Ginsenoside Rb1 from Panax ginseng root is transformed into compound K via ginsenosides Rd and F2 by intestinal bacterial flora. Among 31 defined intestinal strains from man, only Eubacterium sp. A-44 transformed ginsenoside Rb1 into compound K via ginsenoside Rd. The ginsenoside Rb1-hydrolysing enzyme isolated from Eubacterium sp. A-44 was identical to a previously purified geniposide-hydrolysing beta-D-glucosidase. When ginsenoside Rb1 (200 mg kg-1) was administered orally to germ-free rats, neither compound K nor any other metabolite was detected in the plasma, intestinal tract or cumulative faeces 7 or 15 h after administration. Most of the ginsenoside Rb1 administered was recovered from the intestinal tract, especially the caeca, and cumulative faeces indicating poor absorption of ginsenoside Rb1. When ginsenoside Rb1 was administered orally to gnotobiote rats mono-associated with Eubacterium sp. A-44, a significant amount of compound K was detected in the plasma and considerable amounts were found in the caecal contents and cumulative faeces 7 and 15 h after administration. A small amount of ginsenoside Rb1 was detected in the caecal contents only 7 h after administration. These results indicate that orally administered ginsenoside Rb1 is poorly absorbed from the gut but that its metabolite compound K, produced by ginsenoside Rb1-hydrolysing bacteria such as Eubacterium sp. A-44 in the lower part of intestine, is absorbed.

When baicalin was orally administered to conventional rats, it was detected in their plasma for 24 h after administration, but baicalein, the aglycone of baicalin, was not detected. However, when baicalin was given to germ-free rats, only a small amount of baicalin was detected in their plasma within 2 h after the administration, its AUC0-lim (the area under the concentration-time curve from 0 to last determination time) being 12.0% of that in conventional rats. Subsequently, a considerable amount (55.1 +/- 6.2%) of baicalin was recovered from the gastrointestinal tract even 4 h after administration. When baicalein was orally administered to conventional rats, however, baicalin appeared rapidly in their plasma at an AUC0-lim value similar to that obtained after oral administration of baicalin, despite the absence of baicalein in plasma. When intestinal absorption was evaluated by the rat jejunal loop method, baicalein was absorbed readily, but only traces of baicalin were absorbed. Moreover, in conventional rats a small amount (13.4 +/- 3.1%) of baicalin and an appreciable amount (21.9 +/- 3.4%) of baicalein were recovered from the gastrointestinal tract even 4 h after oral administration of baicalin, but only a small amount (3.93 +/- 1.43%) of baicalein was detected in the intestinal tract 1 h after administration of baicalein. Baicalin was transformed to baicalein readily by the rat gastric and caecal contents. When baicalin was administered orally to conventional rats, an appreciable amount of baicalein was recovered in their gastrointestinal tracts. Moreover, baicalein was efficiently conjugated to baicalin in rat intestinal and hepatic microsomes. These results indicate that baicalin itself is poorly absorbed from the rat gut, but is hydrolysed to baicalein by intestinal bacteria and then restored to its original form from the absorbed baicalein in the body.

Enzyme immunoassay (EIA) for the determination of compound K (C-K), a major metabolite of ginsenoside Rb1 (G-Rb1) from Panax ginseng root by intestinal bacterial flora, was explored. Bovine serum albumin (BSA) was coupled to the C-26 position on the unsaturated side chain of C-K. Beta-D-galactosidase was introduced at the C-26 position of the saturated side chain. Antiserum, obtained by immunization of rabbits with C-K-BSA conjugate, possessed high affinity and specificity toward C-K. The EIA for C-K by the double antibody method was established in the range of 0.1--100 ng/tube. Plasma C-K after the oral administration of C-K and G-Rb1 to rats was determined by the established EIA. C-K was rapidly absorbed from the gastrointestinal tract after the administration, then slowly decreased. On the other hand, C-K appeared late and was retained for a long period of time in the plasma after the administration of G-Rb1, which itself is hardly absorbed.

