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Metabolism and pharmacokinetics of

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 Asian Journal of Pharmacodynamics and Pharmacokinetics Paper ID 1608-2281-2006-06020103-18

Copyright by Hong Kong Medical Publisher Received December 12, 2005

ISSN 1608-2281 2006 6(2): 103-120 Accepted March 10, 2006

Metabolism and pharmacokinetics of ginsenosides

Yang Ling1*，Liu Yong1 and Liu Chang-Xiao2
1
Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese
Academy of Sciences, Dalian, 116023. China
2
Tianjin Key Laboratory of Pharmacokinetics and Pharmacodynamics, Tianjin Institute of Pharmaceutical
Research, Tianjin, 300193, China

Abstract Ginseng, an extensively used herbal drug in traditional oriental medicine, has been consumed for preventive
and therapeutic purposes for over 2000 years. In this review, we highlight the most recent advances on the
major active components, ginsenosides, and their degradation products in gastrointestinal lumen. The
absorption from the gastrointestinal tract, the transformation in liver and intestine, in vitro studies about
influence on the key factors determining ADME properties such as metabolizing enzymes, and transporters,
together with the current in vivo pharmacokinetics studies are summarized. We also review the ginseng-drug
interactions based on pharmacokinetics and their possible mechanism. The study about pharmacokinetic
properties of ginseng is in favor of understanding the safety and active mechanism of ginseng. To clarify the
ADME properties of Ginseng, the major active components, ginsenosides, are mainly focused on although
ginseng includes multiple components. In addition, some of ginsenosides are transformated in
gastrointestinal tract by gastric acid and microflora. The inconsistency of detected ginsenosides with real
active components due to the lack of knowledge of active mechanisms, variability of component contents
and so on, make the evaluation of ginseng pharmacokinetics more difficult than that of the so called western
drugs, a single component. In this paper, the studies of naturally occurring ginsenosides and their metabolites
by in vitro and in vivo methods determining pharmacokinetic properties, such as physicochemical properties
of ginsenosides, metabolizing enzymes, transporters and deglycosylation in gastrointestinal tract, as well as
ginsenoside-drug interactions are summarized.

Key words Ginseng; ginsenosides; metabolism; pharmacokinetics; biotrasformation; in vitro and in vivo methods

Intriduction Pharmacokinetics is the mathematics of the time

Ginseng, an extensively used herbal drug in
traditional oriental medicine, has been consumed for
preventive and therapeutic purposes for over 2000
years. Three species: Panax ginseng (Asian ginseng),
Panax japonicus (Japanese ginseng) are the most
in-common use of ginsengs. Ginseng has a wide rang of
pharmacological activities, including immuno-
modulatory effects, anti-inflammatory activity,
improvement of physical stamina, and stimulation of
the appetite, and are also thought to have effects on
learning, memory and behavior[1,2].
______
*Correspondence to Prof. Yong Liu, Dalian Institute of Chemical
Physics, Chinese Academy of Sciences, Dalian, 116023, China. Tel:
+86-411-8437-9317; Email:liuyong@dicp.ac.cn
course of absorption, distribution, metabolism, and
excretion (ADME) of drugs in the body. Many factors
including biological, physiological, and physico-
chemical ones influence the transfer (ADME) process
of a drug in the body, which then affect the rate and
extent of its pharmacological effect, as well as
toxicological action, in the body. Therefore,
pharmacokinetic study plays an essential role in drug
discovery, development and clinical uses.
Different from the so-called western drug as a
single component, ginseng is a complex system
consisting of multiple compounds, which makes
ginseng more difficult in evaluation of pharmacokinetic
and ADME properties.

103
Yang L et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2006; 6(2):103-120

The components of ginseng have been found to
be more than 200 compounds. Among them, the major
active components of ginseng are ginsenosides, a
diverse group of steroidal saponins, which demonstrate
the ability to target multitudinous tissues, producing an
array of pharmacological responses[3]. More than thirty
ginsenosides have been isolated[4], and novel structures
continue to be reported, particularly from Panax
quinquefolius and Panax japonicus[5]. Ginsenosides are
divided into three main categories, the 20(S)-proto-
panaxadiol, 20(S)-proto- panaxatriol and oleanane
families according to the number and position of sugar
moieties on the sterol chemical structure (Fig 1 and 2).
In addition, ginseng and their derived products are
orally administered in most cases, and a number of
metabolites are produced by the degradation of
ginsenosides by acid or intestinal bacteria in
gastrointestinal tract.

Compound R1 R2 R3
Protopanaxadiol type:
Rb1 -Glc2-1Glc -H -Glc6-1Glc
Rb2 -Glc2-1Glc -H -Glc6-1Arap
Rc -Glc2-1Glc -H -Glc6-1Araf
Rd (M10) -Glc2-1Glc -H -Glc
Rg3 -Glc2-1Glc -H -H
Rh2 -Glc -H -H
Gp-XVII (M9) -Glc -H -Glc6-1Glc
Mb (M7) -Glc -H --Glc6-1Araf
M6 -Glc -H -Glc6-1Arap
Gp-LXXV (M13) -H -H -Glc6-1Glc
F2 (M5) -Glc -H -Glc
Mc (M3) -H -H -Glc6-1Araf
C-Y (M2) -H -H -Glc6-1Arap
Compound K (C-K, M1) -H -H -Glc
20(S)-protopanaxadiol (Ppd, M12) -H -H -H
Protopanaxatriol type:
Re -H -O-Glc2-1Rha -Glc
Rg1 -H -O-Glc -Glc
Rg2 -H -O-Glc2-1Rha -H
Rh1 (M8) -H -O-Glc -H
F1 (M11) -H -O-H -Glc
20(S)-protopanaxatriol (Ppt, M4) -H -O-H -H
Notoginsenoside R1 -H -O-Glc-Xyl -Glc
Glc: β-D-glucopyranosyl; Arap: α-L-arabinopyranosyl;
Araf: α-D-arabinofuranosyl; Rha: -L-rhamnopyranosyl

Fig 1. The chemical structures of protopanaxadiol and protopanaxatriol ginsenosides

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 Yang L et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2006; 6(2):103-120

In this review, we highlight the most recent the key factors determining ADME properties such
advances on the major active components, as metabolizing enzymes, and transporters,
ginsenosides, and their degradation products in together with the current in vivo pharmacokinetics
gastrointestinal lumen. The absorption from the studies are summarized. We also review the
gastrointestinal tract, the transformation in liver ginseng-drug interactions based on
and intestine, in vitro studies about influence on pharmacokinetics and their possible mechanism.

