目的 建立黑骨藤的药动学（PK）-药效学（PD）模型。方法 大鼠右后足足垫皮内注射0.1 mL完全弗氏佐剂（CFA），建立大鼠佐剂型关节炎（AA）模型，大鼠ig黑骨藤提取物（87 g/kg），2次/d，连续14 d。于末次给药后5、15、30、45 min，1、1.5、2、3、4、6、8、12、24 h经尾静脉取血，采用液质联用法（HPLC-MS/MS）检测血浆样本中3-O-咖啡酰基奎宁酸、4-O-咖啡酰基奎宁酸、5-O-咖啡酰基奎宁酸的质量浓度，获得药时曲线；采用试剂盒测定血浆样本中白细胞介素-1β（IL-1β）、类风湿因子（RF）、肿瘤坏死因子-α（TNF-α）水平，获得时效曲线；采用WinNonLin软件房室模型分析方法拟合黑骨藤的PK参数；固定PK参数，对时效关系进行拟合，得到PD参数；根据PD参数建立黑骨藤的PK-PD模型。结果 根据WinNonLin软件拟合黑骨藤的PK-PD模型符合Inhibitory Effect Sigmoid E0模型，在该PK-PD模型下可以通过3-O-咖啡酰基奎宁酸、4-O-咖啡酰基奎宁酸、5-O-咖啡酰基奎宁酸的血药浓度计算相应的药效值，也可以根据药效值计算相应的血药浓度。结论 IL-1β、RF、TNF-α的质量浓度与3-O-咖啡酰基奎宁酸、4-O-咖啡酰基奎宁酸、5-O-咖啡酰基奎宁酸的血药浓度存在一定相关性。黑骨藤中的3-O-咖啡酰基奎宁酸、4-O-咖啡酰基奎宁酸、5-O-咖啡酰基奎宁酸可通过抑制IL-1β、RF、TNF-α分泌从而治疗类风湿性关节炎。

Objective To establish a pharmacokinetic (PK)-pharmacodynamic (PD) model of Periploca forrestii. Methods The right hindfoot footpad of rats were 0.1 mL complete Freund's Adjuvant (CFA) to establish adjuvant arthritis (AA) rat model. Rats were ig P. forrestii extract (87 g/kg, twice a day for 14 d) and blood were collected via tail vein at 5, 15, 30, 45 min, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 h after the last administration. The concentrations of 3-O-caffeoylquinic acid, 4-O-caffeoylquinic acid, 5-O-caffeoylquinic acid in plasma samples were detected by HPLC-mass spectrometry (HPLC-MS/MS) to obtain the drug concentration-time curve. The level of interleukin-1β (IL-1β), rheumatoid factor (RF), tumor necrosis factor-α (TNF-α) in plasma samples were determined by kit to obtain the time-effect curve. WinNonLin software was used to fit the PK parameters of P. forrestii, and the time-effect relationship was fitted to obtain the PD parameters. According to the PD parameters, the PK-PD model of P. forrestii was established. Results The PK-PD model of P. forrestii according to the WinNonLin software was fitted in accordance with the Inhibitory Effect Sigmoid E0 model, in which the blood concentrations of 3-O-caffeoylquinic acid, 4-O-caffeoylquinic acid, 5-O-caffeoylquinic acid could be calculated based on the potency values, and the potency values could be calculated based on the blood concentrations. Conclusion There was a correlation between the concentrations of IL-1β, RF, TNF-α and 3-O-caffeoylquinic acid, 4-O-caffeoylquinic acid and 5-O-caffeoylquinic acid. These three components in P. forrestii extract could inhibit the secretion of IL-1β, RF and TNF-α to treat rheumatiod arthritis.

R285.5;R285.61

国家自然科学基金资助项目（81660691，U1812403）；中央引导地方科技专项项目（黔科中引地^[2018]4006）；贵州省科技计划项目（黔科合平台人才^[2019]5660，^[2017]5601）；贵阳市科研创新团队项目（筑科合同^[2017]30-29号）；贵州省大学生创新创业训练计划项目（2018520335）