0 1998 J. Pharm. Pharmacol.

J. Pharm. Pharmacol. 1998, 50: 1155-1 160
Received January 30, 1998
Accepted June 1, 1998

Intestinal Bacterial Hydrolysis is Required for the Appearance ofCompound K in Rat Plasma after Oral Administration ofGinsenoside Rbl from Panax ginseng
TERUAKI AKAO, HIROAKI KIDA*, MATAO KANAOKA, MASAO HATTORI*A N D KYOICHI KOBASHI

Faculty of Pharmaceutical Sciences and *Research Institute for Wakan-Yaku, Toyama Medical andPharmaceutical University, 2630 Sugitani, Toyama 930-01, Japan

Ginsenoside Rbl from Panax ginseng root is transformed into compound K via ginsenosides Rd and F2 by intestinal bacterial flora. Among 3 1 defined intestinal strains from man,
only Eubacterium sp. A-44 transformed ginsenoside Rbl into compound K via ginsenoside
Rd. The ginsenoside Rbl-hydrolysing enzyme isolated from Eubacterium sp. A-44 was
identical to a previously purified geni oside-hydrolysing fi-D-glucosidase.
When ginsenoside Rbl (200 mg kg ) 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 Rbl administered
was recovered from the intestinal tract, especially the caeca, and cumulative faeces
indicating poor absorption of ginsenoside Rbl. When ginsenoside Rbl was administeredorally to gnotobiote rats mono-associated with Eubacterium sp. A-44, a significant amountof 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 ofginsenoside Rbl was detected in the caecal contents only 7 h after administration.
These results indicate that orally administered ginsenoside Rbl is poorly absorbed fromthe gut but that its metabolite compound K, produced by ginsenoside Rbl-hydrolysing
bacteria such as Eubacterium sp. A-44 in the lower part of intestine, is absorbed.

-7

Ginseng, the root of Panax ginseng, is an important
drug used in Oriental medicines. Its main constituents are glycosides of dammarene-type triterpenes, protopanaxadiol and protopanaxatriol(Shibata et a1 1985). Pharmacological and biological activity has been reported for various ginsenosides (Lacaille-Dubois & Wagner 1966; Gillis
1997). Poor absorption of ginsenosides Rgl andRb2 has been observed (Odani et a1 1983a; Takino
1994) and after oral administration to rats ginsenoside Rbl (protopanaxadiol type), the mostabundant constituent of ginsenosides, could not be
detected in the serum by thin-layer chromatography(TLC) and only an extremely low proportion(0.05%) of the dose was excreted in the urine
within 24 h (Odani et a1 1983b). In man ginsenoside Rbl was undetectable in the plasma by highperformance liquid chromatography (HPLC) or by
Correspondence: T. Akao, Faculty of Pharmaceutical
Sciences, Toyama Medical and Pharmaceutical University,
2630 Sugitani, Toyama 930-01, Japan.

a sensitive enzyme immunoassay (EIA), developed by
Kanaoka et a1 (1992), for ginsenoside Rbl afteringestion of red ginseng powder (Kato et a1 1990).
Ginsenosides are transformed into deglucosylated
metabolites by intestinal bacteria in-vitro and invivo (Odani et a1 1983c; Karikura et al 1991;
Kanaoka et a1 1994; Takino 1994; Hasegawa et a1
1996) and ginsenoside Rbl is hydrolysed to compound K, its main metabolite, via ginsenosides Rd
and F2 by intestinal flora in rat and man (Figure 1)(Karikura et a1 1991; Kanaoka et a1 1994). Compound K has been detected in the plasma after oral
administration of ginsenoside Rbl (Akao et a1
1998) or ginseng saponins (Hasegawa et a1 1996) torats, albeit some time later, whereas rapid absorption occurs after oral administration of compound
K itself (Akao et a1 1998). These results suggestthat unabsorbed ginsenoside Rb is transformed
into compound K by intestinal bacteria in the lower
part of the rat intestine and that compound K is thenabsorbed.