OH OH
26 27 26 27
25 25
(R) (S)
24 23 24 23

O O
22 22
OH 20 20
21 21
17 17
11 12
13 16 COO-Glc
19 18
1 14
15
2 9
10 8
3 5 30
7
4 6
HO Glc2-Glc-O

29 28 R

Ginsenoside R0 =Chikusetsusaponin V
Compound 24 R
Ocotillol-type saponins:
Pseudoginsenoside F11 (R) -O-Glc2-Rha
Majonoside R1 (S) -O-Glc2-Glc
R2 (S) -O-Glc2-Xyl

Fig 2. The structure of Ocotillol-type saponins of ginsenosides

The degradation in gastrointestinal lumen of were determined to be 25-hydroxy-23-ene,

ginsenosides 24-hydroxy-25-ene, 25-hydroperoxy-23-ene and
24-hydroperoxy- 25-ene derivative of Rb2, respectively.
The degradation of ginsenosides in the human In this study, it is suggested that 20(S)-protopanaxatriol
gastrointestinal tract includes deglycosylation by acid saponins undergo hydrolysis of the C-20 glycosyl
and intestinal bacteria. moiety and hydration of the side chain, 20(S)-
protopanaxadiol saponins undergo oxygenation of the
Deglycosylation of ginsenosides by acid side chain[6]. Karikura et al. also found that ginsenoside
Karikura et al. investigated the decomposition of Rb1 was hydrolyzed to 20(R,S)- ginsenoside Rg3 in 0.1
ginsenoside Rb2 in rat stomach (in vivo) and with 0.1 N N HCl, and mainly hydroperoxided to 25-hydro-
HCl (in vitro). By treating with 0.1 N HCl, the acidity peroxy-23-ene derivative of Rb1 in rat stomach [7].
of which is similar to that of gastric juice, a part of Rb2 When ginseng water extract was incubated at 60
was hydrolyzed to 20 (R, S)-ginsenoside Rg3. On the ˚C in acidic conditions, its protopanaxadiol
other hand, Rb2 was little decomposed in rat stomach ginsenosides were transformed to ginsenoside Rg3 and
and a small quantity of an unidentified metabolite, Δ20-ginsenoside Rg 3 . However, protopanaxadiol
which was different from the hydrolyzed products in ginsenosides Rb1, Rb2 and Rc isolated from ginseng
0.1 N HCl, was observed. The metabolite was separated were mostly not transformed to Rg3 by the incubation
into four compounds, which were identified by 1H- and in neutral condition. The transformation of these
13
C-nuclear magnetic resonance and fast atom ginsenosides to Rg 3 and Δ20-ginsenoside Rg 3 was
bombardment mass spectrometry. These compounds increased by increasing incubation temperature and

105
Yang L et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2006; 6(2):103-120
time in acidic condition[8]. Ginsenoside Rg1 was easily
hydrated to the same prospogenins in both rat stomach
and 0.1 N HCl solution, but Rb1 and Rb2 were little
decomposed (metabolized) in rat stomach and a small
quantity of their hydroperoxide derivatives were found,
but they were easily hydrated to their prosapogenins by
0.1 N HCl[9].
Deglycosylation of ginsenosides by intestinal
bacteria
The gastrointestinal tract is the first site of
biotransformation for orally administered TCM.
Gastrointestinal microorganisms comprise an important
component of the diverse and dynamic intestinal
ecosystem. There are approximately 1012 parenchymal
cells in an average human (excluding blood cells and
neurons), but about 1012 bacteria on the skin, another
1010 in the mouth, and the gut contains 1014
microorganisms (weighing>1 kg)[10,11]. The main
human intestinal bacteria are predominantly obligate
anaerobes and include species of the genera
Bacteroides, Clostridium, Lactobacillus, Escherichia
and Bifidobacterium, together with various yeasts and
microorganisms coexisting in dynamic ecological
equilibrium. Although the role of gastrointestinal
biotransformation is still not being paid its deserved
attention, there are more than 1000 species of
microorganisms within gut, which present their
contribution to drug/xenobiotic metabolism and the
development of human disease[12].
The potential of intestinal bacteria to hydrolyze
naturally occurring ginsenoside Rb1 to 20-O-β-D-
glucopyranosyl- 20(S)-protopanaxadiol (compound K,
C-K or termed as M1) was found in 79% of the fecal
specimens from 58 human subjects whose age ranged
from 1 to 64 years[13]. Following Rb1-hydrolyzing
activity assay, Prevotella oris strains were then isolated
as major bacterial species possessing the potential. All
the intestinal isolates converted ginsenosides Rb1 and
Rd to C-K, Rb2 to 20-O-[α-L-arabinopyranosyl
(1→6)-β-D-gluco- pyranosyl]-20(S) -protopanaxadiol
(termed as M2 or compound Y), and Rc to
20-O-[α-L-arabinofuranosyl (1→6) -β-D-gluco-
pyranosyl]-20(S)- protopanaxadiol (termed as M3 or
106
Mc) like fecal microflora, but did not attack
ginsenosides Re or Rg1 (protopanaxatriol-type). These
results suggest that the metabolism of protopanaxadiol
saponins to metabolites I-III in the intestines seems
most partly due to intestinal P. oris.
In addition, several kinds of intestinal bacteria
hydrolyzed naturally occurring ginsenosides.
Eubacterium sp., Streptococcus sp. and Bifidobacterium
sp., which more potently hydrolyzed gentiobiose than
sophorose, metabolized Rb1 to C-K via Rd rather than
gypenoside XVII (or termed as M9). However,
Fusobacterium K-60, which more potently hydrolyzed
sophorose than gentiobiose, metabolized to C-K via
gypenoside XVII. Rb2 was also metabolized to C-K via
Rd or compound O by human intestinal microflora.
Eubacterium sp., Streptococcus sp. and Bifidobacterium
sp. metabolized Rb2 to C-K via Rd rather than
compound O. Fusobacterium K-60 metabolized Rb2 to
C-K via compound O[14]. The profile of ginsenoside
metabolites were not changed even if water extract of
Ginseng Radix, instead of the isolated compounds were
used. The enzyme activities were not different with
gender and ages, but significant with individuals[15].
In the rat large intestine, a part of Rb2 was
decomposed and six decomposition products (I-VI)
were founded on thin-layer chromatography (TLC).
Among them, five products (I-V) were isolated and
identified as Rd (I), 3-O-β-D-glucopyranosyl-20-O-
[α-L-arabinopyranosyl(1→6)-β-D-glucopyranosyl]-20(
S)-protopanaxadiol (II), F2 (III), 20-O-[α-L-arabino-
pyranosyl(1→6)-β-D-glucopyranosyl]-20(S)-protopa-
naxadiol (IV), and C-K (V), respectively[16]. Five
degradation products from Rb1 in rat large intestine
were observed and identified as gypenoside XVII
(G-XVII), Rd, ginsenoside F2 (F2), C-K and VIII. The
metabolic modes of Rb1 and Rb2 are considered to be
different because of the hydrolysis rate in the terminal
sugar moiety at the C-20 hydroxyl group in the rat large
intestine[7].
Rc, anaerobically incubated with human fecal
microflora, was metabolized to C-K, the main
metabolite, and protopanaxadiol (Ppd). Most of bacteria,
isolated from human fecal microflora, such as
 Yang L et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2006; 6(2):103-120

