中国中药杂志

2013, v.38(08) 1231-1236

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大黄解热作用与降低血浆一氧化氮作用的PK-PD研究
Pharmacokinetic/pharmacodynamic modeling of antipyretic and reducing plasma concentration of NO effects of Rheum palmatum in rat

李红;张艳;于宜平;王平;李帆帆;孟宪丽;
LI Hong,ZHANG Yan,YU Yi-ping,WANG Ping*,LI Fan-fan,MENG Xian-li(College of Pharmacy,Chengdu University of Traditional Chinese Medicine,Chengdu 611137,China)

摘要(Abstract):

药动学与药效学模型的结合是现代药物研究方法的一个热点,也是评价中药作用的一个重要手段。该文以内毒素复制大鼠发热炎症模型,灌胃大黄水煎液(1.54 g·kg-1)后不同时间点采血,测量体温及血浆NO浓度,同时采用高效液相色谱-荧光法(HPLC-FLD)进行大黄酸血药浓度测定。以Kinetica 5.0.11软件,分别对治疗组大黄酸平均血药浓度与治疗组体温及NO降低值进行PK-PD模型拟合,评价大黄作用特点及可能机制。实验结果表明大黄能够抑制LPS大鼠体温及血浆NO浓度的升高;最终PK-PD模型均以效应室联结的无滞后时间二房室-Sigmod Emax拟合较优;大黄酸在LPS大鼠体内的t1/2,Cmax,AUC与正常大鼠比较显著增大;大黄解热及降低血浆NO浓度的EC50分别为114.1,90.80μg·L-1,两者较为接近;解热作用Emax约为造模后体温升高最大值的111.0%,对NO影响的Emax约为造模后血浆NO升高最大值的8.399%,两者有显著差异;两药效指标的药效动力学曲线均较为陡峭。大黄在正常及LPS大鼠体内的药物动力学过程存在差异;解热及降低血浆NO浓度的作用靶点可能处于同一部位;大黄解热作用机制除通过降低血浆NO浓度外,应具有其他微观作用机制;大黄解热和降低血浆NO浓度作用的量效关系范围较窄,效能较低。
Pharmacokinetic-pharmacodynamic(PK-PD) modeling was used to characterize the antipyretic and anti-inflammatory effects in rats of Rhein,a major component in rhubarb.Twenty-four healthy male Sprague-Dawley(SD) rats were randomly into four groups,of 6 each.The rats in first group were injected intravenously with lipopolysaccharide(LPS,100 μg·kg-1).The second group rats were given rhubarb decoction(RD,1.54 g·kg-1) by oral administration alone.The rats belonging to third group were administered orally RD 30min after LPS injection.The rest rats were given normal saline only as control group.Orbital sinus blood sampling was collected at different time points.The Rhein and NO concentration in plasma and body temperature(BT) were measured.Relevant data of PK-PD modeling were performed with Kinetica 5.0.11.RD could suppress the rise in BT and plasma NO concentration.The antipyretic and anti-inflammatory responses were best described by a Sigmod-Emax model.Delay between exposure and response was accounted for by a transit compartment model with two parallel transit compartment chains.The results showed that some parameters such as t1/2,Cmax and AUC were significantly increased in rats treated with LPS,compared to those in rats treated with normal saline.The EC50 for antipyretic effect and decrease of plasma NO concentration was respectively equal to 114.1,90.80 μg·L-1.The Emax for antipyretic effect was about 111% of that for increase in BT after LPS injection.The Emax for anti-inflammatory action was close to 8.399% of that for elevated NO level after modeling.Meanwhile,there was a difference in pharmacokinetic process of Rhein between the impact of normal saline and LPS.So,it can be concluded that the targets of regulating NO production and BT after RD administration may be at the same location.Not only do that,the antipyretic effect induced by RD maybe completely manifest through reducing the plasma concentration of NO.

关键词(KeyWords): 大黄酸;一氧化氮;体温;药动学-药效学结合模型
rhein;nitric oxide;temperature;pharmacokinetic-pharmacodynamic binding model

Abstract:

Keywords:

基金项目(Foundation): 国家自然科学基金项目(81073118,8100168);; 四川省教育厅自然基金重点项目(11ZA061)

作者(Author): 李红;张艳;于宜平;王平;李帆帆;孟宪丽;
LI Hong,ZHANG Yan,YU Yi-ping,WANG Ping*,LI Fan-fan,MENG Xian-li(College of Pharmacy,Chengdu University of Traditional Chinese Medicine,Chengdu 611137,China)

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