板蓝根总生物碱中表告依春在发热大鼠体内的药动学-药效学结合模型研究

Pharmacokinetic-pharmacodynamic binding model of febrile rats in vivo for study on epigoitrin from total alkaloids of Radix Isatidis

目的应用药动学与药效学结合模型,研究板蓝根总生物碱中主要成分表告依春在酵母致热大鼠体内的药动学和药效学之间的关系。方法给大鼠ig板蓝根总生物碱,不同时间取血并对体温进行观察,采用高效液相法测定血浆中表告依春的浓度,用一房室模型计算药动学参数,采用3种药动学与药效学拟合模型,分别对药效学参数进行拟合。结果表告依春在正常大鼠和发热大鼠体内的主要药动学参数t1/2、Cmax、AUC分别为:(4.94±0.84)h、(4.01±0.21)μg/mL、(28.37±2.42)μg.h/mL和(5.71±0.91)h、(4.15±0.25)μg/mL、(30.35±2.58)μg.h/mL。药理效应与效应室浓度之间的关系用间接反应中的药效产生抑制模型拟合较好,相应的药效学参数分别为Kin为(0.70±0.10)h-1,Kout为(0.54±0.12)h-1,R0为1.33±0.16,IC50为(0.94±0.66)mg/L。结论板蓝根总生物碱中表告依春在正常大鼠和发热大鼠体内的药动学行为无明显差异,表告依春在发热大鼠体内药动学与药效学间符合间接反应中的药效产生抑制模型。

Objective To investigate the relationship between pharmacokinetics （PK and pharmacodynamics PD of epigoitrin, a main component in total alkaloids of Radix Isatidis, in yeastinduced febrile rats with the combined PK-PD model. Methods The plasma concentration of epigoitrin after ig administration with total alkaloids of Radix Isatidis was determined by HPLC method and the body temperature was recorded by electronic thermometer. The individual PK parameters were fitted using one compartmental model. The PD parameters were fitted by three kinds of PK-PD binding models, such as indirect inhibition-Kin model, indirect stimulation KoutPD model, and Sigmoid-Emax model. Results The main PK parameters t（1/2）, Cmax, AUC were （4.94±0.84） h, （4.01±0.21） μg/mL, （28.37±2.42） μg · h/ roland （5.71±0. 91） h, （4. 15±0.25） μg/mL, （30. 35±2. 58） μg·h/mL in both normal and febrile rats, respectively. The relationship between pharmacological effects and effect compartment concentration was better fitted with the indirect inhibition-Kin PD model. The corresponding PD parameters were Kin= （0.70±0. 10） h^-1, K^-1,Kout=（0.54±0.12） h^-1, R0=1.33±0. 16, IC50=（0.94±0.66） mg/L. Conclusion The PK parameters of epigoitrin in total alkaloids of Radix Isatidis show that there is no significant difference in PD behavior in viz,o in both normal and febrile rats. Relationship between in vivo PK and PD of epigoitrin in febrile rats is established using indirect inhibition Kin model.