Bacteroides sp., Eubacterium sp., and were transformed to ginsenoside Rg3 and
Bifidobacterium sp., potently transformed Rc to C-K. Δ20-ginsenoside Rg3. The transformed Rg3
Bifidobacterium K-103 and Eubacterium A-44 andΔ20-ginsenoside Rg3 were metabolized to
transformed it to C-K via Rd, and Bacteroides HJ-15 ginsenoside Rh2 and Δ20-ginsenoside Rh2, respectively,
and Bifidobacterium K-506 metabolized to C-K via by human fecal microflora. The bacteria isolated from
Mb[17]. human fecal microflora, Bacteroides sp.,
The decomposition of Rg1 by intestinal bacteria in Bifidobacterium sp. and Fusobacterium sp. potently
rats or human was investigated both in vitro and in vivo transformed Rg3 to Rh2[19].
by means of TLC and Electron spurt ion mass. It was The main metabolic pathways of ginsenosides by
found that Rg1 was converted into two metabolites, intestinal bacteria are supposed to be as follows:
namely Rh1 and 20(S)-protopanaxatriol (Ppt, or termed protopanaxadiol-type, Rb1→[ M10 (Rd) → M5 (F2) or
as M4), by human intestinal bacteria in vitro, while M9 → M13]→ C-K, Rb2→ M6→ M2→ C-K (M1),
three compounds, namely Rh1, F1, and Ppt, were Rc→ M7→ M3→ C-K, C-K is gradually hydrolyzed to
detected in rat intestinal bacteria metabolism in vitro Ppd (M12); protopanaxatriol-type, Re→Rg1→ M11 (F1)
and in vivo. The pathway of Rg1 metabolism in rat or M8 (Rh1)→ Ppt (M4), Rg1→ M11 (F1) or M8 (Rh1)
intestine is Rg1→Rh1 (F1) →Ppt[18]. →Ppt[20]. The main metabolic pathways of
When ginseng water extract was incubated in protopanaxadiol and protopanaxatriol ginsenosides are
acidic conditions, its protopanaxadiol ginsenosides showed in Figure 3 and 4.

Glc-O
OH

Glc1-6Glc-O
Glc-O
Glc1 -6 Glc-O Glc-O OH
OH OH M5 (F2)

Glc1-6Glc-O
OH
HO
Glc1-2Glc-O Glc1 -6 Glc-O

Rb1 M10 (Rd)

M13(Gp-LXXV)
Glc-O
M9(Gp-XVII)

Arap1 -6 Glc-O
OH Arap 1-6Glc-O Arap1-6Glc-O
OH OH Glc-O
OH
HO
OH

Glc1-6Glc-O Glc-O HO
HO
Rb2 M6 M2(C-Y) HO
M1(C-K) M12(ppd)

Araf1-6Glc-O Araf1-6Glc-O
OH Araf1-6Glc-O
OH OH

Glc1-2Glc-O Glc-O HO

Rc M7(Mb ) M3(Mc)