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Abstract

1156

TERUAKI AKA0 ET AL

glc-6glc-0

Ginsenoside Rb/

HO.

Figure 1. Metabolism of ginsenoside Rbl by intestinal bacterial flora from rat and man.

In this study we have screened 31 defined strains
of intestinal bacteria from man for ginsenoside
Rbl-metabolizing activity and found only one
strain, Eubacterium sp. A-44, capable of transforming ginsenoside Rbl into compound K. After
preparing gnotobiote rats mono-associated with
Eubacterium sp. A-44, we clarified in an in-vivo
experiment that this ginsenoside Rbl -hydrolysing
bacterium was necessary for the appearance ofcompound K in rat plasma after oral administrationof ginsenoside Rbl.

Materials and Methods
Chemicals
Reagents for the compound K enzyme immunoassay (EIA) were prepared or purchased as
described previously (Akao et a1 1998). Ginsenosides Rbl and Rd were kindly supplied by Nikkan
Korai Ginseng (Kobe, Japan). Compound K was
prepared by treating ginsenoside Rbl with crude
naringinase (Akao et a1 1998). General anaerobic
medium (GAM) was purchased from Nissui
Seiyaku (Tokyo, Japan).
Bacterial strains and culture
Bifidobacterium sp. strain SEN (Akao et a1 1994a),
Clostridium innocuum ES24-06 (Hattori et a1
1985), Eubacterium sp. A-44 (Kobashi et a1 1986),
Eubacterium sp. strain BAR (Che et a1 1991) andRuminococcus sp. P o l - 3 (Hattori et a1 1985) havepreviously been isolated from the faeces of man.
Other defined strains of intestinal bacteria fromman were provided by Professor Emeritus T. Mitsuoka, The University of Tokyo. Each strain was
cultured in semi-solid GAM agar and maintained at
4°C.

Thin-layer chromatography (TLC)
Silica gel type 60 plates (Merck, Darmstadt, Germany) were used for determination of ginsenosides
Rbl and Rd (mobile phase CHC13-methanol-H20,
65:35: 10, lower layer), and of compound K (mobile
phase CHC13-methanol, 4: 1) (Kanaoka et a1 1994).
Spots were detected by spraying with phosphomolybdic acid reagent and heating; densitometricscanning (Shimadzu CS-9000) was performed at
600 nm.
Screening of dejined bacterial strains formetabolism of ginsenoside Rbl
Each precultured bacterium (10 ,uL) was added to
GAM broth (10mL) and cultured in an anaerobic
incubator at 37°C for 24 h. The individual precipitates obtained by centrifugation were washedwith saline and suspended with 1.5mL 50 m~
potassium phosphate buffer (pH 7-2). Each bacterial suspension (100,uL) was incubated with 1m~
ginsenoside Rbl at 37°C for 24 h under anaerobic
conditions. The reaction mixture was extractedwith butanol (100,uL) and metabolites such as

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d c 4 3 h jGinsenoside F2

ABSORPTION OF A GINSENOSIDE Rb, METABOLITE

ginsenoside Rd and compound K were analysed by
TLC as described above.

Partial purijication of a ginsenoside
Rbl-hydrolysing B-D-glucosidasefrom
Eubacterium sp. A-44
The method of purification of the enzyme from theextract of Eubacterium sp. A-44, by column chromatography on Butyl-Toyopearl 650M, Sephacryl
S-300 and hydroxyapatite, was fundamentally thesame as for geniposide-hydrolysing P-D-glucosidase (Yan et a1 1995).
Animals, treatment and sampling
Male Wistar germ-free rats (WA/Jic, 5-6 weeks;
CLEA Japan, Tokyo, Japan) were individually
maintained in metabolic cages under germ-free
conditions and fasted overnight before the experiments. Autoclaved water and sterilized standard
laboratory chow (CE-2, X-ray-treated, CLEA
Japan) were otherwise freely available. Six germfree rats were infected with Eubacterium sp. A-44
(2mL medium cultured overnight) on the first andthird days to produce the gnotobiote rats. One week
later sterile ginsenoside Rbl dissolved in pure water
was administered orally to six germ-free rats and to
the gnotobiote rats at a dose of 200mg kg-I. The
cumulative faeces were collected 7 h (three rats)
and 15 h (three rats) after administration. Blood
samples from the abdominal vein and the gastrointestinal tract were taken under pentobarbital
anaesthesia 7 h (three rats) and 15 h (three rats)
after administration. Plasma samples were preparedby centrifugation of the heparinized blood andstored at -20°C until use.

