| Objective:since the biopharmaceutics classification system(biopharmaceutics classification system)is put forward,biopharmaceutics classification system has been widely used,applied in early screening,formulation design,generic bioequivalence evaluation,clinical stage of each link and in the process of important research,etc.on the concept of chemical biopharmaceutics classification system,this research proposed the scientific framework of Chinese medicine biopharmaceutics classification system,the purpose is to apply it in traditional Chinese medicine,better services for traditional Chinese medicine.Water solubility and intestinal permeability is the significance two indicators of biopharmaceutics classification system research.Intestinal permeability is one of the important indicators,however,drugs through the intestinal membrane is a diversified and dynamic process.for example,the intestinal bacteria and enzymes and transporter effects on drug transport.The ways of transport include passive and active transport of drugs and other transport ways.For the active transport of substances,efflux pump that can rely on released energy of ATP decomposition,will reversely pump substrate out of cells,reduce the concentration of the substrate in the cell.Such as P-glycoprotein,multi-drug resistance related proteins,breast cancer resistance protein.The P-glycoprotein efflux protein is the most studied.Licorice is referred to as the old medicinal materials of China,not only is traditional Chinese medicine that is most commonly used,also has high activity,the efficacy of traditional Chinese medicine.therefore,in this article we choice glycyrrhizic acid that is the metabolites of of glycyrrhetinic acid of major high content component in Licorice as the research object,research under the multicomponent environment the effect of P-glycoprotein on permeability of glycyrrhetinic acid and the influence of glycyrrhetinic acid on P-glycoprotein.absorb parameter the coefficient of permeability of effective Peff,absorption rate constant Ka,absorption fraction Fa as indexes,and to detection the permeability of glycyrrhetinic acid under the different components compatibility,and join P-gp inhibitors,compare the difference between results,the first,draw the influence of components compatibility,the second,whether the glycyrrhetinic acid is the substrates of P-gp,the third,whether the effect of compatibility on glycyrrhetinic acid by influencing the function of P-gp.In this paper,through the changes of the permeability of biopharmaceutics classification system in environment,put more glycyrrhetinic acid composition analysis of the factors affecting the permeability of glycyrrhetinic acid,glycyrrhetinic acid and provide basis for the pooling of other drugs,but also the biopharmaceutics classification system for traditional Chinese medicine research accumulated data,provides methods for classifying drugs correctly.Methods:to establish analysis methods for determination of digoxin and phenol red content.adopt positive medicine of phenol red fluorescein and metoprolol in the FDA to verify in situ single pass intestine perfusion model to ensure that study the feasibility of the model;Establish a analysis method for the determination of glycyrrhetinic acid content;in the form of a single component to two components and then to the multicomponent to research compatibility effect on the permeability of glycyrrhetinic acid;To join the P-gpinhibitor verapamil,determine whether glycyrrhetinic acid is the P-glycoprotein substrate.Digoxin as the substrate of P-gp,to study whether the effect of composition on glycyrrhetinic acid is by P-gp to work,With digoxin as the research object,administer glycyrrhetinic acid and view the role of glycyrrhetinic acid on P-gp.Results:1.Validation of in situ single pass intestine perfusion model.effective permeability coefficient Peff of phenol red is(1.09 ±0.62)×10-6cm/s,the experiment result shows that phenol red is low permeability drugs,consistent with the literature.effective permeability of Peff of fluorescein was(0.21±0.14)×10-6 cm/s,the effective permeability coefficient of metoprolol was(5.09±1?21)×10-5cm/s,from the experiment result shows that permeability of fluorescein is close to zero,metoprolol is high permeable,the result is consistent with the literature[3]·Give P-gp substrate digoxin,before and after adding inhibitor verapamil compare changes of effective permeability digoxin,the experimental results showed that after adding inhibitor verapamil,the coefficient permeability of digoxin by(1.07±0.59)×10±1.0-5 cm/s rise to(3.28±1.0)×11-5 cm/s,with the increase of concentration of inhibitors,the effective permeability of digoxin permeability coefficient increases.The experimental results show that the intestinal epithelial cells remained intact and connectcompact,complete P-gp expression,model is feasible.2.Components compatibility effect on permeability of glycyrrhetinic acid.(1)through the single factor investigation combined with full factorial design of experiment,the results of the study showed that baicalin had evident effect on the permeability of glycyrrhetinic acid,make the effective permeability of glycyrrhetinic acid from(4.05±0.78)×10-5 cm/s descend to(2.18±0.63)×10-5 cm/s,reduce the penetration of glycyrrhetinic acid.The puerarin consociation sibeline,berberine had no obvious effect on permeability of glycyrrhetinic acid.Glycyrrhetinic acid and compatibility of puerarin,berberine,the permeability coefficient did not change,glycyrrhetinic acid,puerarin,baicalin and compatibility did not change,the coefficient of permeability of glycyrrhetinic acid and baicalin,berberine,compatibility,lower permeability,by(4.05±0.78)×10-1cm/s descend to(1.35±0.69)×10-5 cm/s,(2)by giving high-concentration(including 100 mol/L)P-gp inhibitor verapamil,found that the effective permeability coefficient of glycyrrhetinic acid peff by(4.05± 0.78)×10-5 cm/s descend to(5.82±0.70)×10-5cm/s,t test,the experimental results have significant difference,that glycyrrhetinic acid affected by P-gp inhibitor verapamil,illustrate glycyrrhetinic acid is the potential substrates of P-gp.(3)with digoxin as substrates for mass concentration of baicalin including 20?g/ml,100?g/ml,the results showed that with the increase of concentration of baicalin,then the coefficient permeability of digoxin decreases gradually and the coefficient of permeability of digoxin by(6.07± 2.94)×10-5 cm/s to(4.81±0.56)×10-5 cm/s descend to(2.68±0.52)×10-5 cm/s,the results suggest that baicalin is inducer of P-gp.This result is consistent with the literature[4].3.The effection of Glycyrrhetinic acid on P-gp.Added different concentrations(20,50,100?g/ml)of glycyrrhetinic acid to digoxin,the effective permeability peff of digoxin were 7.99±1.79 ×10-5 cm/s,(17.4±1.72)×10-5 cm/s and(3.65± 0.06)×10-5 cm/s,the experimental results show that glycyrrhetinic acid inhibit P-gp in low concentration,effection of high concentration is not obvious.Conclusion:glycyrrhetinic acid is the substrates of P-gp,and glycyrrhetinic acid inhibit P-gp at low concentration,the effection is not obvious in high concentration.Baicalin can induce the expression of P-gp,reduce the permeability of glycyrrhetinic acid,that baicalin is inducers of P-gp;Glycyrrhetinic acid with high permeability.In this paper,features of research and innovation points:1.The selection of in vivo model and chioce standard drugs to verify this model,to ensure that the model is feasible,and research the intestinal permeability of drug,improve the precision of the results;2.Considering the characteristics of Multicomponent of Chinese medicine,research the asorption of glycyrrhetinic acid in other high content components compatibility,study the effect of other components on glycyrrhetinic acid absorption;... |
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