The pharmacokinetics of different ginseng saponin compounds has been studied in both animals and humans [1–3]. In order to obtain detectable plasma levels of the compounds, the administered test compound doses were often at the high end of the pharmacological dose range. Yet the pharmacokinetic profile of ginseng has been incompletely understood because of the many diversified and heterogeneous chemical structures of different ginsenosides.
The absorption rate of ginseng saponins is low after oral administration, and doses of test compounds must be high to detect levels in plasma. Extensive metabolism in the gastrointestinal tract [10, 11], poor membrane permeability , and low solubility of deglycosylated products  limit intestinal absorption of ginseng saponins. The bioavailability of the protopanaxadiol (PPD) group of saponins (ginsenosides Ra3, Rb1, Rd, Rg3, and Rh2) [12, 14–17] and of the protopanaxatriol (PPT) group of saponins (ginsenosides Rg1, Re, Rh1, and R1) [14, 18–20] was less than 5%. PPT saponins have better bioavailability than PPD saponins [14, 21], perhaps because PPD saponins degrade faster than PPT saponins. High oral doses may saturate metabolism and increase bioavailability [21, 22]. Changing the pharmaceutical formulation may also improve bioavailability. For instance, micronized Rh2 has doubled its bioavailability .
The time for saponins to reach maximum concentration (Tmax) in plasma was generally less than 2 hr, indicating that saponins are rapidly absorbed and readily distributed in the tissues [23, 24]. In rabbits, the elimination half-lives (T1/2) of Rg1, Re and Rb2 were between 0.8 hr and 7.4 hr . In humans, the T1/2 of the tested saponins was generally less than 24 hr [10, 26].
Tissue disposition showed that liver and bile clear ginseng saponins from circulation [22, 23, 27]. Hepatic cytochrome P450 catalyzed ginsenoside metabolism, and it has been described that CYP3A4 catalyzed metabolism by oxygenation the hepatic disposition of ginsenosides . Attachment of more sugar moieties in the PPD ginsenosides Ra3, Rb1, Rc and Rd blocked their access to biliary transporters and slowed biliary excretion . Most ginsenosides and their deglycosylated products were excreted by the biliary system through active transport . Time curves of ginseng saponins exhibited distinct multiple peaks after oral administration, indicating the involvement of enterohepatic recirculation . Approximately 0.2%–1.2% of ginsenosides were excreted in human urine .
SAPONIN METABOLISM BY GUT MICROBIOTA
After oral administration, ginseng is metabolized extensively by intestinal bacteria [12, 26, 30]. Studies of the degradation and metabolism of ginseng saponins have been conducted using enzymes or intestinal bacteria [32, 33]. Among the metabolic pathways are deglycosylation reactions by intestinal bacteria via stepwise cleavage of the sugar moieties [10, 12, 26]. In the PPD group, Rb1 and Rd are metabolized to Compound K [34, 35]. Rg3 and Rg5 are biotransformed to Rh2 and Rh3, respectively [36, 37]. In the PPT group, Rg1 and Re are converted to Rh1 and F1 [10, 38, 39]. After oral ingestion, ginsenoside metabolites are absorbed from the gut into systemic circulation [12, 26, 30]. In our ongoing studies in human volunteers, ginsenoside Rb1 and Compound K reached the systemic circulation after oral administration of American ginseng (unpublished data).
Because of competitive absorption and metabolism, administration of a single ginsenoside or of a ginseng extract may have different results. The metabolic profile of a ginsenoside also can vary with method of administration. For instance, after intravenous injection of Rd, Rb1 is the dominant metabolite; after oral administration of Rd, Rg3 is dominant35.
As an active ginseng saponin metabolite, Compound K exerts cancer chemoprevention activity. This metabolite induced apoptosis in several tumor cell lines. Compound K inhibited the growth of human leukemia cells by induction of apoptosis via cytochrome c-mediated activation of caspase-3 protease and the caspase-8-dependent pathway [7, 40]. It also arrested the G1 phase of the cell cycle . In human astroglial cells, Compound K suppressed tumor necrosis factor-alpha-induced activation of the NFkappaB and JNK pathways and inhibited matrix metalloproteinase-9 [42, 43]. In HepG2 cells, Compound K induced apoptosis via the Fas/Fas ligand death receptor pathway and mitochondria-mediated pathway [44, 45]. In vivo experiments with mouse skin, Compound K inhibited tumor and COX-2 expression .
We used two human colorectal cancer cell lines HCT-116 and SW-480 to compare the chemopreventive effects of ginsenoside Rb1 and Compound K. The two cell lines differ in the expression of the tumor suppressor gene, p53. HCT-116 is a wild-type for p53 and SW-480 is mutant. Compound K showed significant antiproliferative effects on the colorectal cancer cells at 30 µM; Rb1 did not inhibit activity at 100 µM. To elucidate the mechanisms mediating the anti-proliferative effects in colon cancer cells, we examined alterations in cell cycle and apoptosis. Compound K inhibited G1 progression and increased apoptosis in both cell lines. At 40 µM, HCT-116 showed late apoptosis; SW-