Fig 3. The main metabolic pathways of protopanaxadiol ginsenosides

107
Yang L et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2006; 6(2):103-120
Since the bacterial metabolites are absorbed to
blood circulation instead of parent naturally occurring
ginsenosides, Kobashi et al. proposed the concept of
plant glycoside acting as “natural prodrug”[21,22]. The
degradation of ginsenosides in gastrointestinal tract
may be an important issue to clarify the
pharmacological mechanism of ginseng.
The absorption from the gastrointestinal tract
The absorption of naturally occurring
ginsenosides
In most of commercial ginseng-derived products, major
and abundant components consist of naturally occurring
ginsenosides Rb1, Rb2, Rc, Rd, Re, Rf, Rg1 and so on[23].
Most of them are poorly absorbed from gastrointestinal
tract. After oral administration of red Ginseng extracts,
the plasma concentration of ginsenosides in healthy
volunteers was examined by EIA-HPLC, and the result
Glc-O Glc-O
OH OH
HO HO
O-Glc2-1Rha O-Glc
Re Rg1
HO
Fig 4. The main metabolic pathways of protopanaxatriol ginsenosides
Rg3 was not detected in rat plasma collected after
oral administration at 100 mg·kg-1. Only 0.97-1.15%
Rg3 of the dosed amount was determined in feces[33].
After a single dose (3.2 mg/kg R-Rg3) of oral
administration in 8 male volunteers, the maximal
plasma concentration-time was 16 ng/ml. After an oral
dose of 0.8 mg·kg-1 in 6 other volunteers, R-Rg3 was
108
showed that ginsenoside Rb1 was not detected in the
blood[24]. Akao et al. reported that when ginsenoside
Rb1 (200 mg·kg-1) was administered orally to germ-free
rats, neither C-K nor any other metabolite was detected
in the plasma, and most of the ginsenoside Rb1
administered was recovered from the intestinal tract,
indicating poor absorption of Rb1[25]. In addition,
neither intact Rb1 nor its intermediate derivatives but
only the final C-K was detected at 1.0-7.3 μg·mL-1 in
blood after oral administration of mice with Rb1 (125
mg·kg-1)[13,26]. Another study of Rb1 after oral
administration revealed similar results[27]. Odani et al.
reported that oral bioavailabilities of Rb1 and Rg1 from
intestine were very low, only 0.1% and 1.9%,
respectively[28,30]. Tanizawa et al. reported that 3.7%
Rb2 was absorbed from intestine using 3H-labeled
Rb2[31]. By HPLC analysis, Xu et al. reported that Rb1
(4.35%) and Rg1 (18.40%) were absorbed,
respectively[32].
Glc-O
OH
HO HO
OH
OH M11 (F1)
HO
OH
HO
OH
M4(ppt)
O-Glc
M8 (Rh1)
not detected in rat plasma[34].
These results suggest that the absorption of
naturally occurring ginsenosides is poor, and that their
plasma concentration may be difficult to reach the
needed concentrations exhibiting their reported
pharmacological activities.
 Yang L et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2006; 6(2):103-120
The absorption of ginsenoside metabolites
Using the permeability assay with Caco-2 cell
monolayer, Paek et al. studied the absorption potential
of C-K, a major intestinal bacterial metabolite of
ginsenosides, which showed moderate permeability
with no directional effects, thus suggesting passive
diffusion[26].
After the oral administration of ginseng total
saponins to rats, two major intestinal bacterial
metabolites of protopanaxadiol ginsenosides, namely
C-K and Ppd, together with a major intestinal bacterial
metabolite of protopanaxatriol ginsenosides, Ppt, were
detected in blood. Their intestinal absorption is
time-dependently enhanced. After the oral
administration of ginseng extract (150 mg·kg-1·d-1) in
human, C-K was detected about 0.2 μg·mL-1 in urine at
16-24 h[35]. Another pharmacokinetic study after oral
administration of Rb1 and C-K revealed that the level of
C-K in the serum reached maximum at 8 h (8.5μg·mL-1)
after Rb1 administration, and at 2 h (10.3 μg·mL-1) after
C-K administration, respectively [27].
After the oral administration of standardized
Ginsana extract G115, it was shown that two hydrolysis
products of the protopanaxatriol ginsenosides, namely
Rh1 and F1 were found in the systemic circulation. In
addition, C-K was detected in both plasma and urine,
and Rb1 was only identified in plasma and urine of one
subject. But it is a pity no quantitative data in this study
[36]
. The development of analytic methods
These results suggest that the degradation products
are more permeable than naturally occurring
ginsenosides. However, further studies might be needed
since no direct comparison between naturally occurring
ginsenosides and the degradation products.
Ginsenoside metabolism in Liver
Hasegawa et al. found that C-K (M1) was
selectively accumulated into the liver soon after its
intravenous administration to C57BL/6 mice and Wistar
rats, and mostly excreted to bile as protype. However,
some of C-K was esterified to its mono-fatty acid esters
(called EM1) in the liver. EM1 was isolated from the
rat liver in a recovery dose of approximately 24 mol%
109
and not excreted to bile like M1. It was accumulated in
the liver longer than M1[37].
Ppt (M4) is the main bacterial metabolite of
protopanaxatriol-type ginsenosides. The orally
administered M4 was absorbed from the small intestine
into the mesenteric lymphatic vessels followed by the
rapid esterification of M4 with fatty acids accumulated
in the liver[38].
The current pharmacokinetics studies of
ginsenosides
To understand the safety and active mechanism of
ginseng, a huge quantity of work has been carried out
during the last 30 years in order to develop analytical
methods for pharmacokinetics studies about various
ginsenosides and their intestinal metabolite. Major
advances in analytic techniques have provided rapid and
efficient identification of compounds, and many
pharmacokinetics studies about various ginsenosides
have been achieved. However, the inconsistency of
detected compounds with active components resulting
from the lack of knowledge of real active components
has hampered the uncovery of ADME properties of
ginseng. Fortunately, these studies have offered a lot of
information, which will help us to uncover these
properties.
There are some analytic methods that have been
used in the pharmacokinetics studies of animal or
human oral administered ginseng-derived products to
detect naturally occurring ginsenosides and their
intestinal metabolites.
Recently, a liquid chromatography-mass
spectrometry (LC-MS) method for simultaneously
determining the concentration of Rg1 and its secondary
Rh1 and aglycone Ppt in rat plasma has been
established[39]. The method has been used for the
pharmacokinetic study of Rg1 in rats. Rg1 could be
determined by this LC-MS method over the ranges of
1.56-250 ng/ml and 250-20,000 ng·mL-1 with good
correlation. Chromatographic separation was achieved
in less than 8 mins.
Yang L et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2006; 6(2):103-120
A simple and sensitive high-performance
chromatographic (HPLC) and solid-phase extraction
(SPE) method have been used to simultaneously
determine the concentration of ginsenosides Rg1, Rb1,
Rd and notoginsenoside R1 in Panax notoginseng (PNS)
in rat serum after oral and intravenous administration of
total saponins of PNS to rats[40]. The calibration curves
for the four saponins were linear in the given
concentration ranges. The method also exhibited good
accuracy and precision, as well as a high recovery rate.
A similar method was also reported to simultaneously
determine the concentration in rat urine of ginsenosides
Rg1, Rb1, Rd, and notoginsenoside R1 in rat urine,
which also exhibited good accuracy and precision, as
well as a high recovery rate[41].
A method using HPLC with ultraviolet absorbance
detection and SPE was also described for the
determination of Rg3 in human plasma, with acceptable
accuracy and precision. A good linear relationship was
ranged from 2.5 to 200 ng·mL-1[42].
To determine the concentration in plasma of
ginsenosides Rg1 and Re after iv infusion of Shenmai
injection in human, a LC/MS/MS method was well
established by Liu and co-workers[43]. The linear
regressive curves were obtained in the range of
1.023-1023 μg·L-1 for Rg1 and 1.05-1050 μg·L-1 for Re.
Based on HPLC-ESI-MS in negative ion mode
with the mobile phase additive, a novel method to
