Effects Of Intestinal Flora On The Pharmacokinetics And Pharmacodynamics Of Aspirin In High Altitude Hypoxia

The gut flora is the most important and diverse microbial community found in the digestive tract of humans and animals and is considered to the"hidden organ"of the body.The intestinal flora not only maintains the health of the body,but also metabolizes exogenous substances,especially the ability to metabolize drugs comparable to any organ of the body,including the liver.The gut flora is not static but highly variable.The high altitude environment can cause changes in the intestinal flora,and the specific changes are still unclear.Any alteration or dysbiosis of the gut microbiota can directly or indirectly affect microbial-mediated biotransformation of the drug,thereby further affecting the pharmacokinetics and pharmacodynamics of the drug.Pharmacokinetic parameters are an important theoretical basis for rat ional drug use.Based on previous research by our team,it was found that the pharmacokinetic parameters of many drugs will change at high altitude.There are many factors causing changes of pharmacokinetic parameters.Among them,the changes in the expres sion and activity of metabolic enzymes and transporters after acute plateau are quite important.However,there is little research on the changes of pharmacokinetics mediated by intestinal flora under altitude hypoxia.This will provide new ideas for the changes of pharmacokinetics in plateau and better guidance for people who experienced acute hypoxia to use drugs reasonably.Therefore,the research team consulted the relevant literature and selected aspirin,one of the classic drugs absorbed through the gastrointestinal tract,to design the following experiment to investigate the changes of pharmacokinetics and pharmacodynamics of aspirin mediated by intestinal flora in high altitude hypoxia environment.1.Difference in composition of intestine flora between the plain and the plateau group.（1）Fecal smear results showed that compared with the plain group,the gram-positive bacteria and negative bacteria in the acute plateau group decreased.（2）The 16S rRNA analysis results showed that the number of OTU in the intestinal flora of the acute plateau group was significantly reduced compared with the plain group.Compared with the plain group,the number of Bacteroides,Prevotella,Corynebacterium,and Coprococcus have significant changes in the plateau group.The above results confirmed that the composition and number of intestinal flora changed after the rats entered the plateau rapidly.2.Pharmacokinetic characteristics of aspirin in rats after rapid entry into the plateau.After the rat entered the plateau,the pharmacokinetics of salicylic acid was analyzed by liquid chromatography-tandem mass spectrometry.Compared with the plain group,the area under the indicator conce ntration curve（AUC）and the maximum concentration(C_max)of the drug absorption increased significantly,increasing by 82.20%and 61.03%,respectively,and were statistically significant（P<0.01）;The excreted index plasma clearance CL was significantly reduced by 43.55%and was statistically significant（P<0.01）.There were no significant differences in other parameters.Pharmacokinetic results showed that after the rapid entry into the plateau,the pharmacokinetic parameters of salicylic acid changed s ignificantly,absorption increased,and excretion slowed down.3.Correlation between changes in the pharmacokinetics of aspirin and intestinal flora after rapid entry into the plateau.The results of in vitro rat feces suspension on aspirin metabolism and biotransformation showed:（1）The residual a mount of aspirin in the suspension decreased with time,and the metabolic capacity of the plateau fecal suspension to aspirin was significantly lower than that of the plain group.After incubation for 24 h,the levels of aspirin decreased by 95.12%and 86.84%,respectively,and there was a significant difference between the plain group and the plateau group（P<0.05）.It indicates that the plateau environment inhibits the metabolic activities of intestinal microbes and thus reduces the metabolic capacity of aspirin.（2）With the passage of time,the production of salicylic acid increased continuously,and the salicylic acid in the fecal suspension of the plain group was more than that of the plateau group（24h,P<0.05）.The results further indicated that the intestinal bacteria were involved in the metabolism of aspirin and produces its active metabolite salicylic acid,and the plateau environment inhibits the activity of intestinal microbes and weakens the biotransformation of aspirin.Thereafter,in order to study which bacterial affected the pharmacokinetic characteristics of aspirin,we inoculated the rat feces in the culture medium,and cultured the standard strains which shows differences to be incubated with aspirin respectively.The results showed that Prevotella and Coprococcus have a significant role in the metabolic activity of aspirin,and Prevotella and Coprococcus are bacteria that show significant differences in 16S rRNA results.4.Whether the changes in the pharmacokinetics of aspirin after rapid entry into the plateau have pharmacodynamic significance.We used TXB₂ ELISA kit to quantitatively analyze TXB₂ in plasma.The results showed that TXB₂ was significantly decreased in the acute plateau group,indicating that aspirin inhibited the synthesis of platelet TXB₂,which would be more likely to cause bleeding,suggesting that the use of aspirin in the plateau need to be closely monitored.In summary,this topic mainly draws the following conclusions:After the rapid entry into the plateau,the number and composition of the intestinal flora of the rats have changed significantly,which in turn affects the changes in the pharmacokinetics of aspirin mediated by the intestinal flora.Among them,Prevotella and Coprococcus are mainly involved in the metabolism of aspirin,and the use of plain doses tends to aggravate the bleeding tendency,suggesting that we need to reduce the dose of aspirin after we enter the plateau.The study will provide a more complete experimental basis and medication basis for the rational use of aspirin in the rapidly entering plateau population.