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To clarify the metabolic fate of glycyrrhizin when orally ingested, we investigated the bioavailability of glycyrrhetic acid, the aglycone of glycyrrhizin, after intravenous or oral administration of glycyrrhetic acid (5.7 mg kg-1, equimolar to glycyrrhizin) or glycyrrhizin (10 mg kg-1) at a therapeutic dose in rat. Plasma concentration of glycyrrhetic acid rapidly decreased after its intravenous administration, with AUC of 9200 +/- 1050 ng h mL-1 and MRT of 1.1 +/- 0.2 h. The AUC and MRT values after oral administration were 10600 +/- 1090 ng h mL-1 and 9.3 +/- 0.6 h, respectively. After oral administration of glycyrrhizin, the parent compound was not detectable in plasma at any time, but glycyrrhetic acid was detected at a considerable concentration with AUC of 11700 +/- 1580 ng h mL-1 and MRT of 19.9 +/- 1.3 h, while glycyrrhetic acid was not detected in plasma of germ-free rats at 12 h after oral administration of glycyrrhizin. The AUC value of glycyrrhetic acid after oral administration of glycyrrhizin was comparable with those after intravenous and oral administration of glycyrrhetic acid, indicating a complete biotransformation of glycyrrhizin to glycyrrhetic acid by intestinal bacteria and a complete absorption of the resulting glycyrrhetic acid from intestine. Plasma glycyrrhizin rapidly decreased and disappeared in 2 h after intravenous administration. AUC and MRT values were 2410 +/- 125 micrograms min mL-1 and 29.8 +/- 0.5 min, respectively. Plasma concentration of glycyrrhetic acid showed two peaks a small peak at 30 min and a large peak at 11.4 h, after intravenous administration of glycyrrhizin, with an AUC of 15400 +/- 2620 ng h L-1 and an MRT of 18.8 +/- 1.0 h. The plasma concentration profile of the latter large peak was similar to that of glycyrrhetic acid after oral administration of glycyrrhizin, which slowly appeared and declined. The difference of MRT values (19.9 and 9.3 h) for plasma glycyrrhetic acid after oral administration of glycyrrhizin and glycyrrhetic acid suggests the slow conversion of glycyrrhizin into glycyrrhetic acid in the intestine.

Popular natural glycosides such as glycyrrhizin (GL, licorice), barbaloin (aloe) and baicalin (BG, Scutellaria baicalensis) were studied regarding their metabolic fates and actions in relation to intestinal bacteia by using germ-free and gnotobiote rats. When GL was administered orally, the aglycone, glycyrrhetic acid (GA), was not detected in the plasma or intestinal contents of germ-free rats, but was detected in considerable amounts in the plasma and intestinal contents of conventional and gnotobiote rats, associated with the human intestinal bacterium Eubacterium sp. strain GLH capable of hydrolyzing GL to GA. GL was not detected in the plasma of the three groups of rats after oral administration. GL was effective in the conventional and gnotobiote rats with liver injury caused experimentally by carbon tetrachloride, but not in germfree rats with liver injury. These results indicate that orally administered GL is a prodrug and activated to GA by intestinal bacteria. Barbaloin, a laxative, was ineffective in conventional rats, but showed strong purgative action to gnotobiote rats associated with the human intestinal bacterium Eubacterium sp. strain BAR, which is capable of transforming barbaloin to aloe-emodin anthrone. Barbaloin is also a prodrug and activated to aloe-emodin anthrone by human intestinal bacteria. Animal differences in the laxative effect of barbaloin are due to species differences in intestinal bacteria. When BG was administered orally to conventional rats, BG, but not the aglycone baicalein (B), was found in the plasma. However, when BG was administered to germ-free rats, both BG and B were hardly detected in the plasma. Even after oral administration of B, BG was detected, but not B. These findings suggest that BG is a prodrug hydrolyzed to B by intestinal bacteria, and then conjugated to BG from the absorbed B in the body.

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