Effect Of Yiqi Jianpi Medicine On The Absorption And Metabolism Of Compatible Drugs And Its Mechanism

The Yiqi Jianpi Medicine properties are mostly Gan Wen.The theory of compatibility and attenuation of traditional Chinese medicine believes that Gan can ease and relax,and can limit the toxicity and severe nature of toxic drugs such as aconite and horse money.Modern medical theory believes that the theoretical basis for compatibility and attenuation is that Chinese medicine enters the human body.After metabolism in the body,the medicinal components of the traditional Chinese medicine exist in the form of prototypes or metabolites in the body,and there is a corresponding relationship between their changes and their compatibility.The application of Yiqi Jianpi Medicine in the application of attenuating and synergistic effects and reconciling drugs is not only manifested in the multi-component material basis in vitro interaction and pharmacodynamics / toxicology,but also in the mutual influence on the internal process of drugs.Therefore,it is of great significance to explore the influence of drugs on the biopharmaceutical behavior of compatible drugs.Previous research by this research group has shown that astragalus can reduce its toxicity by inhibiting the intestinal absorption of toxic traditional Chinese medicine active ingredients,so is the compatibility of active ingredient metabolism changes another biopharmaceutical link of its attenuating qi and nourishing spleen medicine?Can Atractylodes have the same effect,therefore,this article will examine the mechanism of Gan-Huan compatibility theory,select Astragalus-Aconite,Atractylodes-Martin,as the model,and use the model drug compatibility group and the absorption,metabolism,pharmacokinetics The study will influence the research,further study the mechanism of compatibility and attenuation,explore the commonness and personality of the application of Yiqi Jianpi medicine,and clarify the scientific connotation of the theory of Chinese medicine compatibility.1.Investigation on the effects of active ingredients of Astragalus membranaceus on the phase Ⅰ enzyme metabolism kinetics of aconite alkaloids.In this section,in vitro incubation technology is used,and six kinds of aconite alkaloids are used as the object of investigation.The substrate elimination method is used to investigate the effects of mucosa isoflavones and astragaloside IV on the enzyme metabolism kinetics of aconite alkaloids in rat and human liver microsomes.The results showed that the metabolic parameters Km,Vmax and Clint of aconite alkaloids in human liver microsomes were 62.51 μM,1.33 μmol /(min · mg protein),and 0.021 min / mg,respectively.Increased,the aconite alkaloid metabolism rate gradually decreased,Vmax,Km and Clint also decreased significantly,indicating that astragaloside 4 and verbas isoflavones can inhibit the metabolism of aconite alkaloids,effectively slow the aconite’s clearance in the liver,while aconite alkaloids can pass Phase Ⅰ metabolism enzyme metabolism can be further carried out on phase Ⅰ metabolism of aconite alkaloids.2.Study on aconite metabolic phenotypeIn order to clarify the mechanism of aconite metabolism,to further understand the biotransformation of drugs in vivo and to predict drug interactions,and to provide theoretical basis for the safe and rational use of aconite in clinical practice,LC-MS technology was used in this test,and liver microsomes were combined with selective chemical inhibition.CYP450 enzyme phenotypes metabolized by aconite 6 alkaloids in human liver microsomes were identified by the incubation method with reagent and c DNA recombinase.Chemical inhibitor test results show that in addition to CYP2D6 inhibitors versus BAC,CYP1A2 inhibitors versus BAC,HA,CYP2C19 inhibitors versus BHA,MA,AC,and CYP2C9 inhibitors against HA,the metabolic conversion of 6 alkaloids is low The rates decreased significantly with the increase of 5 selective inhibitors,with CYP3A4 being the most significant,and the inhibition rate was about30%.In the incubation reaction with CYP450 recombinase,as the reaction timeincreases,all six alkaloids can be eliminated by the recombinases CYP3A4 and CYP2D4.CYP1A2 can catalyze the elimination of three diester alkaloids and BHA.CYP2C19 can eliminate BHA,MA,AC,CYP2C19 can metabolize MA,AC.Comprehensive chemical inhibitor and c DNA recombinase tests showed that all 6aconite alkaloids can be metabolized by CYP3A4.CYP2D6 participates in the metabolism of BHA,BMA,HA,and MA.CYP1A2 participates in the metabolism of AC.CYP2C9 participates in the metabolism of MA and AC.BHA and MA metabolism.3.Metabolic phenotypes of Verbascum and Astragaloside IV and the effects of Verbascum isoflavones on CYP450 enzyme activityIn order to further explore the mechanism of astragalus inhibiting aconite metabolism,this chapter first carried out a metabolic phenotypic study of the active components of astragalus mesoflavone and astragaloside IV,and found that the isoflavones are mainly metabolized by CYP3A4,CYP2D6,and CYP1A2,while the metabolism of astragaloside 1 Several subtype