急进高原后肠道菌群介导的溴吡斯的明体内代谢研究

In vivo metabolism of pyridostigmine bromide mediated by intestinal flora in condition of high altitude

目的 探讨肠道菌群是否参与溴吡斯的明的代谢及急进高原后肠道菌群对其代谢产生的影响。方法 将大鼠随机分为平原给药组、平原空白组、高原给药组、高原空白组,共4组,每组6只大鼠。平原给药组大鼠禁食12 h后于上海(中国人民解放军海军军医大学)进行实验,分别将10.2 mg(约含溴吡斯的明2.3 mg)溴吡斯的明片剂粉末用水溶解后ig给药,于给药前(0 h)及给药后0.33、0.66、1.00、1.50、2.00、3.00、4.00、6.00、8.00、12.00、24.00 h由眼眶后静脉丛取血进行药动学分析。高原给药组大鼠于碌曲县海拔为4 300 m的高原地区,大鼠禁食12 h后开始药动学实验,过程同平原给药组。收集平原空白组和高原空白组大鼠的粪便,通过16S rRNA法分析急进高原后肠道菌群的变化情况;体外孵育实验结合LCMS/MS法分析肠道菌群与溴比斯的明的代谢关系。结果 急进高原后大鼠肠道菌群组成发生了变化,菌群种类和数量均减少;溴比斯的明与大鼠粪便体外孵育实验结果表明肠道微生物群参与溴吡斯的明吸收前的代谢,且在高原缺氧条件下,肠道微生物群对其代谢减慢;急进高原后溴吡斯的明药动学参数药时曲线下面积(AUC_(0~t))增加了57.60%,清除率(CL)降低了35.94%。结论 肠道菌群参与溴吡斯的明吸收前代谢,可能与其生物利用度低有关;并且急进高原后肠道菌群介导的溴吡斯的明代谢减慢,从而增加其吸收。

Objective To investigate whether the intestinal flora is involved in the metabolism of pyridostigmine bromide and the effect of intestinal flora on its metabolism after entering the plateau.Methods Rats were randomly divided into four groups:administration group at low altitude,blank group at low altitude,administration group at high altitude and blank group at high altitude,with six rats in each group.After fasting for 12 h,the rats in the administration group at low altitude were tested in Shanghai(Naval Military Medical University).Pyridostigmine bromide tablet powder of 10.2 mg(about 2.3 mg of pyridostigmine bromide)were dissolved in water and ig administered,blood was taken from the retroorbital venous plexus before administration(0 h) and 0.33,0.66,1.00,1.50,2.00,3.00,4.00,6.00,8.00,12.00 and 24.00 h after administration for pharmacokinetic analysis.The rats in the administration group at high altitude were in the plateau area with an altitude of 4 300 m in Luqu county.The rats began the pharmacokinetic experiment after fasting for 12 h.The process was the same as that in the administration group at low altitude.The feces of rats in blank group at low altitude and blank group at high altitude were collected,and the changes of intestinal flora after entering the plateau were analyzed by 16S rRNA method.In vitro incubation experiment combined with LC-MS/MS method was used to analyze the relationship between intestinal flora and pyridostigmine bromide.Results After acute exposure to high altitude,the composition of intestinal flora changed,and the species and quantity of flora decreased.The results showed that the intestinal microbiota participated in the metabolism of pyridostigmine bromide before its absorption,and the intestinal microbiota slowed down its metabolism under high altitude hypoxia.After entering the plateau,the pharmacokinetic parameter AUC of pyridostigmine bromide increased by 57.60% and CL decreased by 35.94%.Conclusion Intestinal flora is involved in the pre absorption metabolism of pyridostigmine bromide,which may be related to its low bioavailability.After acute exposure to high altitude,the metabolism of pyridostigmine bromide mediated by intestinal flora slows down,which will increase its absorption.