| In this thesis, we choose the classic side, huang-lian-jie-du-tang as the object, main components(geniposide, berberine, baicalin) as the indicator to study the intestinal absorption mechanism of multi-component in Chinese herbal compound.Objectives:inspect the intestinal absorption characteristics of main index components(geniposide, berberine, baicalin) in huang-lian-jie-du-tang, reveal its principles and law of compatibility; study the effects of compound simulation system and compound system on the intestinal absorption links of its main index components to determine the nature of its biological pharmacy and clarify the drug interactions; combine the physicochemical properties of main components in compound and pharmacokinetic characteristics to explore the correlation of physicochemical properties, pharmacokinetics and intestinal absorption and the synergistic mechanism of compound compatibility.Contents:1) study the physicochemical properties of main index components in huang-lian-jie-du-tang.2) study the intestinal absorption characteristics of main index components in huang-lian-jie-du-tang and factors of affecting the absorption(concentration, transporter protein, absorption enhancers, etc).3) study the interaction of intestinal absorption of main index components in huang-lian-jie-du-tang.4) research the effects of huang-lian-jie-du-tang simulation system and compound system on the intestinal absorption of its main index components.5) research the correlation of physicochemical properties, permeability coefficient and pharmacokinetics parameters.Methods:According to the optimization process, this thesis prepared the extract powder of huang-lian-jie-du-tang and determine the content of main index components(geniposide, berberine, baicalin). Huang-lian-jie-du-tang simulation system was prepared based on the ratio of these three components methoded above. First, we preliminary study the physicochemical properties of there monomers, and then research the intestinal absorption characteristics of the monomers, main index components in huang-lian-jie-du-tang simulation system and compound system by in situ single pass intestinal perfusion model and Caco-2cell model. Finally, pharmacokinetics characteristics of studies was combined to explore the differences of administration in monomer and compound environment.Results:the studies of the apparent solubility and apparent oil-water partition coefficient have shown that the physicochemical properties of geniposide is stable, solubility is common, but permeability is poor. Papp is0.094(1gPapp=-1.03), and geniposide is stable under neutral conditions. The solubility and permeability of berberine are poor, Papp is0.874(1gPapp=-0.06) the apparent solubility and Papp will increase under alkaline conditions, so increasing the pH values of berberine absorption environment may improve its oral bioavailability. Baicalin(weak acid) is similar to geniposide, Papp is0.48(1gPapp=-0.32), the apparent solubility is higher under alkaline conditions, but Papp is lower. The studies of in situ single pass intestinal perfusion model have shown that geniposide has better absorption in duodenum and the broad absorption window. Geniposide is mainly the passive diffusion, and may also include anctive transport or facilitated diffusion. It may not be effected by P-gp, Na+dependent glucose transporter(SGLT1) and MRP2, but may be effected by EDTA. Berberine has better absorption in colon and it is mainly the passive diffusion. It may not be effected by MRP2and EDTA, but may be effected by P-gp and SGLT1. Baicalin has poorer absorption in each segment, it is mainly the passive diffusion and has no specific absorption site. It may not be effected by Na+dependent glucose transporter(SGLT1), but may be the substrate of MRP2. The absorption of the above three components in small intestine can be improved by the absorption enhancers in certain concentration(0.5%sodium dodecyl sulfate and tween80). Berberine and baicalin may effect the intestinal absorption of geniposide. Comparing to the geniposide monomer, it can promote mutual absorption in a certain ratio(the ratio of berberine and geniposide is about2:1, the ratio of baicalin and geniposide is about1.5:1). Caco-2cell model have shown that geniposide is mainly the passive diffusion, may also include cell bypass transporter, but may not be regulated by the efflux transport protein p-gp. Berberine is mainly the passive diffusion, may not be effected by EDTA, but may be effected by P-gp. Two models both show that the absorption of main index components in huang-lian-jie-du-tang simulation system(monomer mixture of main index components:berberine+baicalin+geniposide) and compound system are significantly increased compared with the monomer in same concentration, whitch may be because of the synergistic mechanism of the above three components, other components and associated substances in compound.Conclusions:the intestinal absorption characteristics of main index components in compound and compound context were studied by two types of biological pharmacy models in this study. Combine the physicochemical properties of main index components and pharmacokinetics characteristics of monomer, compound environment to study the correlation of physicochemical properties, intestinal absorption and pharmacokinetics characteristics, whitch may lay theoretical foundation for clarifying compatibility law of traditional Chinese medicine complex system to further provide reference to design preparations of its compound and compound preparation contained the main components. The experiment concluded that two models have good qualitatively correlation, and Caco-2cell model has good reproducibility, high reliability. In situ single pass intestinal perfusion model can keep the original physical structure of the body and can be used to screen the absorption site of drug to design new formulations of traditional Chinese medicine preparations. |
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