目的 探討腸道菌群是否參與溴吡斯的明的代謝及急進(jìn)高原后腸道菌群對(duì)其代謝產(chǎn)生的影響。方法 將大鼠隨機(jī)分為平原給藥組、平原空白組、高原給藥組、高原空白組，共4組，每組6只大鼠。平原給藥組大鼠禁食12 h后于上海（中國人民解放軍海軍軍醫(yī)大學(xué)）進(jìn)行實(shí)驗(yàn)，分別將10.2 mg（約含溴吡斯的明2.3 mg）溴吡斯的明片劑粉末用水溶解后ig給藥，于給藥前（0 h）及給藥后0.33、0.66、1.00、1.50、2.00、3.00、4.00、6.00、8.00、12.00、24.00 h由眼眶后靜脈叢取血進(jìn)行藥動(dòng)學(xué)分析。高原給藥組大鼠于碌曲縣海拔為4 300 m的高原地區(qū)，大鼠禁食12 h后開始藥動(dòng)學(xué)實(shí)驗(yàn)，過程同平原給藥組。收集平原空白組和高原空白組大鼠的糞便，通過16S rRNA法分析急進(jìn)高原后腸道菌群的變化情況；體外孵育實(shí)驗(yàn)結(jié)合LCMS/MS法分析腸道菌群與溴比斯的明的代謝關(guān)系。結(jié)果 急進(jìn)高原后大鼠腸道菌群組成發(fā)生了變化，菌群種類和數(shù)量均減少；溴比斯的明與大鼠糞便體外孵育實(shí)驗(yàn)結(jié)果表明腸道微生物群參與溴吡斯的明吸收前的代謝，且在高原缺氧條件下，腸道微生物群對(duì)其代謝減慢；急進(jìn)高原后溴吡斯的明藥動(dòng)學(xué)參數(shù)藥時(shí)曲線下面積（AUC_0~t）增加了57.60%，清除率（CL）降低了35.94%。結(jié)論 腸道菌群參與溴吡斯的明吸收前代謝，可能與其生物利用度低有關(guān)；并且急進(jìn)高原后腸道菌群介導(dǎo)的溴吡斯的明代謝減慢，從而增加其吸收。

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.

R969.1

國家自然科學(xué)基金資助項(xiàng)目（82001995）；甘肅省科技計(jì)劃基金項(xiàng)目（20JR10RA010）；澳門青年學(xué)者計(jì)劃項(xiàng)目（AM2020018）