商陆药效伴随药代动力学及其药效机制的研究  

Study on pharmacodynamics and pharmacokinetics of Phytolacca acinosa Roxb.and its mechanism

作　　者：孙文学 盛云华 黄坚 孙杰 魏舒婷 唐黎明 SUN Wen-xue;SHENG Yun-hua;HUANG Jian;SUN Jie;WEI Shu-ting;TANG Li-ming(Shanghai Institute of Food and Drug Control Institute for Pharmacology,Shanghai 201203,China)

机构地区：[1]上海市食品药品检验研究院药理室,上海201203

出　　处：《中国药理学通报》2022年第9期1429-1434,共6页Chinese Pharmacological Bulletin

基　　金：国家重点研发计划项目(No 2017YFC1702004)。

摘　　要：目的探索商陆的利尿作用、利尿机制与药代动力学,明确商陆的“量-时-效”关系。方法取合格大鼠,造模水负荷模型,给予不同剂量商陆水提物,考察商陆的利尿作用。采用蛋白免疫印迹法检测肾组织中水通道蛋白2、4(AQP2、AQP4)与血管紧张素Ⅱ1型受体(ATGR1)、血管紧张素Ⅱ2型受体(ATGR2)、肾素的蛋白表达情况。采用建立的LC-MS/MS生物分析方法检测大鼠血浆中的商陆皂苷甲(EsA)含量,计算药代动力学参数及分析血药浓度与药效的相关性。结果与模型组相比,商陆低、中、高剂量组(0.9、1.8、3.6 g生药·kg^(-1))与EsA皆有明显的利尿作用(P<0.05)。机制研究结果表明,商陆水提物与EsA显著下调了AQP2、AQP4、ATGR1、肾素蛋白的表达。药代动力学结果显示,商陆水提物低、中、高剂量组大鼠血浆内EsA的达峰浓度(C_(max))与曲线下面积(AUC_(0-1))随剂量升高而升高。结论商陆具有利尿作用,EsA是商陆利尿的主要成分之一;利尿作用机制为抑制水通道蛋白AQP2、AQP4的表达以及抑制血管紧张素Ⅱ1型受体与肾素的表达。商陆的量-时-效关系为给药剂量越大,大鼠血浆内EsA的浓度越高,但利尿作用不随剂量升高而增强。Aim To explore the diuretic effect,diuretic mechanism and pharmacokinetics of Phytolacca acinosa Roxb.,and clarify its“quantity-time-effect”relationship.Methods Firstly,qualified rats were modeled by water load model,given different doses of Phytolacca acinosa Roxb.aqueous extract,then the diuretic effect was investigated.Secondly,Western blot was used to detect the protein expression of aquaporins AQP2,AQP4 and the angiotensin II receptors ATGR1,ATGR2,and renin in the RAAS system in kidney tissues.Thirdly,the established LC-MS/MS biological analysis method was used to detect the esculentoside A(EsA)content in the plasma,calculate the pharmacokinetic parameters and analyze the correlation between the blood concentration and the drug effect.Results The water load model was successfully established.Compared with the model group,hydrochlorothiazide had a significant diuretic effect(P<0.01).Low,medium and high dose groups of Phytolacca acinosa Roxb.all had obvious diuretic effects(P<0.01),EsA also had a significant diuretic effect(P<0.05).Phytolacca acinosa Roxb.aqueous extract and EsA significantly down-regulated the expression of AQP2,AQP4,ATGR1 and renin protein.The pharmacokinetic results showed that the Cand AUCof EsA in the plasma of rats in the low,medium,and high dose groups of aqueous extract increased with the increase of the dose.Conclusions Phytolacca acinosa Roxb.had a diuretic effect,which is related to inhibiting the expression of aquaporins AQP2 and AQP4 and inhibiting the expression of angiotensin II type 1 receptor and renin,thereby inhibiting the reabsorption of renal tubules and collecting ducts.

关 键 词：商陆 商陆皂苷甲 利尿作用 利尿作用机制 药代动力学 “量-时-效”关系 

分 类 号：R-332[医药卫生] R284.1R322.61R969.1R983.1