摘要
本研究利用P-gp经典探针药地高辛(digoxin,DG)考察6个五酯片木脂素活性成分(WZ lignans)对大鼠灌胃和静脉给药后DG药代动力学过程的影响,评价WZ木脂素对肠道及肝肾P-gp活性的影响;并利用体外Caco-2细胞模型考察WZ木脂素对DG转运的影响,确证各活性成分对P-gp活性的作用。结果表明,五味子甲素、乙素、醇乙及酯甲均可升高DG的血药浓度,其中五味子醇乙的作用最强。合用五味子醇乙使灌胃给药DG的AUC升高99.0%(P<0.05),使静脉注射DG的AUC升高109.2%(P<0.05),五味子醇乙对灌胃给药及静脉注射DG的AUC影响程度相近,提示五味子醇乙主要通过抑制DG在肝肾的清除而使DG血药浓度升高。此外,五味子甲素、乙素、醇乙及酯甲可抑制DG在Caco-2细胞的转运,提示上述成分可抑制体外P-gp的活性。总之,WZ木脂素可抑制大鼠体内P-gp活性,其可能通过抑制肝肾的P-gp活性减少DG的消除而使DG的血药浓度升高。
This study was aimed to investigate the effects of six Schisandra lignans of Wuzhi tablet（WZ,a preparation of ethanol extract of Schisandra sphenanthera） on the pharmacokinetic process of digoxin（DG,a classical P-gp substrate） after intravenous and oral administration in rats.The effect of Schisandra lignans on the transportion of DG in Caco-2 cells was further elucidated.Our data showed that the plasma concentrations of DG were increased to different extent following co-administration of schisandrin A,schisandrin B,schisandrol B and schisantherin A,respectively.Schisandrol B showed the most potent effect among the six lignans.However,schisandrin C and schisandrol A showed little effect on pharmacokinetic of DG.Schisandrol B led to 99.0%（P〈0.05） and 109.2%（P〈0.05） increase in the AUC after orally or intravenously administered of DG,suggesting that co-administration of schisandrol B induced a more potent effect on increasing hepatic bioavailability of DG than that of intestinal.Furthermore,in vitro transport experiment showed that schisandrin A,schisandrin B,schisandrol B and schisantherin A inhibited P-gp-mediated efflux of DG,suggested that these lignans inhibited the P-gp-mediated efflux of DG.In conclusion,the exposure of DG in rats was increased when co-administered with Schisandra lignans,and schisandrol B showed the strongest effect.The dramatic increase in oral bioavailability of digoxin in the presence of schisandrol B may be due to the inhibition of hepatic/renal P-gp activity.
作者
覃小玲
段文海
王莹
陈孝
黄民
毕惠嫦
QIN Xiao-ling;DUAN Wen-hai;WANG Ying;CHEN Xiao;HUANG Min;BI Hui-chang(Guangdong Food and Drug Vocational College,Guangzhou 510520,China;School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou 510006,China;Department of Pharmacy,The Second Affiliated Hospital,Sun Yat-sen University,Guangzhou 510080,China;Department of Pharmacy,the First Affiliated Hospital,Sun Yat-sen University,Guangzhou 510080,China)
出处
《药学学报》
CAS
CSCD
北大核心
2018年第8期1337-1343,共7页
Acta Pharmaceutica Sinica
基金
国家自然科学基金资助项目(81703609)
广东省医学科学技术研究基金资助项目(A2017287)
作者简介
通讯作者:毕惠嫦,Tel:86-20-39943035,Fax:86-20-39943000,E-mail:bihchang@mail.sysu.edu.cn
