滇白珠有效成分水杨酸乙酯糖苷治疗类风湿性关节炎生物代谢机制及PK/PD研究

With the development of rheumatoid arthritis (RA) in the worldwide, the research of medicament for treating the disease should be addressed. Ethyl salicylate 2-O-β-D-lactoside (ESL) which was the extract from Gaultheria yunnanensis express a good anti-inflammatory and analgesic activity in our prior experments. Compared to the traditional non-steroidal anti-inflammatory drugs, ESL almost has no side effects on gastrointestinal tract. Based on this characteristic, we design our project on the metabolism and the metabolic mechanism of organism about the compounds. (1) Using UPLC-MS/MS technology to detect the oral absorption pharmacokinetics after administration in rat, using Q-TOF-MS, LC-MSE technology identify the comprehensive structure of metabolites in feces, urine and bile. (2) Introduced the combined technology about liver from the whole animal; in vitro tissues; intestinal microflora and liver microsomal enzymes and other aspects to clarify the biological characteristics of metabolism and metabolic mechanis which explain the pharmacodynamic characteristics and mechanism of pharmacological action.(3) Using rheumatoid arthritis animal models, established the PK/PD model between the blood concentration-time-pharmacodynamics which combinated the pharmacokinetics and pharmacodynamics indicator to lay the foundation for the development and application of the compound.

随着类风湿性关节炎在全球范围内发病率和致残率的逐年升高，疾病治疗药物的研发亟待重视和解决。水杨酸乙酯糖苷为滇白珠有效成分的提取物，前期药理药效学实验发现其具有非常好的抗炎镇痛活性，且相比于传统的非甾体类抗炎药，几乎不具有胃肠道副作用。基于此特点，本项目以该化合物在生物体内的代谢过程及代谢机制为切入点，采用UPLC-MS/MS技术研究水杨酸乙酯糖苷大鼠口服给药后的吸收动力学特征，利用Q-TOF-MS等技术全面鉴定大鼠粪便、尿液和胆汁中代谢产物的结构，确定其生物代谢途径和方式；利用液质联用技术，从整体动物器官、离体组织、肠道菌群及肝微粒体酶等方面阐明水杨酸乙酯糖苷的生物代谢特点和代谢机制，解释药效作用机理；利用类风湿性关节炎大鼠动物模型，建立基于血药浓度—时间—药效学指标三者之间的PK/PD模型，将药物在机体的药代动力学过程与药效量化指标动力学过程相结合，为该化合物的研发和应用奠定基础。

随着类风湿性关节炎在全球范围内发病率和致残率的逐年升高，疾病治疗药物的研发亟待 重视和解决。水杨酸乙酯糖苷为滇白珠有效成分的提取物，前期药理药效学实验发现其具有非 常好的抗炎镇痛活性，且相比于传统的非甾体类抗炎药，几乎不具有胃肠道副作用。基于此特 点，本项目以该化合物在生物体内的代谢过程及代谢机制为切入点，采用UPLC-MS/MS技术研究 水杨酸乙酯糖苷大鼠口服给药后的吸收动力学特征，利用Q-TOF-MS等技术全面鉴定大鼠粪便、 尿液和胆汁中代谢产物的结构，确定其生物代谢途径和方式；利用液质联用技术，从整体动物 器官、离体组织、肠道菌群及肝微粒体酶等方面阐明水杨酸乙酯糖苷的生物代谢特点和代谢机 制，解释药效作用机理；通过研究化合物的生物代谢过程及机制，为该化合物的后续研发和临床前应用奠定基础。