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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


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

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

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

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

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

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

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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

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

Since the bacterial metabolites are absorbed to showed that ginsenoside Rb1 was not detected in the
blood circulation instead of parent naturally occurring blood[24]. Akao et al. reported that when ginsenoside
ginsenosides, Kobashi et al. proposed the concept of Rb1 (200 mg·kg-1) was administered orally to germ-free
plant glycoside acting as “natural prodrug”[21,22]. The rats, neither C-K nor any other metabolite was detected
degradation of ginsenosides in gastrointestinal tract in the plasma, and most of the ginsenoside Rb1
may be an important issue to clarify the administered was recovered from the intestinal tract,
pharmacological mechanism of ginseng. indicating poor absorption of Rb1[25]. In addition,
neither intact Rb1 nor its intermediate derivatives but
The absorption from the gastrointestinal tract 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
The absorption of naturally occurring mg·kg-1)[13,26]. Another study of Rb1 after oral
ginsenosides administration revealed similar results[27]. Odani et al.
In most of commercial ginseng-derived products, major reported that oral bioavailabilities of Rb1 and Rg1 from
and abundant components consist of naturally occurring intestine were very low, only 0.1% and 1.9%,
ginsenosides Rb1, Rb2, Rc, Rd, Re, Rf, Rg1 and so on[23]. respectively[28,30]. Tanizawa et al. reported that 3.7%
Most of them are poorly absorbed from gastrointestinal Rb2 was absorbed from intestine using 3H-labeled
tract. After oral administration of red Ginseng extracts, Rb2[31]. By HPLC analysis, Xu et al. reported that Rb1
the plasma concentration of ginsenosides in healthy (4.35%) and Rg1 (18.40%) were absorbed,
volunteers was examined by EIA-HPLC, and the result respectively[32].

Glc-O
OH

Glc-O Glc-O HO HO
OH OH OH
OH M11 (F1)

HO
OH
HO HO HO
O-Glc2-1Rha O-Glc OH

Re Rg1 M4(ppt)
HO
O-Glc

M8 (Rh1)
Fig 4. The main metabolic pathways of protopanaxatriol ginsenosides

Rg3 was not detected in rat plasma collected after not detected in rat plasma[34].
oral administration at 100 mg·kg-1. Only 0.97-1.15% These results suggest that the absorption of
Rg3 of the dosed amount was determined in feces[33]. naturally occurring ginsenosides is poor, and that their
After a single dose (3.2 mg/kg R-Rg3) of oral plasma concentration may be difficult to reach the
administration in 8 male volunteers, the maximal needed concentrations exhibiting their reported
plasma concentration-time was 16 ng/ml. After an oral pharmacological activities.
dose of 0.8 mg·kg-1 in 6 other volunteers, R-Rg3 was

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

The absorption of ginsenoside metabolites and not excreted to bile like M1. It was accumulated in
Using the permeability assay with Caco-2 cell the liver longer than M1[37].
monolayer, Paek et al. studied the absorption potential Ppt (M4) is the main bacterial metabolite of
of C-K, a major intestinal bacterial metabolite of protopanaxatriol-type ginsenosides. The orally
ginsenosides, which showed moderate permeability administered M4 was absorbed from the small intestine
with no directional effects, thus suggesting passive into the mesenteric lymphatic vessels followed by the
diffusion[26]. rapid esterification of M4 with fatty acids accumulated
After the oral administration of ginseng total in the liver[38].
saponins to rats, two major intestinal bacterial
metabolites of protopanaxadiol ginsenosides, namely The current pharmacokinetics studies of
C-K and Ppd, together with a major intestinal bacterial ginsenosides
metabolite of protopanaxatriol ginsenosides, Ppt, were
detected in blood. Their intestinal absorption is To understand the safety and active mechanism of
time-dependently enhanced. After the oral ginseng, a huge quantity of work has been carried out
administration of ginseng extract (150 mg·kg-1·d-1) in during the last 30 years in order to develop analytical
human, C-K was detected about 0.2 μg·mL-1 in urine at methods for pharmacokinetics studies about various
16-24 h[35]. Another pharmacokinetic study after oral ginsenosides and their intestinal metabolite. Major
administration of Rb1 and C-K revealed that the level of advances in analytic techniques have provided rapid and
C-K in the serum reached maximum at 8 h (8.5μg·mL-1) efficient identification of compounds, and many
after Rb1 administration, and at 2 h (10.3 μg·mL-1) after pharmacokinetics studies about various ginsenosides
C-K administration, respectively [27]. have been achieved. However, the inconsistency of
After the oral administration of standardized detected compounds with active components resulting
Ginsana extract G115, it was shown that two hydrolysis from the lack of knowledge of real active components
products of the protopanaxatriol ginsenosides, namely has hampered the uncovery of ADME properties of
Rh1 and F1 were found in the systemic circulation. In ginseng. Fortunately, these studies have offered a lot of
addition, C-K was detected in both plasma and urine, information, which will help us to uncover these
and Rb1 was only identified in plasma and urine of one properties.
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 There are some analytic methods that have been
are more permeable than naturally occurring used in the pharmacokinetics studies of animal or
ginsenosides. However, further studies might be needed human oral administered ginseng-derived products to
since no direct comparison between naturally occurring detect naturally occurring ginsenosides and their
ginsenosides and the degradation products. intestinal metabolites.
Recently, a liquid chromatography-mass
Ginsenoside metabolism in Liver spectrometry (LC-MS) method for simultaneously
determining the concentration of Rg1 and its secondary
Hasegawa et al. found that C-K (M1) was Rh1 and aglycone Ppt in rat plasma has been
selectively accumulated into the liver soon after its established[39]. The method has been used for the
intravenous administration to C57BL/6 mice and Wistar pharmacokinetic study of Rg1 in rats. Rg1 could be
rats, and mostly excreted to bile as protype. However, determined by this LC-MS method over the ranges of
some of C-K was esterified to its mono-fatty acid esters 1.56-250 ng/ml and 250-20,000 ng·mL-1 with good
(called EM1) in the liver. EM1 was isolated from the correlation. Chromatographic separation was achieved
rat liver in a recovery dose of approximately 24 mol% in less than 8 mins.

