Exploring The Pharmacodynamic Material Basis Of Guizhi Decoction Based On The Digestion And Absorption Process In Vivo

Objective: Guizhi Decoction(GZD)is a classical prescription from Treatise on Febrile Diseases,a famous ancient Chinese book of traditional Chinese medicines(TCMs).It is composed of five herbal slices,including Cinnamomi Ramulus,Paeoniae Radix Alba,Rhizoma Zingiberis Recens,Fructus Jujubae,and Radix Glycyrrhizae.GZD is usually used to expel pathogenic factors from muscles and to relieve exterior syndromes by sweating as well as harmonizing yingfen and weifen in the field of TCM.The pharmacodynamic material basis of TCM after oral administration is derived from blood components.Therefore,this study explored the pharmacodynamic material basis of GZD through the process of digestion and absorption in vivo.Methods: 1 HPLC-MS/MS was used to establish the determination methods of GZD,serum samples after rats were given GZD,and main components of GZD in intestinal contents of rats.2 To explore the pharmacokinetic characteristics and oral absolute bioavailability(Fabs)of the main components in rats after oral administration and intravenous administration of GZD.Compare differences in the digestion,absorption,and metabolism processes of prototype components and metabolites in vivo.3 A non-inverted model of rat isolated intestinal that simulate the gastrointestinal function to discuss the absorption and transformation of GZD in different parts of the gastrointestinal tract.4 After induction of fever in rats by yeast,the anal temperature was measured after oral administration of GZD,and the pharmacodynamic effects of different doses of GZD were investigated.5 GZD is divided into prototype components and blood components.Based on the network pharmacology method,the components and disease targets are predictedrespectively,and the component-target-disease network is established to obtain the component-related disease targets.Using IPA software to enrich and analyze the pathogenesis of disease-related targets,and screen the core ingredients and targets of GZD in the treatment of the above two diseases,so as to explore the pharmacodynamic basis of GZD and the mechanism of the same disease.Results: 1 The established HPLC-MS/MS method was used to simultaneously determine the 14 components(including 5 metabolites)in the serum of rats after administration of GZD,and the determination method of 12 components in the contents of rat gastrointestinal tract.The above method has high specificity and good sensitivity.2 The AUC0-∞ and Cmax of different components increased obviously as the dose increased,showing obvious first-order pharmacokinetic characteristics.The results indicated that the liposoluble components of GZD,such as cinnamic acid and 6-gingerol,were absorbed directly by the body in the form of prototypes,while most of the glycosides,such as liquiritin and glycyrrhizic acid,that have high watersolubility were mainly existed in the form of metabolites and had a high blood concentration and bioavailability.The blood concentration of the prototype component in the blood after intravenous administration of Guizhi Decoction in rats was significantly higher than that of metabolites.After the oral administration of GZD,most of the prototype components are affected by the intestinal flora and enzymes,so that they are mainly absorbed and utilized in the form of metabolites in the body.3 The results of in vitro intestinal non-inversion model showed that the main components of GZD had better absorption rate and penetration rate in the upper part of the small intestine(duodenum)and colon,suggesting that it may be the main absorption site of GZD.The conversion rate of each component in the cecum is high,suggesting that it may be the main site of drug metabolism.4 The pharmacodynamic evaluation results showed that the body temperature of the rats continued to increase after the injection of yeast,and the temperature of the rats in the GZD group increased with the increase of the dose.High and medium doses group have significant antipyretic effects,P<0.05.5 According to the results of network pharmacology research,there are 10 components related to fever disease in GZD,which are derived from the blood components of five herbs(mostly metabolites),and 17 components related to gastrointestinal inflammatory diseases.All derived from the prototype componentsof Zingiberis Rhizoma Recens.It is suggested that the prototype ingredients in GZD and the metabolic components in the body play different pharmacodynamic effects.The results of the pathway indicate that the prototype components and blood components of GZD are different disease-related targets acting on the same pathway to achieve the same effect.Conclusion: After oral administration of Chinese medicine,it is a key step for the drug to exert its pharmacodynamic effect.Therefore,the “real” medicinal component of traditional Chinese medicine(TCM)should be present in the components absorbed into the blood,including the prototype components and metabolites.Oral pharmaceutical ingredients are affected by the intestinal flora and related enzymes,causing changes in the form of substances that enter the body,and are often absorbed and utilized by the body in the form of metabolites,suggesting that this process may affect the pharmacodynamic effects of GZD.Therefore,studying the biological processes of drug prototypes and metabolites in the body helps to find the pharmacodynamic basis of TCM.