Ginsenosides are large molecules which are apparently hydrolysed in the acid medium of the stomach, rapidly absorbed into the blood stream and excreted shortly afterwards yet their effects linger for a long period. Unravelling this problem has proved difficult as suitable sensitive radioimmunoassay methods are only slowly being developed. Nevertheless data is steadily accumulating.
Administering radioactively labelled ginseng saponins to rats orally, Joo et al. (1982) observed that total recovery of the radioactivity was only about 30 per cent and they concluded that the saponins had bound with macromolecular and membrane structures in forms which were not readily extractable. The saponins were widely distributed in the body tissues and especially in liver, kidney, blood serum, stomach and gastrointestinal tract.
Early study of the pharmacokinetics of ginseng saponins revealed that little of the important protopanaxadiol-derived compound ginsenoside Rb1 is absorbed from the upper digestive tract after oral administration (100 mg/kg) in rats. Intravenous injection (5 mg/kg) in rats resulted in the serum level declining slowly and biexponentially with a half-life in the ¿¡-phase of about 14j hours. Ginsenoside Rb1 persists for a long time in the serum and tissues, persistence being due to the high activity of plasma protein binding, but eventually it is slowly excreted in significant amounts into the urine, although not apparently into the bile. The unabsorbed ginsenoside Rb was rapidly decomposed in the digestive tract and/or metabolised chiefly in the large intestine (Odani et al., 1983a).
The other important saponin, ginsenoside Rg1, derived from protopanaxatriol, was absorbed rapidly from the upper parts of the digestive tract (up to one fifth of the dose taken orally) and the serum level of ginsenoside Rg1 attained a peak in 30 min and tissue maximum levels were reached in about 1.5 h. Ginsenoside Rg1 was not apparent in the brain tissues of the rat and was not significantly metabolised in the liver. The decomposition and/or metabolism occurred mainly in the rat stomach and large intestine and excretion of ginsenoside Rg1 was via rat urine and bile in the ratio 2:5 (Odani et al., 1983b). Employing 3H-labelled ginsenoside Rg1 and single intravenous or oral doses in mice, Huo et al. (1986) reported that the descending order of tissue distribution was kidneys, adrenal gland, liver, lung, spleen, pancreas, heart, testes and brain. After oral ingestion, the absorption of ginsenoside Rg1 was 49 per cent and in vitro the drug protein binding in the plasma, liver, testes and brain was 24, 48, 22 and 8 per cent respectively. About 17.5 per cent only of orally-administered ginsenoside Rg1 remained unchanged, the rest being metabolised. Strömbon and Sandberg (1985), also using mice, reported that about 30 per cent of orally administered tritium-labelled ginsenoside Rg1 was absorbed within one hour and confirmed the distribution in body organs, adding that the concentration in muscle and endocrine organs was very low and that intact ginsenoside Rg1 was excreted in small amounts in mouse urine and faeces but the concentration of accompanying metabolites was high.
Experimenting with the ginsenosides Rb1, Re and Rg1 given orally to mice, Han and his colleagues (1986) observed that the gastrointestinal uptake of ginsenosides varied from about 10-50 per cent; administration of higher doses than normal resulted in lower absorption uptake. The major component excreted in the urine was intact ginsenoside but in 26 hours only 1-2 per cent of the ingested dose was excreted. At the subcellular level tritium-labelled protopanaxadiol-derived ginsenoside Rb1 was not detected in the mitochondrial (or cell powerhouse) fraction but was demonstrated to possess strong binding affinity with high molecular weight membrane fractions of organ homogenates and with serum proteins. However, the protopanaxatriol-derived ginsenosides Re and Rg1 showed very weak binding to such fractions.
Although little is known of the pharmacokinetics of other ginsenosides, Sawchuck et al. (1980) suggested that the protopanaxadiol-derived ginsenosides such as ginsenosides Rb2 and Rd possessed plasma protein binding of >99 per cent and long elimination half lives on intravenous injection (ca. 445 min) while the protopanaxatriol-derived ginsenosides such as ginsenosides Re and Rg1 demonstrated lower protein binding (45.5 per cent and 33.2 per cent respectively) and much shorter elimination half lives (49.8 and 82.6 min respectively).
