基于电化学传感技术的丹参注射液多成分整合药代动力学研究

The essential goal of pharmacokinetics study of traditional Chinese medicines (TCMs) is to clarify the in vivo process of TCMs so that it can serve for modern administration scheme designing for TCMs in clinics.Due to that the active components of TCMs are numerous and complex and the contribution weight of ingredients to the treatment effect is different from each other, it is necessary to study on the integrative pharmacokinetics of multiple active components by combination consideration of the effect contribution weight to provide the possibility of elucidating the in vivo process of TCMs so that the guidance value of pharmacokinetics can be fulfilled for practice administration in clinics. However, it is still lack of sufficient understanding and available methodology about how to characterize the contribution weight of active ingredients to the whole treatment effect of TCMs and how to proceed the integrative pharmacokinetics study of multiple active components by combination consideration of the effect contribution weight. All these problems above-mentioned are tremendous challenges in current TCMs pharmacokinetic investigations. Danshen injection (DSI) is a TCM preparation for the treatment of heart blood vessel diseases, and the antioxidation is one of the main treatment effects. In this study, taking DSI as a carrier, the program will explore the methodological investigation of integrative pharmacokinetics of TCMs by combination consideration of the treatment effect weight of multiple active ingredients. On the basis of our previous investigation outcomes (Previously,an electroactive bionic phospholipid membrane modification electrode was successfully built. The modification electrode could integrate and characterize the antioxidation of multiple active ingredients as a single electrochemistry signal. The peak current could be used as a quantification index for the total quantity of the multiple ingredients, as well as one total quantification index for their contribution weight to the whole treatment effect), it is put forward to use the above mentioned modification electrode as a sensor to develop the methodology of the integrative determination for DSI's multiple active ingredients in plasma and make a scientific approach to the DSI's multiple active ingredients pharmacokinetic investigation.

中药药代动力学研究最基本目的是阐明中药体内过程，为临床给药方案设计服务。但由于中药有效成分众多，各成分对药效作用的贡献"权重"不尽相同，必须考虑药效贡献权重进行多成分整合药代动力学研究，才有望较准确阐释中药体内过程，并对临床用药有实质性指导意义。然而，如何表征成分对整体药效的贡献权重及如何开展整合药效权重的多成分整合药动学研究，尚缺乏认识和方法，是当前研究面临的难题。 丹参注射液（DSI）是治疗冠心病等心血管病的中药制剂，抗氧化是其主要药效作用之一。本项目以DSI为研究载体，探索整合药效权重的多成分整合药代动力学研究方法。项目以前期研究为基础（已构建电活性仿生磷脂膜修饰电极，将DSI多成分抗氧化作用成功整合表征为单一的电化学氧化峰，峰电流即是整合了抗氧化作用权重的各成分量总和的定量依据），提出采用该磷脂膜修饰电极为传感器，建立血浆中DSI多成分整合检测方法，探讨用于DSI整合药代动力学研究

中药药代动力学研究最基本目的是阐明中药体内过程，为临床给药方案设计服务。但由于中药有效成分众多，各成分对药效作用的贡献“权重”不尽相同，必须考虑药效贡献权重进行多成分整合药代动力学研究，才有望较准确阐释中药体内过程，并对临床用药有实质性指导意义。然而，如何表征成分对整体药效的贡献权重及如何开展整合药效权重的多成分整合药动学研究，尚缺乏认识和方法，是当前研究面临的难题。.本项目以丹参注射剂为研究载体，探索整合药效权重的多成分整合药代动力学研究方法。首先对丹参注射剂的化学物质基础进行了研究，采用常规HPLC，建立了包括丹参素钠、原儿茶酸、原儿茶醛、咖啡酸、迷迭香酸、丹酚酸A及丹酚酸B在内的共7个成分的同时含量测定方法；随后在玻碳电极表面优化构建了仿生细胞磷脂传感膜，即GPC－HAD－poly(5-HT)修饰膜，并应用该仿生传感电极预测了丹参素、原儿茶醛、迷迭香酸、丹酚酸B及丹酚酸A等成分的体内抗氧化活性排序；兼顾考虑成分在制剂中的含量、给药后各成分在体内的原型浓度水平等，研究5个主要成分的大鼠体内药代动力学行为；采用心肌缺血小鼠模型，进一步比较研究了丹参素、原儿茶醛、迷迭香酸及丹酚酸A的体内抗心肌缺血作用，进一步验证了仿生细胞磷脂膜修饰电极所预测的成分体内活性排序结果；在此基础上，以最强活性成分丹酚酸A为参考化合物，建立了基于仿生细胞磷脂膜修饰电极的丹参注射液整合药代动力学研究方法，并用于其在大鼠体内的整合研究。. 该研究优先揭示了丹参注射剂整体体内过程，所得整合药代动力学参数不仅反应了多成分的整合浓度信息，同时也反映了多成分在体内的整合药效作用信息，这一研究成果，为中药注射剂多成分的药代动力学研究提供了重要借鉴和方法参考。 . 项目取得成果丰硕，已发表SCI源刊论文7篇，已接受SCI源刊论文2篇，其中影响因子大于3的SCI论文3篇，获授权发明专利1项，正在申请国家发明专利1项；后续还在开展的相关药代动力学研究多个，预期2年内会产出更多成果。项目正在培养中的硕士研究生1名。