基于PK-PD模型的独活凝胶贴膏经阳陵泉穴位给药治疗类风湿性关节炎研究  

Study on Angelicae Pubescentis Radix gel paste acupoint stickers administration of Yanglingquan(GB 34)in the treatment of rheumatoid arthritis based on PK-PD model

作　　者：王锐[1] 于春峰 卓雪群 王金锐 杨若依 杨婧[1] WANG Rui;YU Chun-feng;ZHUO Xue-qun;WANG Jin-rui;YANG Ruo-yi;YANG Jing(Heilongjiang University of Chinese Medicine,Harbin 150040,China)

机构地区：[1]黑龙江中医药大学,哈尔滨150040

出　　处：《中华中医药杂志》2022年第6期3441-3444,共4页China Journal of Traditional Chinese Medicine and Pharmacy

基　　金：国家自然科学基金项目(No.82074271);黑龙江省自然科学基金项目(No.H201472);2020年黑龙江中医药大学研究生创新科研项目(No.2020yjscx055)。

摘　　要：目的:通过独活凝胶贴膏穴位贴敷的药效学与其有效成分蛇床子素、二氢欧山芹醇当归酸酯的药动学和药效学研究,揭示药物在体内的药动学与药效学动态变化规律,验证穴位贴敷的滞后性及应答性。方法:采用微透析采样法对类风湿性关节炎(RA)家兔关节腔组织液进行采样,并用UPLC-MS/MS法测定独活有效成分蛇床子素、二氢欧山芹醇当归酸酯的含量建立药物动力学模型(PK);用ELISA法检测药效学指标IL-1β、TNF-α和IL-6的抑制率(PD),以效应-时间-药物浓度绘制曲线并进行相关分析;采用Win Nonlin Examples Guide 5.2.1软件对药物效应-血药浓度进行PK-PD模型拟合。结果:在药动学研究中,阳陵泉经皮给药途径符合血管外给药的一级药物动力学模型并得到两组药动学参数:蛇床子素药动学参数:k_(01)=0.15(1/h),k_(10)=0.17(1/h),AUC=3597.07(h·ng/mL),T_(max)=6.00 h,C_(max)=373.18 ng/mL;二氢欧山芹醇当归酸酯药动学数:k_(01)=0.12(1/h),k_(10)=0.18(1/h),AUC=1197.80(h·ng/mL),T_(max)=6.90 h,C_(max)=125.65 ng/mL。在PK-PD模型研究中,通过药效学拟合得到阳陵泉给药途径下IL-1β、TNF-α和IL-6的PK-PD参数以及拟合方程,分别为E=95.72·Ce/568.08+Ce;E=46.32·Ce/618.27+Ce;E=48.32·Ce/118.47+Ce。结论:基于微透析技术和ELISA法的独活凝胶贴膏PK-PD研究方法可行、数据直观、结论理想,说明经络穴位对药物的治疗作用具有放大效应,穴位贴敷对经皮给药途径具有生物促进作用。Objective:By studying the pharmacokinetics and pharmacodynamics of point application of Angelicae Pubescentis Radix gel paste and its active components:osthole and dihydroparsley angelic acid,the dynamic changes of pharmacokinetics and pharmacodynamics of the drug in vivo were revealed,and the hysteresis and responsiveness of point application were verified.Methods:Microdialysis sampling was used to sample the tissue fluid in the joint cavity of rabbits with rheumatoid arthritis(RA).UPLC-MS/MS method was used to determine the content of the active components,namely osthole and dihydroparsley,to establish a pharmacokinetic model(PK).The inhibitory rate(PD)of IL-1β,TNF-αand IL-6 were measured by ELISA,and the curves were plotted by effect-time-concentration method.Adopt-blood drug concentration Win Nonlin Examples Guide 5.2.1 software on drug effect to PK and PD model fitting.Results:In the pharmacokinetic study,the transdermal route of Yanglingquan(GB 34)was in line with the first-order pharmacokinetic model of extravascular administration and the two groups of pharmacokinetic parameters were obtained:k_(01)=0.15(1/h),k_(10)=0.17(1/h),AUC=3597.07(h·ng/mL),T_(max)=6.00 h,C_(max)=373.18 ng/mL.Pharmacokinetic numbers of dihydroparsley angelic acidester:k_(01)=0.12(1/h),k_(10)=0.18(1/h),AUC=1197.80(h·ng/mL),T_(max)=6.90 h,C_(max)=125.65 ng/mL.In the study of PK-PD model,the PK-PD parameters and fitting equations of IL-1β,TNF-αand IL-6 were obtained by pharmacodynamic fitting under the Yanglingquan(GB 34)route,E=95.72·Ce/568.08+Ce;E=46.32·Ce/618.27+Ce;E=48.32·Ce/118.47+Ce,respectively.Conclusion:The research method of PK-PD based on microdialysis technology and ELISA is feasible,the data is intuitive,and the conclusion is ideal.It shows that meridian acupoints have amplification effect on drug therapy,and acupoint sticking has biological promotion effect on percutaneous drug delivery.

关 键 词：独活 凝胶贴膏 穴位贴敷 微透析 PK-PD模型 阳陵泉 类风湿性关节炎 

分 类 号：R285.5[医药卫生—中药学]