Evaluation of polyphenols disposition

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Kampo medicines contain many kinds of glycosides as main and effective constituents, but the action mechanisms of pharmacological effects of most of glycosides except cardiac glycosides have not been clarified. When humans ingest Kampo medicines, their components seem to be metabolized in the human intestinal tract, in which more than 200 species and hundreds of billions of bacteria inhabit, before absorption and via enterohepatic circulation. Glycosides, which bind hydrolytic sugar(s), are generally difficult to be absorbed from the gastrointestinal tract, so they are retained in the tract and easily metabolized by intestinal bacteria. Thus the bioavailability of orally ingested glycosides is very low, and they seem to show no pharmacological effects. In general, glycosides are hydrolyzed by human intestinal flora to the corresponding aglycones. We have isolated and identified the responsible bacteria, from human feces, capable to hydrolyzing such glycosides as barbaloin, geniposide, … More ginsenoside glycyrrhizin, paeoniflorin, sennosides, and so on.Polyphenols distribute widely in plant kingdom and present in abundant as glycosides. They have many kinds of pharmacological effects, especially potent antioxidant effects. We assessed the disposition of magnesium lithospermate B, a main potent antioxidant of Radix Salviae Miltiorrhizae. On the other hand, Baicalin is a main active constituent from Scutellariae Radix and very famous flavonoid polyphenol glycoside. When baicalin was orally administered, baicalin itself is poorly absorbed from rat gut, but is hydlolized to baicalein, an aglycone of baicalin, by intestinal bacteria and then baicalein is absorbed. The absorbed baicalein is then reconverted to its original form, baicalin, after absorption to appear to rat blood plasma. The unique metabolic fate of baicalin seems to be due to metabolism in rat intestine and liver after absorption. In fact, using rat jejunal loop and everted sac system we demonstrated that baicalein, not baicalin, was rapidly absorbed and efficiently conjugated to baicalin in rat intestine during absorption, supported by the results that rat intestinal microsomes had high UDPG-glucuronosyl transferase activity for baicalein. Surprisingly, the formed baicalin was excreted into rat intestinal lumen. This was also demonstrated in rrt in vivo experiment and baicalin was suggested to be excreted through multidrug-associated protein 2 (MRP2) using Eisai hyperbilirubinemic rat, in which MRP2 is hereditarily defect. Finally, using Caco-2 cell monolayer model, which is well established to study the absorption and disposition of drugs in human intestine, we demonstrated that baicalein absorbed in Caco-2 cells was not transferred into the basolateral side, but first transformed into baicalin and excreted into the apical side through MRP2, similar to rat. These results suggest that intestinal disposition such as absorption, metabolism and excretion is related to the bioavailability of polyphenols such as baicalin in human. Less