structure is bornyl vanillate.4. The author synthesized bornyl vanillate by direct esterification, vanillic acid and borneol as raw materials. 5. A novel high performance liquid chromatography/time-of-flight mass spectrometry method to determinate the bornyl vanillate in rat (or stasis rat) plasma and tissue was established, and applied it in its pharmacokinetic study and tissue distribution after intravenous injection bomyl protocatechuate. The statistical results indicated that the plasma concentration-time course of bornyl vanillate in rat (or stasis rat) confirmed to a1-compartment open model with long half-life and the its tissue distribution was of c lung>c heart＞c kidney＞c spleen＞c liver＞c brain(or c heart＞c kidney＞c spleen＞c lung＞c liver＞c brain), demonstrating that the method can be applied in studying the clinical and non-clinical pharmacokinetic of bornyl vanillate.更多还原