quantitatively analyze Rg3, Rh2 and Ppd in rat plasma
was developed and validated[44]. The exhibited good
accuracy and precision, as well as the high recovery
rate suggested that the method is specific, simple,
sensitive and suitable for the measurement of plasma
Rg3, Rh2 and Ppd concentrations. Another method
based on LC-MS and MS-MS was also established to
determine Rg3 and its metabolites in rat plasma, urine
and feces samples[33]. This method offered a
satisfactory sensitivity for the determination of R-Rg3
in plasma, with good precisions and accuracy[45].
In addition, a method of isotope labeling was used
in the pharmacokinetics studies of ginsenoside Rb2[24].
This method of specific position labeling of Rb2 may be
applicable to other ginsenosides. Micro-detection of
ginsenosides by EIA (enzyme immunoassay) method
110
combined with HPLC was developed by Kanaoka et al.,
however, Rb1 was not detected in human blood[46].
Pharmacokinetics of ginsenosides
By applying various chemical and spectroscopic
methods, researchers have found that the genuine
aglycones were protopanaxadiol and protopanaxatriol,
which both have a dammarane skeleton. On acid
treatment of protopanaxadiol and protopanaxatriol, a
tertiary hydroxyl group attached to C-20 participates in
ring closure with a double bond in the side chain. 31
ginsenosides have been isolated from the roots of white
and red ginseng. They can be categorized in three
groups depending on their aglycones: proto-
panaxadiol-type ginsenosides, protopanaxatriol-type
ginsenosides, and oleanolic acid-type saponins. In the
past decades, various investigations dealing with the
pharmacokinetics of these ginsenosides have been
published. From these studies, it can be concluded that
the decomposition modes are different for
protopanaxadiol and protopanaxatriol saponins.
Ginsenoside Rg1 (protopanaxatriol-type) showed
an extremely short half-life of 27 min after intravenous
administration into minipigs. In contrast, the
protopanaxadiol-type ginsenoside Rb 1 showed a
half-life in the ß-phase of 16 h. These results correlated
with the pharmacokinetic results in rats and in rabbits.
The high persistence of Rb1 in serum and tissues was
attributed to a high degree of plasma protein binding.
Rg 1 was rapidly absorbed by mice after oral
administration (~30% after 1 h). The concentration of
Rg1 and metabolites was high in the blood, liver, bile,
subcutis, conjunctiva, and epithelia of the oral cavity,
esophagus, and nasal cavity; the concentration was low
in muscle and endocrine organs and very low in the
brain. Rg1 also was metabolized rapidly. Intact Rg1 was
excreted in mouse urine and feces in very small
amounts, but the metabolite concentration was high.
Five metabolites could be detected; two of them were
ginsenoside Rh1 and 25-OH-Rh1. Intact cells were used
to study the metabolism of ginsenoside Rh2[28]. Odani et
al. reported that the amount of Rg1 and Rb1 absorbed
from the gastrointestinal tract of rat were 1.9% and
0.1%, respectively [ 2 9 , 3 0 ] . Rb 2 was detected to
 Yang L et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2006; 6(2):103-120
be 3.7% using 3H-labeled Rb2. Rg1 was excreted into
the urine (0.4%) and bile (1.1%) in oral administration
of a single dose (100mg·kg-1) in rats[31]. By HPLC
analysis, Rb1 and Rg1 in the same serum were
determined after administering saponins of Panax
notoginseng (PNS) to rats. The decline of Rb1 in serum
could be described by a two-compartment model. The
half-life of α phase was 23.40 min and that of β phase
was 17.96 h. Rb1 was absorbed from the digestive tract
and the bioavailability via P.O. was 4.35%. The
pharmacokinetics of Rg1 in rats also could be described
by a two- compartment model. The half-lives of Rg1
were 24.23 min for α phase and 14.13 h for β phase[47].
After iv infusion of Shenmai injection to volunteers, the
concentration- time curves of Rg1 and Re fitted to the
two-compartment model[46].
Aqueous humor, cornea and iris-ciliary body of
rabbit were collected at a range of time following
topically applying S-Rg3 eyeointment. The result
showed that the pharmacokinetics of S-Rg3 in rabbit
eye were described by one-compartment model [48]. An
average half-life of 18.5 min was obtained after Rg3
was intravenously dosed at 5 mg·kg-1. However, Rg3
was not detected in rat plasma collected after oral
administration at 100 mg·kg-1[33]. The pharmacokinetics
of R-Rg3 in healthy volunteers showed that after oral
administration, the absorption of R-Rg3 was rapid in
man, and its elimination was rapid after oral
administration of R-Rg3[34].
An average half-life of 16 min in plasma was
obtained after intravenous administration Rh2 to male
Sprague-Dawley rats. No Rh2 was detected in plasma
samples following oral administration, and only a small
amount was found in the feces samples after
oraladministration. Three metabolites of Rh2 were
detected in the feces samples. Oxygenation and
deglycosylation were found to be the major metabolic
pathways of Rh2. Intense metabolism, rather than
excretion, appears to be the reason for the fast clearance
of this ginsenoside[49]. The oral bioavailability of Rh2 in
dog was relative high for male (17.6%) and female
(24.8%) dogs, respectively[50]. However, a similar
method did not detected Rh2 and Ppd in dog plasma[44].
About 24.4%-26.2% and 54.3%-81.7% of C-K
111
were recovered for i.v. and oral administration from the
entire gastrointestinal tract, respectively. Following oral
administration, dose-normalized AUC was increased at
the 20 mg/kg dose, compared with those at lower doses.
Subsequently, the absolute oral bioavailability was
increased about 8-20 times[26]. Additionally, another
study after oral administration of Rb1 and C-K revealed
that intact Rb1 was not detectable in serum for 24 h by
HPLC analysis, whereas the level of C-K in the serum
reached maximum at 8 h (about 8.5 μg·mL-1) after Rb1
administration, and at 2 h (about 10 μg·mL-1) after C-K
administration, respectively[27].
After the oral administration of ginseng total
saponin (1 g·kg-1·d-1) to rats, C-K was detected about
0.9 μg·mL-1 in blood at 6 h and 5.1μg·mL-1 at 24 h, 3.8
μg·mL-1 in urine at 0-24 h and 3.7μg·mL-1 at 24-48 h.
Ppd was detected about 0.6 μg·mL-1 in blood at 24 h,
and not detected in urine. Ppt was detected about 0.4
μg·mL-1 in blood at 6 h and 0.7 μg·mL-1 at 24 h, and not
detected in urine. Their intestinal absorption is
time-dependently enhanced. After the oral
administration of ginseng extract (150 mg·kg-1·d-1) in
human, C-K was detected about 0.2 μg·mL-1 in urine at
16-24 h[35].
In summary, the simultaneous monitoring of all
compounds including naturally occurring ginsenosides
and their degradation products is not practical due to
the limitation of techniques and cost. However, the
current studies about have offered a lot of information.
Based on this, the diagnostic compounds may be
identified in the near future, which can be used as
markers of pharmacokinetics properties of ginseng or
its products.
Drug–drug interactions and influence on
cytochrome P450
There are two types of drug–drug interactions
based on pharmacokinetics and pharmacodynamics.
Adverse events are generally linked to the association
of concomitant drugs able to induce or inhibit drug
metabolizing enzymes or transporters and drugs with a
narrow therapeutic window[51]. In the last decades, the
consumption of herbal medicine has increased by
Yang L et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2006; 6(2):103-120
unprecedented proportions.
Although herbal remedies are often promoted as
natural and therefore harmless, they are not free from
adverse effects. It has been well documented that they
are associated with clinically significant drug-drug
interactions (DDI) via the inhibition of cytochrome
P450 isoforms (CYPs), and with adverse events that
include all levels of severity, organ systems, and age
groups[52-54]. A recent survey in China indicated that
75% of respondents had used traditional Chinese
medicine (TCM) during the past year in treatment of
diseases[55]. A similar survey in USA also showed that
in 1997, 42.1% U.S. households used unconventional
therapy including herbal medicine, and an estimated 15
million adults took prescription medications
