基于“有故无殒”理论建立民族药羊耳菊抗炎活性成分的PK-PD结合模型

The theory of You Gu Wu Yun documented in Huang Di Nei Jing, which means that a drug will reveal its therapeutic effect when it is prescribed to patients with the correct indications. However, it may produce deleterious effects in both sick and healthy people as a result of incorrect indications. The You Gu Wu Yun theory devotes important values in the toxicity assessment and rational use of TCM drugs, whose scientific connotation has been extend to the differences of TCM in PK and PD features between physiological and pathological states. Inula cappa are commonly used as medicinal materials of ethnic minorities in Guizhou for the treatment of inflammatory diseases and have been good curative effect. However, the specific material basis for exerting anti-inflammatory activity is not yet clear, and establishing their PK-PD binding model can be used to elucidate effective material basis of Chinese materia medica. More importantly, our study found that absorption amount of the potential anti-inflammatory activity of Inula cappa in the inflammatory model was significantly higher than that in normal rats. Therefore, a hypothesis was proposed, that is, the anti-inflammatory material basis of Inula cappa will be clarified by establishing the PK-PD binding model of active substances in Inula cappa in vitro and in vivo inflammatory model based on the theory of You Gu Wu Yun . In order to verify this hypothesis, firstly, the model of inflammatory rats and cell will be induced by LPS. Then, the PK-PD binding model of active substances in Inula cappa in vitro and in vivo inflammatory model will be set up by combining with the theory of cellular pharmacokinetics to elucidate the anti-inflammatory material basis of of Inula cappa.

源自于《黄帝内经》的“有故无殒”理论，即“有病则病当之，无病则体受之”，对指导中药毒性评价与合理用药具有重要的意义，其科学内涵已延伸到中药在生理病理状态下的PK特征和PD反应的差异。羊耳菊为贵州少数民族常用药材，用于治疗炎症疾病具有较好的疗效，然而其发挥抗炎活性的具体药效物质基础尚不清楚，而建立其PK-PD结合模型可以为阐明其药效物质基础提供依据。更重要的是，研究发现羊耳菊潜在的抗炎活性成分在炎症大鼠模型体内的吸收量显著高于正常大鼠。鉴于此，本课题提出“基于‘有故无殒’理论建立羊耳菊活性成分在体内外炎症状态下的PK-PD结合模型可以阐明羊耳菊抗炎作用的药效物质基础”这一科学假说。为了验证该假说，本项目拟在建立脂多糖诱导的大鼠炎症模型和细胞炎症模型的基础上，结合细胞药代动力学的理论，建立羊耳菊抗炎活性成分在体内外炎症状态下的PK-PD结合模型，进而阐明羊耳菊发挥抗炎作用的药效物质基础。

羊耳菊为贵州少数民族常用药材，用于治疗炎症疾病具有较好的疗效，然而其发挥抗炎活性的具体药效物质基础尚不清楚。本项目首先采用平衡透析法测定羊耳菊提取物中抗炎活性成分的血浆蛋白结合率，抗炎活性成分在人和大鼠血浆中的平均蛋白结合率分别在(41.07±0.046)%～( 94.95±0.008)%，( 37.66±0.043)%～(97.46±0.013)%。 然后在“有故无殒”理论的指导下，基于脂多糖诱导的大鼠炎症模型，建立羊耳菊抗炎活性成分的体内整合PK-PD结合模型，以IL-4为药效指标时，可得羊耳菊中多效应成分整合后的PK-PD模型为E=14.42*Ce/(1.00+Ce)；以IL-6为药效指标时，可得羊耳菊中多效应成分整合后的PK-PD模型为E=181.78*Ce/(1.00+Ce)；以TNF-α为药效指标时，可得羊耳菊中多效应成分整合后的PK-PD模型为E=592.47*Ce/(1.00+Ce)。最后，在建立脂多糖诱导的细胞炎症模型的基础上，比较羊耳菊潜在抗炎活性在正常细胞和炎症细胞内的药代动力学过程，发现炎症状态会改变羊耳菊抗炎活性成分在细胞内的药动学行为。并从细胞药代动力学的角度，建立羊耳菊抗炎活性成分的体外整合PK-PD结合模型。以NO为药效指标时，羊耳菊中多效应成分整合后的PK-PD模型为E=7.45×[1-Ce^5.74/(78.24^5.74+Ce^5.74)]；以TNF-α为药效指标时，羊耳菊中多效应成分整合后的PK-PD模型为E=79.28×[1-Ce^6.45/(85.10^6.45+Ce^6.45)]。因此，本项目基于“有故无殒”理论建立了羊耳菊活性成分在体内外炎症状态下的PK-PD结合模型，为阐明羊耳菊发挥抗炎作用的药效物质基础提供重要的参考。