【作者】 孙亚彬； 苗勇； 许重远；

【Author】 SUN Ya-bin~1,MIAOYong~2,XU Zhong-yuan~1 1.GCP Center,Nanfang Hospital,Southern Medical University,Guangzhou 510515, China; 2.Department of Plastic Surgery,Nanfang Hospital,Southern Medical University, Guangzhou 510515,China;

【机构】 南方医科大学南方医院药物临床试验中心； 南方医科大学；

【摘要】 目的:评价甘草与京大戟配伍对大鼠肠粘膜P-gp的影响。方法:对大鼠口服甘草煎液,京大戟煎液,甘草京大戟合煎液,生理盐水一周后,使用UssingChamber技术,评价罗丹明123（R123）和荧光素钠（CF）经大鼠小肠粘膜的经时吸收方向和分泌方向的透过量和表观渗透系数;应用RT-PCR技术评价mdrla基因的表达情况;应用在体In situ实验研究甘草与京大戟合用对R123肠道给药后血浆中药物浓度及各药动学参数的影响。结果:京大戟煎液与甘草京大戟合煎液均可以增加R123经吸收方向透过性,并减少其分泌方向的透过（P<0.05,与生理盐水组比较）。甘草水提液灌胃后,R123在吸收方向与分泌方向中的透过与生理盐水组(P_app=0.28±0.15和P_app=1.16±0.46)比较,没有显著性差异。RT-PCR的结果显示,京大戟及合煎液均可以显著降低mdrla的表达,与空白组相比,差异具有统计学差异（P<0.01）。体内in situ结果显示甘草组R123最高血浆浓度Cmax、曲线下面积AUC 0-240min和生物利用度F与对照组比较无统计学差异,而京大戟、合煎组Cmax、AUC 0-240min和F均大于对照组（P<0.01）,并且合煎组AUC 0-240和F与京大戟组相比,增加了将近一倍,差异有统计学意义（P<0.01）,;大鼠灌胃京大戟后,CF的各药动学参数与对照组比较无统计学差异。结论:京大戟可能是一种P-gp抑制剂,而甘草与京大戟合用后对R123透过的影响与单用京大戟相似,可能是甘草与京大戟有协同作用,是其毒性成分吸收增加,这可能是两者配伍产生毒性的机制之一。更多还原

【Abstract】 Objective:To investigate the modulation on the P-glycoprotein in the intestine by combined use of Glycyrrhiza inflata and Euphorbia pekinensis with Ussing Chamber,RT-PCR and in situ method.Methods:The permeability of rhodamine123（R123） or fluorescein sodium（CF）via Wistar rat intestine membranes was evaluated by in vitro Ussing Chamber and in situ after oral administration of five different decotions of Glycyrrhiza inflata and Euphorbia pekinensis and and combined of two drugs and 0.9%sodium chloride and verapamilfor 1 week.And the concentration of R123 or CF was determined by the fluorospectrophotometry and LC-MS/MS in the receiving solution.Meanwhile the expression of mdrla in P-gp were detected by real-time fluorogenetic quantitative PCR.Results:After oral administration of Combine decocion of the two drugs and Euphorbia pekinensis,the absorptive directed permeability of R123 was significantly increased（P<0.01, compared with control group）,On the other hand,Euphorbia pekinensis and Combine decoction of the two drugs also decrease the permeability of secretory directed transport（P<0.05 compared with control group）.While no action of Glycyrrhiza inflata was found on the secretory transport of R123（Papp =0.28±0.15） across the intestine tissues,while P_app of control group was（Papp=1.16±0.46）.After oral adminstration of Euphorbia pekinensis decoction for 1 week,the levels of mdrla expression in Wistar rats were lower than the control group,andhave significant difference in the results.Meanwhile,Glycyrrhiza inflata had no effect on transport of CF across the intestine tissues,though the other three groups could decrease the permeability of CF,as compared with control group.By in situ closed loop method,it was found that the largest plasma concentration(C_max),area under curve（AUC） and bioavailability（F） of R123 of Glycyrrhizae group had no statistics difference compaired with control group.However,The other three groups significantly enhanced the intestinal absorption of R123 in rats（P<0.01,compared with control group）,while the groups administration Glycyrrhizaecombined with Euphorbia pekinensis,have been close to the results with administration Euphorbia pekinensis, alone.Conclusion:Euphorbia pekinensis may slightly inhibit P-glycoprotein function in the intestinal membrane.For another,some compositions in Euphorbia pekinensis inhibit P-glycoprotein function,and some others strengthen the tight junction between cells in the intestinal membrane to decrease permeability of CF.As the inhibitory action to P-glycoprotein was enhanced by combination of Glycyrrhiza inflata and Euphorbia pekinensis,based on the results,it may be one of the mechanisms of creating toxicity once co-administration of Glycyrrhiza inflata and Euphorbia pekinensis.更多还原