Constituents In Glycyrrhizae Radix Et Rhizoma That Affect The Pharmacokinetics Of Coptidis Rhizoma Alkaloids

Aim Coptidis Rhizoma?Huanglian?and Glycyrrhizae Radix et Rhizoma?Gancao?are often used together.Huanglian is bitter and cold,hence can easily injure spleen and stomach if it is taken for a long time.Gancao can relief the bitter and cold property of Huanglian.Gancao has significant effect on the pharmacokinetic properties of Coptidis Rhizoma alkaloids.Gancao contains saponins,flavonoids,polysaccharides,proteins and other constituents,but the effects of the constituents on the pharmacokinetic properties of Coptidis Rhizoma alkaloids are unclear.Therefore,in this paper,the pharmacokinetic effects of various constituents of Gancao on four alkaloids of Coptidis Rhizoma were comparatively studied,in order to determine the main constituents that mediate the pharmacokinetic interactions.Methods The macromolecular and micromolecular components of Gancao were prepared by dialysis;total saponins was prepared by macroporous resin;Each component was decocted and boiled with Huanglian extract;the contents of alkaloids in Huanglian were quantitatively analyzed based on liquid chromatography-tandem mass spectrometry;the effects of Gancao fractions on the solubility and dissolution of the Huanglian alkaloids were determined;the effects of Gancao fractions on the in vitro absorption of Huanglian alkaloids were studied based on in vitro everted gut sacs experiment;the effects of Gancao fractions on the intestinal absorption,tissue distribution and systemic circulation exposure levels of the Huanglian alkaloids were determined in mice.Results Gancao significantly reduced the AUC and C_max of berberine in the systemic circulation,portal vein and liver of mice that received oral Huanglian extract,indicating that Gancao combination can reduce the in vivo exposure level of berberine in mice,and suggesting that the mechanism is mainly related to the reduction of intestinal absorption of berberine.Each tested fractions significantly reduced the solubility of four kinds of Huanglian alkaloids.Among them,the saponin fraction and the polysaccharide fraction decreased 41.1%and 48.6%berberine solubility.In addition,the saponin fraction and the polysaccharide fraction significantly and respectively inhibited about 27.5%and 20.7%the dissolution of berberine in gastric and intestinal fluids.The saponin fraction and the polysaccharide fraction respectively inhibited about 64.1%and 58.9%the in vitro absorption of berberine.The pharmacokinetic experiments in mice showed that the saponin fraction significantly reduced the exposure levels of alkaloids in portal vein,systemic circulation and liver(AUC_{0-2 h})of the Huanglian alkaloids?all except epiberberine in liver p<0.05?.Conclusion The above results showed that the saponin fraction of Gancao could reduce the solubility and dissolution of the alkaloids and thereby reducing their intestinal absorption and reducing the in vivo exposure level of the Huanglian alkaloids,i.e.,the saponin fraction was the main constituents of Gancao that influencing the pharmacokinetics of the four Huanglia alkaloids.