Determination of compound K in plasma
Plasma (50 pL) was extracted with methanol(2 x 200pL) and the extract was dried in-vacuo
and redissolved in methanol (20pL). Buffer A(20 m phosphate-buffered saline, pH 6.8, 80 pL,
containing 0.1% BSA, 0.1% NaN3 and 0.001%
MgC12) was added and the concentration ofcompound K was measured by an EIA method
described elsewhere (Akao et a1 1998).
Determination of ginsenoside Rbl and compound K
in intestinal contents and faeces
Suspensions of the contents of the small intestine,
caecum and colon-rectum, and faecal suspensions
were extracted with an equal volume of watersaturated butanol. A sample of the butanol layer
was analysed by TLC as described above todetermine the ginsenoside Rbl and compound K
contents.

Results and Discussion
Screening of dejined strains of intestinal bacteria
from man for metabolism of ginsenoside Rbl
Of 31 strains of intestinal bacteria only one,
Eubacterium sp. A-44, metabolized ginsenoside
Rbl (Table 1). This bacterium transformed ginsenoside Rbl into compound K and ginsenoside Rd, ina manner similar to that of faecal flora from rat andman (Karikura et a1 1991; Kanaoka et a1 1994).
Although Eubacterium is one of the most predominant genera of the intestinal flora of man, few
strains seem to be able to hydrolyse ginsenoside
Rbl, because a 3% probability was found on
screening for this ability. This is supported by thefinding that only one species, Prevotella oris, isolated from human faeces by Hasegawa et a1 (1997)
was a ginsenoside Rbl-metabolizing bacterium.
Ginsenoside Rbl-hydrolysing activity (9.6 nmol
min-' mg-') has also been observed in a crude
extract of Eubacterium sp. A-44 which contained
three different kinds of P-D-glucosidase (Akao et a1
1994b) with geniposide-hydrolysing (Yan et a1
1995) or other activity. These enzymes were clearly
separated by column chromatography on ButylToyopearl 650M. The first eluted peak fractionhydroly sed p-nitrophenyl P-D-glucopyranoside andgeniposide. This fraction also hydrolysed ginsenoside Rbl to ginsenoside Rd and compound K, butwith less activity (one third of that of p-nitrophenyl
P-D-glucopyranoside and one half that of geniposide), but did not hydrolyse ginsenoside Rgl (protopanaxatriol type). This ginsenoside Rbl- andgeniposide-hydrolysing activity was further copurified by column chromatography on Sephacryl
S-300 and hydroxyapatite. These results indicate

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Enzyme assay
P-D-Glucosidase activity was measured as described previously (Yan et al 1995) using p-nitrophenyl P-D-glucopyranoside as substrate. Arylsulphotransferase was assayed using p-nitrophenyl
sulphate and tyramine as the donor and acceptor,
respectively, by a minor modification of the methodof Kim et a1 (1986). To measure ginsenoside Rblhydrolysing activity reaction mixture containing
ginsenoside Rbl (0.5 pmol) and enzyme solution inpotassium phosphate buffer (50 m, pH 6.3;
200 pL) was incubated at 37°C for 20-60 min thenthe reaction was stopped by adding 200pL watersaturated butanol. The amounts of hydrolysates
were determined by TLC as described above. Protein was determined by the method of Lowry et a1(1951) using bovine serum albumin (BSA) as astandard.