enzymes are involved.Incubation of veraphan isoflavones and probe drugs at different concentrations in rat and human liver microsomes,and the effects of veraphan isoflavones on various enzymes were observed.As a result,the effects of veraphan isoflavones on enzyme activity were significantly different in the two types of liver microsomes,especially It is a CYP3A4 enzyme,which has an induction effect in rat liver microsomes with an induction rate of 20%,but the opposite is true in human liver microsomes.The other four subtype enzymes are inhibited in both rat and human liver microsomes.But the degree of inhibition is different.Verbascum isoflavones have certain inhibitory effects on CYP2C9,CYP2C19,and CYP3A4 enzymes in human liver microsomes,with IC50 values ??of 29.8,87.2,and 40.12 μM,respectively,and IC50 values ??of CYP1A2 and CYP2D6 are greater than 100 μ M,which have weaker inhibitory effects.In the IC50 Shift test,the inhibition of mucosa isoflavone on human liver microsomes was reversible.The results of the type of inhibition showed that it was anti-competitive inhibition on CYP1A2,non-competitive inhibition on CYP2C19,CYP2C9,and competitive CYP2D6 Inhibition,competitive inhibition of CYP3A4,Kivalues of 61.2,85.0,30.0,65.0,and 24.9μM,respectively.In combination with IC50 and Ki values,it can be seen that Verbascum isoflavones are not easy to interact with other drugs and will interact with aconite alkaloids.Competing for CYP3A4 enzyme metabolism.Verbena isoflavone and astragaloside IV phenotypes and the effects of verbas isoflavones on CYP450 enzyme activity.The results show that verbas isoflavones can reduce the metabolism of aconite alkaloids by inhibiting CYP enzyme activity or competing with aconite for CYP3A4 enzyme.Elevation is not conducive to reducing aconite toxicity.4.Effect of Astragalus on Pharmacokinetics of Aconite AlkaloidsAstragalus can inhibit the absorption and metabolism of aconite at the same time,which will have opposite effects on the blood concentration in vivo.Therefore,in this chapter,LC-MS method is used to determine the drug concentration in plasma of rats at different times after a single administration.Aconite 3 kinds of monoester alkaloids(benzoyl hypoconicinogen BHA,benzoyl neoconicinogen BMA,benzoyl aconitinogen BAC)and 3 diester alkaloids(secondary aconite Of alkaloids HA,neoaconitine MA,aconitine AC)in rats.DAS 3.3 was used to calculate the pharmacokinetic parameters of the drug.SPSS 13.0 software was used to analyze the differences in the main pharmacokinetic parameters of Aconite before and after compatibility with Astragalus.Results The AUC(0-t)and AUC(0-∞)of the 6alkaloids were significantly reduced after the compatibility with Astragalus.The CLz/ F of the 5 alkaloids except HA increased;the Cmax of the 3 monoester alkaloids Decreased,Tmax prolonged;the volume of distribution(Vz / F)of BMA and MA increased.Astragalus can inhibit the absorption of aconite alkaloids,induce the distribution of aconite alkaloids to the whole body,and accelerate the elimination of aconite alkaloids in the body.5.Study on the mechanism of Atractylodes macrocephala inhibiting the absorption of pomegranateIn previous studies,Atractylodes can inhibit the absorption of stroma,and the transport mode of strachine and shining in stroma is mainly based on passive transport.In this chapter,Caco-2 cell Transwell transmembrane transport model was first usedto study the absorption mechanism of active ingredients of pomegranate,and the results showed that the addition of LPS and EDTA-2Na,two tightly connected openers and P-gp inhibitors,resulted in Both Papp increased significantly,indicating that the absorption mechanism of BRU and STR in pomegranate can be absorbed and transported through the paracellular pathway,and the facilitated diffusion process of passive transport is mainly mediated by P-glycoprotein.Next,the effect of Atractylodes macrocephala water extract on protein expression of efflux transporters(P-gp,Mrp2,Bcrp)and tight junction proteins(Claudin-1,Occludin,ZO-1)in Caco2 cells was investigated by Western blot.WB The results showed that the expression of 6 kinds of absorption-related proteins of Atractylodes were all up-regulated,except that the low-dose Atractylodes had no significant difference in the expression of Mrp2 and Claudin-1,the other groups had significant differences.From this we can infer that Atractylodes can enhance the absorption barrier function by regulating the expression of efflux transporters and tight junction proteins,and prevent p-gp-mediated facilitation diffusion and transmembrane transport of paracellular pathways,Which affects the blood concentration and efficacy of pomegranate.In this subject,the mechanism of attenuating qi and nourishing spleen to toxic drugs was studied from the perspectives of absorption,metabolism,and pharmacokinetics in vivo.The principle of astragalus-aconite,atractylodes-mazhuzi compatibility was further clarified.The commonness and individuality of the drug compatibility application provided ideas for the development of new preparations of Yiqi Jianpi medicine.