Evaluation of polyphenols disposition

汉方药物含有多种苷类成分作为主要有效成分，但除强心苷外，大多数苷类成分的药理作用机制尚不清楚。当人类摄入汉方药物时，其成分似乎在人体肠道中代谢，其中居住着200多个物种和数千亿细菌，然后通过肠肝循环吸收。结合水解糖的糖苷通常难以从胃肠道吸收，因此它们保留在肠道中并容易被肠道细菌代谢。因此，口服摄入的糖苷的生物利用度非常低，并且它们似乎没有显示出药理作用。一般而言，糖苷被人肠道植物群水解成相应的糖苷配基。我们已经从人类粪便中分离并鉴定了能够水解诸如芦荟苷、京尼平苷， 关于我们 多酚类化合物广泛分布于植物界，以糖苷形式存在。具有多种药理作用，尤其是抗氧化作用。本研究探讨了丹参主要有效抗氧化剂紫草酸镁B的处理。另一方面，黄芩苷是黄芩的主要活性成分，也是著名的黄酮多酚苷。黄芩苷经口给药时，黄芩苷本身在大鼠肠道吸收较差，但黄芩苷被肠道细菌水解为黄芩苷元，然后黄芩苷元被吸收。被吸收的黄芩素在吸收后重新转化为其原始形式黄芩苷，出现在大鼠血浆中。黄芩苷独特的代谢命运似乎是由于吸收后在大鼠肠道和肝脏中代谢。事实上，使用大鼠空肠袢和外翻囊系统，我们证明了黄芩素，而不是黄芩苷，在吸收过程中迅速吸收，并有效地结合到黄芩苷在大鼠肠道，支持的结果，大鼠肠微粒体具有较高的UDPG-葡萄糖醛酸转移酶活性黄芩素。令人惊讶的是，形成的黄芩苷被排泄到大鼠肠腔。在体内实验中也证实了这一点，并建议黄芩苷通过多药相关蛋白2（MRP 2）排泄，其中MRP 2是遗传缺陷的高胆固醇血症大鼠。最后，利用已建立的研究药物在人小肠吸收和分布的Caco-2细胞单层模型，我们证明了黄芩素在Caco-2细胞中的吸收不是转移到基底侧，而是首先转化为黄芩苷，并通过MRP 2排泄到顶侧，类似于大鼠。这些结果表明，黄芩苷等多酚类物质在人体内的吸收、代谢和排泄等肠道处置过程与其生物利用度有关。少

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