Effect of Tebuconazole exposure on oral Atenolol absorption in rats,based on bile acid homeostasis  

作　　者：TAO Quan XU Yu-jing ZHANG Yu-feng TAO Yu-chen ZHUANG Xu-zhen YIN Deng-ke YANG Ye 

机构地区：[1]Anhui University of Traditional Chinese Medicine,Hefei 230012,China [2]Anhui Provincial Key Laboratory of Pharmaceutical Preparation Technology and Application,Hefei 230012,China

出　　处：《Journal of Hainan Medical University》2023年第7期15-22,共8页海南医学院学报（英文版）

基　　金：supported by National Natural Science Foundation of China(81874348);Academic Support Program for Top Talents of Higher Education in Anhui Province(GXBJZD2022027);Science and Technology Innovation Project of Anhui Drug Administration(AHYJ-KJ-202110)。

摘　　要：Objective:This study is aimed to explore the effect of triazole fungicide tebuconazole(TEB)exposure on the oral absorption behavior of atenolol(AT),based on the homeostasis of bile acids(BAs).Methods:TEB was daily gavaged to rats with 3 mg/kg dose for 28 days to establish the TEB-exposure rat model.The amounts of glycocholic acid,glycochenodeoxycholic acid,taurocholic acid and taurine deoxycholic acid in the small intestine contents of normal and TEB-exposure rats were detected by LC-MS/MS.AT(10 mg/kg)were gavaged to the normal and TEB-exposure rats,and then blood were collected from orbital venous plexus at predetermined time-points.The concentration of AT in plasma was detected by LC-MS/MS,and the pharmacokinetic parameters were calculated by the DAS pharmacokinetic software.An intestinal circulation perfusion model was established in normal rats,and perfused with the perfusates containing the model drug of fluorescein and the BAs with the same compositions as the normal/TEB-exposure rats.After perfusion,the absorption and permeability of fluorescein in intestine were detected,as well as the oxidative stress status and ZO-1 expression level in the intestinal tissues.Results:Compared with normal rats,TEB-exposure increased the amounts of glycocholic acid,glycochenodeoxycholic acid,taurocholic acid and taurine deoxycholic acid in intestine significantly(P<0.001).In TEB-exposure rats,the maximum plasma concentration and area under the curve of AT were increased significantly than those of normal rats(P<0.05),and the peak time was significantly delayed(P<0.05).The TEB-induced BAs homeostasis perturbance increased intestinal permeability,and this effect was associated with the elevation of oxidative stress and the down-regulation of intercellular tight junction proteins in intestinal tissues.Conclusion:TEB-exposure can affect the oral absorption behavior of AT,which is probably related with the intestinal BAs homeostasis perturbance,thus it might affect the clinical efficacy and safety of this drug.

关 键 词：TEBUCONAZOLE ATENOLOL Bile acids PHARMACOKINETICS Tight junction protein Oxidative stress 

分 类 号：R965[医药卫生—药理学]