The mechanism of degradation of the protopanaxatriol-derived ginsenoside Rg2 was investigated by Chen (1987), who reported that on incubation with rat gastric juice at 37° C three metabolites were formed, 25-hydroxy-20(S/)-ginsenoside Rg2, 20^-ginsenoside Rg2 and 25-hydroxy-20(R)-ginsenoside Rg2. Further breakdown occurred when these compounds were incubated in rat intestinal fluid. In a series of papers the Japanese group of Karikura et al. (1991) carefully studied the degradation, distribution and metabolites of ginsenosides both in vivo and in vitro using chromatographic methods, 1H- and 13C-nuclear magnetic resonance spectroscopy and fast atom bombardment mass spectrometry. Orally administered ginsenosides were rapidly partially hydrolysed in the gastric acid medium and then underwent further hydrolysis in the intestinal tract and colon. In addition hydroperoxidation of ginsenosides Rb was detected in the rat stomach, the major hydroperoxide being the 25-hydroperoxy-23-ene derivative of ginsenoside Rb1. Significantly the pattern of hydrolysis of the 20(S)-protopanaxatriol-derived ginsenoside Rg1 in the rat stomach was different from that of the 20(S)-protopanaxadiol-derived ginsenosides Rb1 and Rb2 in the rat colon. Hydrolytic degradation differs for the various ginsenosides and is dependent on the protopanaxadiol or protopanaxatriol nucleus and also on the side-chain substituent sugars at C-3 and especially at C-20, the possible sugars being glucose, arabinose, rhamnose and xylose. Chromatographic analysis of rat large intestine contents revealed the presence of the hydrolytic and oxidative products gypenoside XVII, ginsenoside Rd, ginsenoside F2, compound K (20-0-[^-D-gluco-pyranosyl]-20(S)-protopanaxadiol) and 25-hydroperoxy-23-ene-ginsenoside Rb1. In in vitro experiments using the crude enzyme hesperidinase ginsenoside Rb1 degraded to gypenoside XVII, ginsenoside F2 and compound K, and ginsenoside Rb2 yielded 3-0-^-D-glucopyranosyl-20-[a-L-arabino-pyranosyl(1^6)-^-D-glucopyranosyl]-20(S)-protopanaxadiol, ginsenoside F2 and compound K; thus hydrolysis by the ^-glucosidase present in the rat intestine was different from that with crude hesperidinase. It was also noted that tetracycline-resistant bacteria decomposed ginsenosides Rb1 and Rb2 to their respective prosapogenins but not ginsenoside Rd and the respective hydroperoxides. Ginsenoside Rd and the hydroperoxides of ginsenosides Rb1 and Rb2 were produced by the action of enteric enzymes.
To further clarify the degradation pattern, the important ginsenosides Rb1 and Rg1 were cultured anaerobically with fresh human faeces and it was confirmed that they were metabolised by successive hydrolyses, ginsenoside Rb1 rapidly within 8 hours and ginsenoside Rg1 slowly within 48 hours. The proposed pathways by successive removal of glucose units were ginsenoside Rb^ginsenoside Rd^ ginsenoside F2^compound K^20(S)-protopanaxadiol and ginsenoside Rg1^ ginsenoside Rh1^20(S)-protopanaxatriol (Kanoaka et al., 1994).
Hasegawa et al., 1996) administered P. ginseng extract orally to human subjects and to specific pathogen-free rats. The main metabolites of the panaxadiol ginsenosides Rb1, Rb2 and Rc and the panaxatriol ginsenosides Re and Rg1, identified after anaerobic incubation with faecal flora, were 20-0-^-D-glucopyranosyl-20(S)-protopanaxadiol (I), 20-0-[a-L-arabinopyranosyl(1^6)-^-glucopyranosyl]-20(S)-protopanaxadiol (II), 20-0-[a-L-arabinofuranosyl(1^6)-^-glucopyranosyl]-20(S)-protopanaxadiol (III) and 20(S)-protopanaxatriol. The hydrolytic degradation rate and mode would be affected by the fermentation media. Significantly these 4 main metabolites and 20(S)-protopanaxatriol were found in the urine (2.2-96 ^g/ml) and blood (0.3-5.1 ^g/ml) of human subjects and also in the urine and blood of rats.
Further work by Hasegawa et al. (1997) shewed that Prevotella oris bacterial strains in humans possessed the potential to convert ginsenosides Rb1 and Rd to metabolite (I), ginsenoside Rb2 to metabolite (II) and ginsenoside Rc to metabolite (III). The protopanaxatriol-derived ginsenosides Re and Rg1 were unaffected. In the trial 79 per cent of 58 human subjects aged between 1 and 64 years yielded faecal specimens capable of such conversions and it was considered reasonable to involve intestinal P. oris in the conversion of protopanaxadiol saponins to metabolites (I-III). It was also speculated that metabolites (I-III) were the most likely forms in which such saponins were absorbed from the intestines because only the final metabolite (I) was detected in the blood stream at 1.0-7.3 ^g/ml after oral administration of ginsenoside Rb1 (125 mg/kg) in mice, no intact ginsenoside Rb1 or intermediate derivatives being present. The ginseng metabolites (I), 20-O-[a-D-arabinopyranosyl(l^6)-^-D-gluco-pyranosyl]-20fSj-protopanaxadiol (IV) and 20-O-[a-D-arabinofuranosyl(1^6)-^-D-glucopyranosyl]-20(^Sj-protopanaxadiol (V), produced by human intestinal bacteria, have been tested in vitro for antigenotoxicity versus benzo[a]pyrene-induced mutagenicity in Salmonella typhimurium TA98 and TA100 and clastogenicity in Chinese hamster lung fibroblast cells (Lee et al., 1998). The mutagenicity of benzo[a]pyrene was inhibited by metabolites I, IV and V in a dose-dependent manner and metabolites I and V reduced the frequency of benzopyrene-induced chromosome aberrations. Some such metabolites of the ginseng saponins have been patented as immunopotentiators with inhibitory actions on the vascularisation of tumours and the extravasation of cancer cells (see Chapter 9).
The progress of pharmacokinetic studies on the many constituent chemicals in ginseng is still hampered by lack of reliable, sensitive radioimmunoassay techniques. Although little published work based on human subjects is apparently available, reports concerning rats, mice, rabbits and mini-pigs are in the literature and the mini-pig is considered similar to man in its metabolism of ginsenosides. Thus Jenny and Soldati (1985) determined the half-life of ginsenoside Rb1 in the ¿¡-phase in the mini-pig as 16 hours but for ginsenoside Rg1 the half-life was only 27 min. More research is necessary to provide similar data on the metabolism of the large molecules of other ginsenosides, polysaccharides, polyacetylenes, etc. and on the occurrence, identity, fate and functional significance of the ginseng metabolites.
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