concurrently with herbal remedies and/or high-dose
vitamins (18.4% of all prescription users)[56]. There are
also several surrey indicating that ginseng is one of the
most commonly used herbs[57-59]. This means that
numerous persons are at risk for potential
herb-prescription drug interactions.
The in vitro study of influence on transporters
The transporters are known to be important in the
transport of many xenobiotics into/out of cells. Among
these transporters, P glycoprotein (Pgp) is a drug
transporter responsible for the efflux of xenobiotics out
of cells that influence the pharmacokinetics of
numerous drugs. On one hand, Pgp is distributed within
a lot of organs and tissues implicated in the absorption
or excretion of xenobiotics, and drug–drug interactions
with this protein may increase the bioavailability of
simultaneously administered active drugs. On the other
hand, Pgp is linked to the integrity of blood–tissue
barriers, such as the blood–brain barrier or placenta,
and a partial blockage of Pgp could be responsible for a
new drug distribution in the organism with possible
increase of drug rates in organs behind these barriers.
Therefore, concomitant administration of substrates and
Pgp inhibitors would modify drug pharmacokinetics by
increasing bioavailability and organ uptake, leading to
more adverse drug reactions and toxicities[60].
Molnar et al. reported that ginsenosides Rg1, Re,
Rc, and Rd were found to have a moderate inhibitory
112
effect on the drug efflux pump in multidrug resistant
mouse lymphoma, and increased drug accumulation
and tumor antigen expression at low concentrations[61].
Using rhodamine 123 as an artificial substrate, Rg3
promoted accumulation of rhodamine 123 in
drug-resistant KBV20C cells in a dose-dependent
manner, but it had no effect on parental KB cells.
Additionally Rg3 inhibited 3H-vinblastine efflux and
reversed MDR to doxorubicin, COL, VCR, and VP-16
in KBV20C cells. The further study showed that
inhibition of drug efflux by Rg3 was due to neither
repression of MDR1 gene expression nor Pgp level.
Photo-affinity labeling study revealed that Rg3
competed with anticancer drug for binding to Pgp
thereby blocking drug efflux[62]. In addition, Rh2 can act
either additively or synergistically with chemotherapy
drugs to hypersensitize multidrug-resistant breast
cancer cells to paclitaxel[63].
Besides Pgp, Fuchikami et al. examined the effects
of herbal extracts used in dietary supplements on the
function of organic anion transporting polypeptide B
(OATP-B; OATP2B1), which is expressed on human
intestinal epithelial cells, and is considered to be
involved in the intestinal absorption of various drugs.
Specifically, the effects of extracts of Siberian ginseng
on uptake of estrone-3-sulfate, a typical OATP-B
substrate, by human embryonic kidney 293 cells stably
expressing OATP-B were evaluated. The extracts of
Siberian ginseng moderately inhibited estrone-3-sulfate
uptake. These results suggested that co-administration
of ginseng-derived products may decrease the
absorption of orally administered substrates of
OATP-B[64].
In a recent study, Caco-2 cells were used as
models to evaluate the effect of purified kaempferol
from ginseng on Pgp-mediated efflux of the human
immunodeficiency virus (HIV) protease inhibitor
ritonavir. In addition, the inhibitory effect of
kaempferol on CYP3A4-mediated metabolism was
determined by using cortisol as a model compound.
Kaempferol exhibited a remarkable inhibition of
Pgp-mediated efflux of ritonavir by increasing its
cellular uptake in these models. There was a significant
decrease in the Apical to Basal/Basal to Apical
 Yang L et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2006; 6(2):103-120
(AP-BL/BL-AP) transport ratio of ritonavir in presence
of kaempferol. When tested with the Vivid CYP3A4
assay kit, kaempferol caused substantial inhibition of
cortisol metabolism, compared with the control[65].
The in vivo study of Ginseng-drug interactions
Numerous persons have taken ginseng or its
derived products. However, they are not free from
adverse effects, and there are a number of reports about
ginseng-prescription drug interactions. Therefore, it is
vital to evaluate whether ginseng, one of the most
commonly used herbal products, and its active
components possess the potential to exert drug
interactions. However, data suggest that the ginsenoside
composition varies widely among commercially
available ginseng products[23]. This variability makes it
difficult to evaluate the safety and efficacy of ginseng
products.
There are several clinical studies about the
interactions of ginseng with prescription drugs.
However, the reported ginseng-drug interactions in the
clinical trials are somewhat contradictory, as these
studies have shown that ginseng may have no
significant effects, or have statistically significant
interactions.
Interactions with warfarin, digoxin and
albendazole sulfoxide
The interactions are particularly important if a
drug has a narrow therapeutic index, such as warfarin.
A case report describes a probable interaction between
warfarin and a ginseng product (Ginsana)[66]. The
International Normalized Ratio (INR) of the patient
was 3.1 four weeks before he started taking ginseng.
Two weeks after the patient started taking ginseng,
hisINR declined to 1.5. Ginseng was discontinued, and
the INR returned to 3.3 in two weeks.
In a randomized, double-blind, placebo-controlled
trial, the interactions between American ginseng and
warfarin was evaluated. The peak INR statistically
significantly decreased after 2 weeks of ginseng
administration compared with placebo. The INR area
under the curve (AUC), peak plasma warfarin level,
and warfarin AUC were also statistically significantly
113
reduced in the ginseng group as compared with the
placebo group. Peak INR and peak plasma warfarin
level were positively correlated. Because of the narrow
therapeutic index of warfarin, keeping its anticoagulant
effect in a target range is crucial[67].
However, in another trail in 12 healthy male
subjects, INR and platelet aggregation were not
affected by treatment with ginseng. Ginseng did not
affect the apparent volumes of distribution or protein
binding of warfarin enantiomers. Although ginseng
diminished the urine excretion rate (UER) of
S-7-hydroxywarfarin, the metabolite from S-warfarin,
co-administration of warfarin with ginseng did not
affect the pharmacokinetics or pharmacodynamics of
either S-warfarin or R-warfarin[68]. A similar study in
male rats showed no significant impact of ginseng on
the pharmacokinetics/pharmacodynamics of warfarin
when they are concomitantly administered[69].
A clinical study with class IV cardiac function
showed that the co-administration of Red Ginseng
improved the hemo-dynamical and biochemical indexes
of digoxin, Red Ginseng and digoxin had synergism for
treatment of congestive heart failure[70]. However, in
other cases, the apparent interaction may be misleading.
It has been shown that when Siberian ginseng was used
in combination with digoxin, the interaction resulted in
elevated plasma digoxin levels[71], but in this particular
case there was evidence that the increased levels of
digoxin were due to interference with the assay rather
than as a result of PK effects[72].
A recent study with rat suggested that Panax
ginseng increased the intestinal elimination of the
benzimidazole derivative albendazole sulfoxide
(ABZSO)[73]. An upper small intestine segment was
isolated and perfused in situ with saline, while ABZSO
solution was administered intravenously. Systemic
co-administration of ginseng increased significantly the
clearance of ABZSO. The increase in ABZSO
elimination could be the result of the effect of ginseng
on metabolic pathways.
In vivo study of DDI via the influence on
cytochrome P450
Yang L et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2006; 6(2):103-120
Metabolizing enzyme-based drug interactions
constitute the major proportion of clinically important
drug interactions. The inhibition of CYPs activities may
result in clinically significant DDI[74].
There are several in vivo studies about the effects
of ginseng, ginseng extracts, or naturally occurring
ginsenosides on CYPs activities. However, the reported
