Study On Absorptive Mechanism And Modulation Of Hawthorm Leaves Flavonoids

Oral administration is the popular way of drug application (a mainly used way in drug's clinical application). The ADME of the active ingredients in traditional Chinese medicine (TCM) is the key point for TCM research; furthermore, their absorption mechanism is the first step for ADME research of TCM, which is also the premise for the accomplishment of the therapeutic effects. In order to establish the basic methods for the biopharmaceutical research of TCM and to scientifically illustrate the composition theory of TCM, it is profitable to reveal the absorption mechanism of active ingredients. Besides, the comprehension of the factors that influence absorption, clarification of the roles and effect extent of tranporters as well as the investigation of the interactions of various active ingredients are also important in the process of absorption.Studying the ADME and the interactions of TCM, especially the active ingredients, by means of bipharmaceutics and pharmacokinetics, the project aimed to provide foundation and valuable information for the formulation screening, technique modifying, quality evaluating in addition to rational drug application.Hawthorn Leaves Flavonoids (HLF), the main extract from Hawthorn Leaves has been wildly used for thousands years in China and exhibits extensive therapeutic effects for cardiovascular diseases. Its active ingredients-Glucosylvitexin (GLV), Rhamnosylvitexin (RHV), Vitexin (VIT), Rutin (RUT) and Hyperoside (HP) were chosen as model drugs. The absorption mechanism and modulation methods of HLF were systematically investigated based on the models of in situ perfusion, intestine loop, Caco-2 cell, whole animal and bacterium metabolism in intestinal tract.The results indicated that the five active ingredients (GLV, RHV, VIT, RUT and HP) all could be poorly absorbed by gastrointestinal tract in the form of prototype. Their absorption and metabolism showed the site difference; colon and caecum are the main sites for A&M. Besides, the process of absorption accompanied the phenomenons of metabolism by enterobacteria, bile excretion, entero secretion and enterohepatic circulation. Mediated by the membrane transporters, e. g. sodiumdependent glucose transporter (SGLT1), they could be transported. The five ingredients were P-gp efflux substrate, and their excretion can be inhibited by the P-gp inhibitor, e. g. verapamil and digoxin, so their absorption can be enhanced by absorption enhancer, e. g. SDS and cow bile salts. Bile salts excretion pumps (BSEP) inhibitor (Rifampin) inhibited the bile excretion, which subsequently improved the absorption of ingredients. Quercetin in HLF could increase the absorption of GLV and RHV via the prohibition of P-gp efflux. Thus it is more reasonable to administrate an effective part rather than a single ingredient for HLF application.VIT, the intermediate product of GLV and RHV, was transformed by the enterobacteria but its further metabolism was not clear at present. The active ingredients in HLF exhibited bi-direction transport (co-existence of absorption and excretion) across Caco-2 cell monolayers and efflux extent was in direct proportion with the drug concentration. Different ingredient complied with different transport mechanism, namely with passive transport or carrier-mediated transport. The excretion enhance while the drug concentration are increased and can be inhibited while coadministrated with Verapamil hydrochloride. After intravenous administration of HLF to rats in the doses range of 10-40 mg/kg, the plasma concentration-time curves of GLV and RHV both conformed to open three-compartment pharmacokinetic model and showed the linear pharmacokinetic property. However, after intragastric administration of HLF to rats in the doses range of 0.643～2.570g·kg^-1, the pharmacokinetic properties of GLV and RHV was complicated with both linear and nonlinear characteristics involved and multi-peak phenomenon observed, which might result from the transform among several components, enterohepatic circulation, and multiple sites of absorption of gastrointestinal tract.It is rarely reported to explore the absorption mechanism of active ingredients and their interaction by multi-angle method and multi-biopharmaceutical models. There is little literature about the preparation design of TCM under the guidance of biopharmaceutical principles. This study prepared for the development of HLF pharmaceuticals and provided new approaches for the in vivo research of TCM, which also enriched the content of biopharmaceutics and pharmacokinetics.