1157

1158

TERUAKI AKA0 ET AL

Table 1. Intestinal bacterial strains from man used to test the
metabolism of ginsenoside Rbl (GRbl) with percentages of therecovered substrate.
GRblt

Bacteroides fragilis ss thetaotus
B. fragilis ss vulgatus
Bifdobacterium adolescentis
B. angulatum
B. b$dum a E319
B. breve S-2 kz 1287
B. longum IV-55
B. pseudolongum PNC-2-9-G
B. sp. SEN
Clostridium butyricum
C. innocuum ES 24-06
C. innocuum KZ-633
C. perjringens TO-23
Enterococcus faecalis 11- 136
Eubacterium aerofaciens
Eubacterium sp. A-44
E. sp. BAR
Fusobacterium nucleaturnKlebsiella pneumoniae ATCC 13883
Lactobacillus acidophilus ATCC 4356
L. brevis 11-46
L. fermentum ATCC 9338
L. plantarum ATCC 14927
L. xylosus ATCC 15775
Peptostreptococcus anaerobius 0240
P. intermedius EBF77/25
Proteus mirabilis S2
Ruminococcus sp. PO 1-3
Veilloneella parvula ss parvula ATCC 10790

87.5
91.6
94.3
82.7
93.9
83.3
85.9
88.3
87.1
85.4
89.6
84.2
87.2
89.4
84.5

N.D.*
89.1
91.4
83.4
91.8
91.0
83.5
95.4
84.0
82.4
81.6
86.9
93.0
91.7

?No metabolites were detected for all of the intestinalbacteria except E.sp.A-44. *Metabolites ginsenoside Rd(16.8%) and compound K (70.3%) were detected.

that the previously purified enzyme capable ofhydrolysing geniposide (Yan et a1 1995) has broad
substrate specificity and also hydrolyses ginsenoside Rbl to compound K via ginsenoside Rd. We
have recently clarified that this enzyme hydrolyses
saikosaponins a, bl, b2 and d, which are resistant tovarious other /?-D-glucosidases,to the corresponding prosaikogenins (Kida et a1 1997).
Eubacterium sp. A-44 is required for theappearance of compound K in plasma after
oral administration of ginsenoside Rbl
Although the caecal contents of germ-free rats
showed no /?-D-glucosidase or arylsulphate sulphotransferase activity (Table 2), this activity waspresent to a significant extent in the caecal contents
of gnotobiote rats infected with Eubacterium sp.
A-4.4 which produces two unique enzymes, arylsulphotransferase (Kim et a1 1986) and ginsenoside
Rbl-hydrolysing /?-D-glucosidase. Thus, Eubacterium sp. A-44 inhabited the intestinal tracts of thegnotobiote rats produced during this study. Afteroral administration of 200 mg kg-' ginsenoside Rbl

Table 2. fl-D-Glucosidase and arylsulphotransferaseactivityof the caecal contents of germ-free and gnotobiote rats.
AnimalTime (h) Enzyme activity (nmol min-' mg-')
fl-D-GlucosidaseArylsulphotransferase

Germ-free rats
Gnotobiote rats

7
15
7
15

N.D.

N.D.

N.D.
5 5 7 f 3.37
6.63f3.97

4.40 f 1.97
4.80 f2.09

N.D.

Values are means fs.d. (n = 3) 7 and 15 h after oral administration of ginsenoside Rbl. N.D., not detected.

