Effects Of Plateau Hypoxia And Intestinal Microorganisms On The Metabolism Of Metoprolol And Metronidazole

ObjectiveTo explore the effects of plateau hypoxic and intestinal microorganisms on the metabolism of metoprolol and metronidazole in rats.Methods:1.The polyethylene glycol electrolytes powder is combined with the quadruple antibiotic?vancomycin+streptomycin+penicillin+ornidazole?to give rats a gavage,resulting in a pseudo-sterile model of the rat intestine.2.Divide the rats into the plateau bacteria group,the plateau aseptic group,the plain bacteria group and the plain sterile group,and collect blood from the orbital venous plexus of rats at 0.25 h,0.5 h,0.75 h,1 h,1.5 h,2 h,2.5 h,3 h,4 h,6 h,8 h,12 h and24 h after administration.Process the plasma samples,and analyze the differences in pharmacokinetics of metoprolol in the four groups of rats with the liquid chromatography-tandem mass spectrometry?UFLC-MS/MS?,to investigate the effect of high altitude hypoxia environment and intestinal flora on the pharmacokinetics of metoprolol in rats.3.Divide the rats into the plateau bacteria group,the plateau aseptic group,the plain bacteria group and the plain sterile group,and collect blood from the orbital venous plexus of rats at 0.083 h,0.167 h,0.25 h,0.5 h,0.667 h,0.75 h,1 h,1.5 h,2 h,3 h,4 h,6 h,8 h,12 h and 24 h after administration.Process the plasma samples,and analyze the differences in pharmacokinetics of metronidazole in the four groups of rats with the liquid chromatography-tandem mass spectrometry?UFLC-MS/MS?,to investigate the effect of high altitude hypoxia environment and intestinal flora on the pharmacokinetics of metronidazole in rats.4.Incubate metoprolol and metronidazole with rat fecal suspension for 6 h and 12 h respectively,and use liquid chromatography tandem mass spectrometry?UFLC-MS/MS?to analyze the remaining drug in each incubation solution,to investigate the direct metabolism of intestinal flora on metoprolol and metronidazole.Results:1.Give rats gavage with polyethylene glycol electrolytes powder and quadruple antibiotics,and collect rat feces and small intestine tissue of the plain bacteria group,the plain sterile group,the plateau bacteria group and the plateau sterile group after modeling.Stool smear analysis and 16S rRNA analysis shows that the gavage method significantly reduces the number of intestinal bacteria in rats.The small intestine tissue was made into pathological sections,and the HE staining results indicated that the modeling method did not cause significant damage to the rat intestine.Therefore,the above modeling method is feasible.2.Compare the pharmacokinetic parameters of metoprolol of the plateau bacteria group,the plateau aseptic group,the plain bacteria group and the plain sterile group.The results are as follows:compared with the plain bacteria group,the AUC and C_max of the plateau bacteria group decreased by 28.1%and 32.5%?P<0.05?;compared with the plain sterile group,the AUC and C_max of the plateau sterile group increased by 29.1%and 32%,and the CL decreased by 44.7%?P<0.05?;compared with the plain bacteria group,the AUC and C_max of the plain sterile group were decreased by 22.3%and 24.3%?P<0.05?,and the CL increased by 26.4%;compared with the plateau bacteria group,the AUC and C_max of the plateau aseptic group increased by 39.5%and 48.2%,and the CL decreased by 31.4%,and the changes were statistically significant?P<0.05?.3.Compare the pharmacokinetic parameters of metronidazole of the plateau bacteria group,the plateau aseptic group,the plain bacteria group and the plain sterile group.The results are as follows:compared with the plain bacteria group,the AUC and C_maxax of the plateau bacteria group decreased by 31.6%and 44.5%,and the CL and V increased by 45.7%and 44.3%respectively,and all the changes were statistically significant?P<0.05?;compared with the plain sterile group,the AUC and C_max of the plateau sterile group decreased by 50.5%and 42.6%?P<0.01?,the CL and V increased by 202.3%?P<0.01?and 150.5%?P<0.05?respectively;compared with the plain bacteria group,the AUC and C_max of the plain sterile group increased by 71.6%and37.9%,and the CL and V decreased by 61.6%and 41.4%respectively,and the changes of AUC and CL were statistically significant?P<0.05?;compared with the plateau bacteria group,the AUC and C_max of the plateau aseptic group increased by 24.2 and42.5%,and the CL decreased by 20.3%,and all the changes were statistically significant?P<0.05?.4.Metoprolol and metronidazole were incubated anaerobicly with rat fecal suspension for 6 h and 12 h,respectively,and then the remaining drug amount in the incubation system was measured.The results showed that the remaining amount of metoprolol did not decrease with the incubation time,while the remaining amount of metronidazole decreased significantly with the increase of the incubation time.After 12 hours of incubation,the amount of metronidazole in the system was none.Conclusion:Plateau hypoxic environment and intestinal flora can affect the pharmacokinetic process of metoprolol and metronidazole in rats.Rat gut flora can directly metabolize metronidazole,but can not metabolize metoprolol directly.