基于代谢靶点、毒性靶点的中药蟾酥配伍作用规律和潜在相互作用的预测研究

项目名称： 基于代谢靶点、毒性靶点的中药蟾酥配伍作用规律和潜在相互作用的预测研究

项目编号： No.81473334

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 马骁驰

作者单位： 大连医科大学

项目金额： 75万元

中文摘要： 中药蟾酥药理活性显著但具有心脏毒性,治疗窗窄,临床常以复方使用。因此，阐明蟾酥配伍作用规律和合理性就显得尤为重要。根据前期研究和临床复方用药情况，本项目拟基于代谢/毒性靶点,研究常见配伍中药对于蟾毒甾烯ADME/Tox属性的影响，揭示蟾酥配伍作用规律与合理性。通过体内代谢手段，揭示配伍中药对蟾毒甾烯的药代动力学影响，再结合ADME体外研究手段，测定相关代谢动力学参数，从代谢靶点角度诠释配伍成分对蟾毒甾烯代谢的影响规律。同样，通过心脏灌流等整体药效学手段，考察配伍中药对于蟾酥心脏毒性的影响；再利用原代细胞(Na+-K+ ATP酶)，基于毒性靶点揭示配伍成分对于其毒性的影响规律。在此基础上,利用计算化学手段根据关键的代谢/毒性靶点,构建结构与配伍作用的定性、定量构效关系模型，预测存在的潜在相互作用。最终基于代谢/毒性靶点科学揭示毒性中药蟾酥的配伍规律和合理性，指导蟾酥及其复方的安全合理应用。

中文关键词： 蟾毒甾烯；配伍关系；代谢靶点；毒性靶点；相互作用

英文摘要： Although Chinese medicine Chansu exhibited significant bioactivities, it usually had the cardiotoxicities and unsatisfactory therapeutic window, which resulting in its clinic application as Chinese herbal compound. Therefore, it is very important and necessary to elucidate its compatibility rule and rationality in clinic. On the basis of our preliminary investigation and clinic usage of Chansu, we intend to study the influences of other Chinese medicine in the combination, to ADME/Tox parameters of bufadienolides, according to their metabolism and cardiotoxicity targets. These findings would reveal the compatibility rule and rationality of TCM Chansu clearly. Firstly, PK parameters of bufadienolides between alone and combination were compared by the in vivo metabolism methods, and these experimental data could indicate which Chinese herbs may affect the in vivo metabolism of Chasu significantly. And then the kinetic parameters related to the interaction, were measured using the in vitro metabolism methods of ADME, which providing the vital compatibility regulations of Chansu in the combination with major chemical constituents of other herbal medicines, on the basis of metabolic targets of Chansu. Similarly, we used the in vivo pharmacodynamics approaches such as myocardial infusion, to investigate the influence of combinating herbal medicines for the toxicity of Chansu, and then molecular biological approaches were applied to reveal the interaction mechanism on the level of cell. Based on the previous data, we would summarize the qualitative and quantitative mode, according to major metabolism or cardiotoxicity targets, to predict the possible drug-drug interaction by using computational chemistry and molecular docking methods. All of these results would indicate that the compatibility rule and rationality of toxic medicine Chansu on the basis of the molecular targets of metabolism and toxicity, and give the vital and useful guidance for the safe and reasonable usage of Chansu and its related preparations.

英文关键词： bufadienolides;compatilibility relationship;metabolism target;toxicity target;drug interaction