基于“毒、浊-代谢”交互性探讨健脾祛湿剂参苓白术散调控MATE1转运体缓解顺铂肾毒性的作用机制及物质基础

顺铂被广泛应用于多种恶性肿瘤的治疗，但严重肾毒性使其临床应用受限。结合中医理论，顺铂肾毒性属于“药毒”范畴，是肾脾功能受损所致“湿浊中阻”而引起的一种药物代谢异常性副作用。我们前期证实健脾祛湿剂参苓白术散可以降低顺铂在肾组织的蓄积，缓解肾毒性，其机制与增强顺铂肾内转运体多药及毒素外排蛋白1（mammal multidrug and toxin extrusion proteins 1, MATE1）的表达密切相关。由此设想，健脾祛湿剂参苓白术散可通过增强MATE1的表达，影响顺铂在体内的代谢过程，从而达到缓解顺铂肾毒性的作用。本研究拟通过“脾虚湿困”证大鼠模型、人肺癌裸鼠异种移植瘤模型，药物代谢动力学检测，血清药理学结合体外活性导向分析，LC/MS检测等方法探讨参苓白术散降低顺铂肾毒性的机制和物质基础，为开发缓解顺铂肾毒性的临床办法提供新思路，促进中医药的科学转化。

Cisplatin is widely used in treating a variety of malignant tumors, but severe nephrotoxicity limits its clinical application. Combining with traditional Chinese medicine theory, nephrotoxicity of cisplatin belongs to the category of "drug toxicity", which is a side effect of abnormal drug metabolism caused by renal and spleen function damage leading to damp turbidity obstructing in middle-JIAO. We previously confirmed that Shenlingbaizhu Powder, a Jianpiqushi formula, could reduce the accumulation of cisplatin in the kidney tissue and relieve the nephrotoxicity. Its mechanism was closely connected with enhancing the expression of mammal multidrug and toxin extrusion proteins 1 (MATE1). Therefore, it was assumed that Shenlingbaizhu Powder could affect the metabolic process of cisplatin in the body by enhancing the expression of MATE1, so as to alleviate the nephrotoxicity. Thus, the "splenasthenic fluid-retention" syndrome rat model, human lung cancer nude mouse xenograft tumor model, pharmacokinetic testing, serum pharmacology in combination with activity-oriented analysis in vitro, LC/MS and other methods were conducted to explore the mechanism and material basis of Shenlingbaizhu Powder. In order to provide new ideas for alleviating the nephrotoxicity of cisplatin in clinic and promote the scientific transformation of traditional Chinese medicine.