effects of ginseng on CYPs activities in the clinical
trials are somewhat contradictory, as these studies have
shown that ginseng may have no significant effects, or
have statistically significant inhibition of some CYPs
activities.
In a recent clinical trial, single timepoint,
phenotypic metabolic ratios were used to determine
whether long-term supplementation of St John's wort,
garlic oil, Panax ginseng, and Ginkgo biloba affected
CYP1A2, CYP2D6, CYP2E1 or CYP3A4 activity in
twelve healthy aged volunteers[75]. The results showed
that P. ginseng inhibition of CYP2D6 was statistically
significant, but the magnitude of the effect did not
appear to be clinically relevant. In addition, long-term
ginseng supplementation has been shown to produce
modest increases in nifedipine plasma concentrations,
implying an inhibitory effect on CYP3A4[76].
By contrast, another clinical trial in 12 normal
volunteers indicate that standardized extracts of
Siberian ginseng (SG) at generally recommended doses
for over-the-counter use are unlikely to alter the
disposition of co-administered medications primarily
dependent on the CYP2D6 or CYP3A4 pathways for
elimination[77]. In addition, in a 12 healthy volunteers
trail, a long-term supplementation (28 days) of Panax
ginseng did not significant effect on CYP3A4,
CYP1A2, CYP2E1, and CYP2D6 activity[78]. Further,
health subjects received Panax ginseng standardized
extracts for 14 days, and Panax ginseng did not
significantly alter the urinary 6-β-OH-cortisol/cortisol
ratio, the marker of CYP3A activity[79].
In vitro study of drug-drug interactions via
influence on cytochrome P450
Because ginseng products are orally administered
in most cases, the influence of ginsenosides on CYPs
activities in vivo includes the influence on both
114
intestinal and hepatic P450 activities. The majority of
naturally occurring ginsenosides including Rb1, Rb2,
and Rg1 is poorly absorbed[24-32]. They have been found
to be deglycosylated by colonic bacteria followed by
transit to the systemic circulation[20]. Thus, every orally
administered component and their degradation products
in gastrointestinal tract are possible of exerting an
influence on intestinal CYPs. However, the influence
on hepatic CYPs should be subject to the precondition
that the ginsenosides can be absorbed from the
gastrointestinal tract and enter systemic circulation.
In vitro study of influence on cytochrome P450
Metabolism of compounds represents a key
process by which drugs are cleared from the body. They
are mainly eliminated by cytochrome P450 (CYPs or
P450) enzymes (Phase I metabolism) and by
conjugating enzymes (Phase II metabolism), such as
UDP-glucuronosyl transferases and N-acetyl
transferases[80-82]. These enzymes add functional groups
to make lipophilic molecules more hydrophilic and
hence easier to eliminate. CYPs, a superfamily of
heme-containing isoenzymes located primarily in
hepatocytes, are responsible for the oxidative
metabolism of the majority of drugs and xenobiotics[83].
In liver, the most important CYPs from the
viewpoint of drug metabolism are CYP1A2, CYP2A6,
CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4,
which represent about 70% of the total CYPs enzymes
and are responsible for the oxidation of more than 90%
clinical drugs[84,85]. In intestine, CYP3A4 is the
predominant CYP, while only a very limited number of
other CYPs including CYP2C9, CYP2C19, and
CYP1A1 are expressed[86,87]. Intestinal CYPs also have
been shown to contribute significantly to the
metabolism of several drugs, including nifedipine and
midazolam[88,89]. The inhibition of CYPs activities may
result in clinically significant DDI[90].
There are some in vitro studies about the effect of
ginseng, ginseng extracts or naturally occurring
ginsenosides on CYPs activities. Henderson et al.
achieved the evaluation of the effects of seven naturally
occurring ginsenosides Rb1, Rb2, Rc, Rd, Re, Rf, and
Rg 1 and eleutherosides B and E (active
 Yang L et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2006; 6(2):103-120
components of the ginseng root) on the catalytic
activity of cDNA expressed CYPs (CYP1A2, CYP2C9,
CYP2C19, CYP2D6 and CYP3A4) in in vitro
experiments. Of the components tested, three
ginsenosides (Rd, Rc, and Rf) modified the activity of
the recombinant enzymes. Rd produced weak inhibitory
activity against the surrogate substrates for CYP3A4
and CYP2D6 and even weaker inhibitory activity
against the surrogate substrates for CYP2C19 and
CYP2C9. Rc produced an weak increase in the activity
of CYP2C9 and Rf produced an increase in the activity
of CYP3A4. The authors suggest that the ginsenosides
and eleutherosides tested are not likely to inhibit the
metabolism of co-administered medications in which
the primary route of elimination is via cytochrome
P450; the potential of ginsenosides to enhance the
catalysis of certain substrates requires further
investigation[91]. In a study in human liver microsomes,
Rd was found inhibitory potency on both CYP2C9- and
CYP3A4-mediated index reactions with IC50 values of
105 and 62 μmol/L, respectively. Rb1, Rb2, and Rc had
limited inhibitory activities on both enzyme reaction
systems[92].
In another in vitro study, the effect of a
standardized Panax ginseng (or Asian ginseng) extract
(G115), a standardized Panax quinquefolius (or North
American ginseng) extract (NAGE), and individual
ginsenosides (Rb1, Rb2, Rc, Rd, Re, Rf, and Rg1) on
CYP1 catalytic activities, were examined. G115 and
NAGE decreased human recombinant CYP1A1,
CYP1A2, and CYP1B1 activities in a occurring ginsenosides in gastrointestinal tract, namely
concentration-dependent manner. Except for the
competitive inhibition of CYP1A1 by G115, the mode
of inhibition was the mixed-type in the other cases.
NAGE was 45-fold more potent than G115 in inhibiting
CYP1A2. Compared with G115, NAGE also
preferentially inhibited 7-ethoxyresorufin
O-dealkylation activity in human liver microsomes. Rb1,
Rb2, Rc, Rd, Re, Rf, and Rg1, either individually or as a
mixture and at the levels 100 μg·mL-1 of NAGE or
G115, did not influence CYP1 activities. However, at a
higher ginsenoside concentration (50μg·mL-1), Rb1, Rb2,
Rc, Rd, and Rf inhibited these activities. The findings
indicate that standardized NAGE and G115 extracts,
115
which were not treated with calf serum or subjected to
acid hydrolysis, inhibited CYP1 catalytic activity in an
enzyme-selective and extract-specific manner, but the
effects were not due to Rb1, Rb2, Rc, Rd, Re, Rf, or
Rg1[93]. In addition, using primary cultures of human
hepatocytes from 17 individuals, Raucy assessed the
inducibility of CYP3A4 mRNA by prototypical
inducers, dietary flavonoids, and botanicals. Ginseng
produced about 1.5 times of control CYP3A4
mRNA[94].
Utilizing the probe reaction of CYP3A activity,
testosterone 6β-hydroxylation, and rat liver microsomes,
Liu et al. found that ginsenosides from the
20(S)-protopanaxadiol and 20(S)-protopanaxatriol
family including naturally occurring ginsenosides
including Rb1, Rb2, Rc, Re, Rg1 and one of the
intestinal bacterial metabolites of ginsenosides, C-K,
had no inhibitory effect, had no inhibitory effect,
whereas Rg2, 20(S)-panaxatriol (Pt) and another
intestinal bacterial metabolite, Ppt, exhibited potent
inhibition against rat CYP3A activity with the
inhibition constants (Ki) of about 86.4, 1.7, and 3.2
μmol·L-1, respectively [95]. Using a “cocktail” approach
including four probe drugs caffeine, dapsone,
chlorzoxazone and omeprazole by HPLC determination,
Fan et al studied the influence of ginsenosside Re on
CYP1A2, 3A4, 2E1, and 2C19 in rats. The results
suggested that Re could induce CYP1A2 and 3A4, and
did not influence on CYP2E1 and 2C19[96]. Tawab et al.
reported that two hydrolysis products of naturally
Rh1 and F1 can enter systemic circulation[29]. Liu and
co-workers found that Rh1 and F1 exhibited moderate
competitive inhibition of the activity of CYP3A4. F1
also exhibited weaker inhibition of the activity of
CYP2D6. Rh1 exhibited weak stimulation rather than
inhibition of the activity of CYP2E1[97].
Based on the previous studies, Liu et al. further
conducted a systematic study about influence of a set of
ginsenosides on CYPs activities, and found that
