基于大鼠类风湿性关节炎模型建立黑骨藤的PK-PD模型

Pharmacokinetic-pharmacodynamic link model of Periploca forrestii based on rheumatiod arthritis rat model

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-αand 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-αto treat rheumatiod arthritis.