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Intestinal bacteria

to the germ-free rats, none of its intestinal bacterial
metabolites, including compound K, were detectable in their intestinal tracts or cumulative faeces.
Ginsenoside Rbl itself was detected mostly in the
caeca. More than 90% of the ginsenoside Rbl
administered was recovered from the intestinal
tracts and cumulative faeces of the rats tested 7 hafter administration, and more than 70% from thoseof the rats tested after 15 h (Table 3). These results
indicate that orally administered ginsenoside Rbl is
excreted in the faeces without being metabolized
and that it is not absorbed from the intestinal tractsof the germ-free rats. They also confirm earlier
suggestions of poor absorption of ginsenoside Rbl
on the basis of previous reports (Odani et a1 1983b;
Kato et a1 1990; Hasegawa et a1 1996, 1997) thatginsenoside Rb was undetectable in plasma frommice, rats and man after oral administration. Afteroral administration to the gnotobiote rats significant
amounts of ginsenoside Rbl and compound K weredetected in the rats' intestinal tracts and cumulative
faeces after 7 h, and a considerable amount ofcompound K, but no ginsenoside Rbl, was detectedin their caeca and faeces after 15 h (Table 3). Onlya small amount of ginsenoside Rd, one of the otherintestinal bacterial metabolites, was detected. Thus,
ginsenoside Rbl had mostly been transformed into
compound K in the caeca and colons of the gnotobiote rats within 7 h of administration, which iscompatible with the finding that ginsenoside Rbl
almost disappeared from the digestive tracts of
conventional rats within 6 h of oral administration
at a dose of 100 mgkg-' (Odani et a1 1983b).
However, it seems that not all the compound K
produced is absorbed from the gut, because excretion of an appreciable amount into the faeces
occurred 15 h after administration. This suggeststhat compound K is slowly absorbed from theintestinal tract.
Although compound K has appeared at concentrations of 10-100 ngmL-' in the plasma ofABSORPTION OF A GINSENOSIDE Rb, METABOLITE

1159

Table 3. Recovery of ginsenoside Rbl, and the compound K content of the intestinal tracts and cumulative
faeces of germ-free and gnotobiote rats 7 and 15 h after oral administration of ginsenoside Rbl.
Germ-free rats

Small intestine
CaecumColon +rectum
Faeces

Ginsenoside Rbl
Compound K
Ginsenoside Rbl
Compound K
Ginsenoside Rbl
Compound K
Ginsenoside Rbl
Compound K

Gnotobiote rats

7h

15 h

7h

15 h

13.5
N.D.
67.3
N.D.
4.5
N.D.
5.6
N.D.

2.9
N.D.
51.7
N.D.
7.4
N.D.
8.8
N.D.

N.D.
5.6
32.0
9.3
3.5
0.6
2.5
0.7

N.D.
6.7
N.D.
19.2
N.D.
2.1
N.D.
18.9

conventional rats within 4-24 h of oral administration of 200mg kg-' ginsenoside Rbl (Akao
et a1 1998), no compound K was detected in theplasma of the germ-free rats either 7 or 15 h after
oral administration of the same dose of ginsenoside
Rbl. Compound K was detected at concentrationsof 4.8 and 83-4 ngmL-' in the plasma of thegnotobiote rats 7 and 15 h, respectively, after oral
administration of ginsenoside Rbl. The
concentration of compound K in the plasma of
gnotobiote rats was similar to that found in conventional rats. These findings accord with theabove results showing that compound K was produced in the intestinal tracts of the gnotobiote rats
after oral administration of ginsenoside Rbl, butthat no compound K was generated by the germfree rats.
In conclusion, ginsenoside Rbl-hydrolysing bacteria such as Eubacterium sp. A-44 are essential forthe appearance of compound K in the plasma after
oral administration of ginsenoside Rbl to rats, andthis probably applies to man also. Orally administered ginsenoside Rbl reaches the lower part of theintestinal tract without being absorbed, is transformed into compound K and other metabolites byintestinal anaerobes, and these metabolites are thenabsorbed. Punax ginseng root (ginseng) contains
ginsenosides Rb2, Rb3, Rc and Rd, and ginsenoside
Rbl. These are all glycosides of protopanaxadiol,and these saponins are also transformed mainly tocompound K by intestinal bacterial flora (Karikura
et al 1991; Kanaoka et a1 1994; Hasegawa et a1
1996). Accordingly, when man ingests ginseng,
compound K seems to be one of the main compounds absorbed.
Acknowledgements
We thank Miss S. Sugimoto and Miss A. Imanishi
for their technical assistance and the Animal
Experimental Center of our university for breeding

the rats. This work was supported by a grant from
Nikkan Korai Ginseng Public Co. and was partially
funded by a grant-aid for Scientific Research (No.
09672219) from the Ministry of Education, Japan.

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TERUAKI AKA0 ET AL

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