naturally occurring ginsenosides, including Rb1, Rb2,
Rc, Re, and Rg1, exhibited no inhibition on CYPs
activities, and another naturally occurring ginsenoside
Rd exhibited weak inhibition on CYP1A2, CYP2C9,
Yang L et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2006; 6(2):103-120
CYP2D6, and CYP3A4. Their degradation products
Rg2, S-Rg3, and Rh2 also exhibited no inhibition on
P450 activities, except the weak inhibition of S-Rg3 on
CYP2D6 and of Rh2 on CYP3A4. However, the
intestinal metabolites of ginsenosides including C-K,
Ppd and Ppt demonstrate a wide range of inhibition of
CYPs -mediated metabolism. C-K, Ppd and Ppt, all
exhibited moderate inhibition against the activity of
CYP2C9 in human liver microsomes. Ppd and Ppt were
found to have strongly competitive inhibition against
CYP3A4 in both human liver microsomes and
cDNA-expressed CYP3A4. There is no
mechanism-based inhibition of P450 induced by
naturally occurring ginsenosides or their degradation
products[98].
These results suggested that the degradation of
ginsenosides in gastrointestinal tract may play an
important role in the influence on CYPs.
Prediction of drug-drug interactions via
influence on cytochrome P450
There are some in vitro studies about the effect of
ginseng, ginseng extracts or naturally occurring
ginsenosides on CYPs activities. Some studies
suggested naturally occurring ginsenosides have no or
limited influence on CYPs activities. However, Liu et
al found that the deglycosylation products of naturally
occurring ginsenosides including Rh1, F1, C-K, Ppd and
Ppt demonstrate a wide range of inhibition of
CYPs-mediated metabolism. Among these, Ppt and Ppd,
exhibited potent inhibition against CYP3A4 activity;
Rh1, F1 exhibited moderate inhibition against CYP3A4
activity; and C-K, Ppd and Ppt also exhibited moderate
inhibition against CYP2C9 activity. These results
demonstrate that ginseng-derived products might have
potential for significant ginseng-drug
interactions[95,97,98]
. hypoglycemic activity.
Both the content and activity of CYPs exhibit a
high degree of inter- and intra-individual variability[99].
The genetic polymorphism of CYPs is extensive, and
the rate of metabolism for a certain drug can even differ
1000-fold between phenotypes [100]. In addition, human
intestinal bacteria exhibit a high degree of
intra-individual variability, as which are very
116
changeable in dependence of host conditions, including
diet, health, and even stress. The bacterial
ginsenoside-hydrolyzing potentials also exhibit a high
degree of inter-individual variability in humans and
experimental mice[20]. Moreover, substantial variability
in ginsenoside content has been reported among
commercial ginseng preparations[23]. These reports
imply that the clinically significant effects of ginseng
on CYPs activity might be individual-dependent and
product-dependent, which might be responsible for the
inconsistency of those clinical studies[98].
Discussion
Ginseng, the king of traditional Chinese medicines,
is the most famous Asian herb, and has been in
medicinal use for thousands of years. Materia Medica
of Divine Plowman written in China about 2,000 years
ago records ginseng as the highest quality herb.
Ginseng has been used widely in Asia, Europe and
America.
The main active agents in Panax ginseng are
ginsenosides, which are triterpene saponins. The
majority of published research on the medicinal activity
of Panax ginseng has focused on ginsenosides. These
are the compounds to which some ginseng products are
now standardized. Research reviews[101, 102] postulate
that extracts of Panax ginseng affect the
hypothalamus-pituitary-adrenal axis and the immune
system, which could account for many of the
documented effects. Animal models and in vitro studies
mentioned that Panax ginseng enhances phagocytosis,
natural killer cell activity, and the production of
interferon; improves physical and mental performance
in mice and rats; causes vasodilation; increases
resistance to exogenous stress factors; and affects
The chemical constituents of ginseng root have
been investigated since the beginning of the 20th
century, and several classes of compounds have been
isolated: triterpene saponins; essential oil-containing
polyacetylenes and sesquiterpenes; polysaccharides;
peptidoglycans; nitrogen-containing compounds; and
various ubiquitous compounds such as fatty acids,
 Yang L et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2006; 6(2):103-120
carbohydrates, and phenolic compounds.
The biologically active constituents in Panax
ginseng are the complex mixture of triterpene saponins
known as ginsenosides, which are mainly triterpenoid
dammarane derivatives. Ginsenosides Rx according to
their mobility on thin-layer chromatography plates,
with polarity decreasing from index "a" to "h". The root
contains 2-3% ginsenosides of which Rg1, Rc, Rd, Rb1,
Rb2, and Rb0 are quantitatively the most important. At
least 30 ginsenosides have been isolated and
characterized. [101-105]
By applying various chemical and spectroscopic
methods, researchers have found that the genuine
aglycones were protopanaxadiol and protopanaxatriol,
which both have a dammarane skeleton. On acid
treatment of protopanaxadiol and protopanaxatriol, a
tertiary hydroxyl group attached to C-20 participates in
ring closure with a double bond in the side chain. Total
of 31 ginsenosides have been isolated from the roots of
white and red ginseng. They can be categorized in three
groups depending on their aglycones: protopanaxadiol-
type ginsenosides, protopanaxatriol- type ginsenosides,
and oleanolic acid-type saponins. All dammarane
ginsenosides isolated from ginseng root (white ginseng)
are derivatives of the 20S protopanaxadiol and the 20S
Fig 5. An HPLC gradient elution chromatogram shows the differences
between red and white ginseng. (cited from Reference 104)
Conclusion
The study about pharmacokinetic properties of
ginseng is in favor of understanding the safety and
117
protopanaxatriol, with the exceptions of 20R
ginsenoside Rg3, Rh4, and koryoginsenoside R2.
Ginseng is specified in the German, Swiss, Austrian,
and French pharmacopeias, among others. The Swiss
pharmacopeia demands a total ginsenoside content,
calculated as ginsenoside Rg1, of not less than 2.0%.
According to the German pharmacopeia, the total
ginsenoside content should be not less than 1.5%. Both
pharmacopeias use a spectrophotometric method for
quantification. However, a draft for the European
pharmacopeia demands the content of ginsenosides Rg1
and Rb1 to be not less than 0.3%, measured with an
HPLC method. HPLC separations such as the one
published by Samukawa and co-authors enable the
separation of additional ginsenosides; 22 ginsenosides
can be separated in a single run (Fig 5).
In fact, the pharmacokinetics, metabolism and
drug-drug interactions of these compounds were only
studied for a part ginsenosides. Because of complex
of metabolism process, the determination of
ginsenosides and their metabolites in biological
samples can be not separated in a single run.
Therefore, we will face many difficult challenges in
this field.
active mechanism of ginseng. To clarify the ADME
properties of Ginseng, the major active components,
ginsenosides, are mainly focused on biotransformation
includes in vitro and in vivo metabolism of multiple
Yang L et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2006; 6(2):103-120
components. In addition, some of ginsenosides are
transformated in gastrointestinal tract by gastric acid
and microflora.
The inconsistency of detected ginsenosides with
real active components due to the lack of knowledge of
active mechanisms, variability of component contents
and so on, make the evaluation of ginseng
pharmacokinetics more difficult than that of the so
called western drugs, a single component. In this
chapter, the studies of naturally occurring ginsenosides
and their metabolites by in vitro and in vivo methods
determining pharmacokinetic properties, such as
physicochemical properties of ginsenosides,
metabolizing enzymes, transporters and deglycosy-
lation in gastrointestinal tract, as well as
ginsenoside-drug interactions are summarized.
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