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

A simple and sensitive high-performance combined with HPLC was developed by Kanaoka et al.,
chromatographic (HPLC) and solid-phase extraction however, Rb1 was not detected in human blood[46].
(SPE) method have been used to simultaneously
determine the concentration of ginsenosides Rg1, Rb1, Pharmacokinetics of ginsenosides
Rd and notoginsenoside R1 in Panax notoginseng (PNS) By applying various chemical and spectroscopic
in rat serum after oral and intravenous administration of methods, researchers have found that the genuine
total saponins of PNS to rats[40]. The calibration curves aglycones were protopanaxadiol and protopanaxatriol,
for the four saponins were linear in the given which both have a dammarane skeleton. On acid
concentration ranges. The method also exhibited good treatment of protopanaxadiol and protopanaxatriol, a
accuracy and precision, as well as a high recovery rate. tertiary hydroxyl group attached to C-20 participates in
A similar method was also reported to simultaneously ring closure with a double bond in the side chain. 31
determine the concentration in rat urine of ginsenosides ginsenosides have been isolated from the roots of white
Rg1, Rb1, Rd, and notoginsenoside R1 in rat urine, and red ginseng. They can be categorized in three
which also exhibited good accuracy and precision, as groups depending on their aglycones: proto-
well as a high recovery rate[41]. panaxadiol-type ginsenosides, protopanaxatriol-type
A method using HPLC with ultraviolet absorbance ginsenosides, and oleanolic acid-type saponins. In the
detection and SPE was also described for the past decades, various investigations dealing with the
determination of Rg3 in human plasma, with acceptable pharmacokinetics of these ginsenosides have been
accuracy and precision. A good linear relationship was published. From these studies, it can be concluded that
ranged from 2.5 to 200 ng·mL-1[42]. the decomposition modes are different for
To determine the concentration in plasma of protopanaxadiol and protopanaxatriol saponins.
ginsenosides Rg1 and Re after iv infusion of Shenmai Ginsenoside Rg1 (protopanaxatriol-type) showed
injection in human, a LC/MS/MS method was well an extremely short half-life of 27 min after intravenous
established by Liu and co-workers[43]. The linear administration into minipigs. In contrast, the
regressive curves were obtained in the range of protopanaxadiol-type ginsenoside Rb 1 showed a
1.023-1023 μg·L-1 for Rg1 and 1.05-1050 μg·L-1 for Re. half-life in the ß-phase of 16 h. These results correlated
Based on HPLC-ESI-MS in negative ion mode with the pharmacokinetic results in rats and in rabbits.
with the mobile phase additive, a novel method to The high persistence of Rb1 in serum and tissues was
quantitatively analyze Rg3, Rh2 and Ppd in rat plasma attributed to a high degree of plasma protein binding.
was developed and validated[44]. The exhibited good Rg 1 was rapidly absorbed by mice after oral
accuracy and precision, as well as the high recovery administration (~30% after 1 h). The concentration of
rate suggested that the method is specific, simple, Rg1 and metabolites was high in the blood, liver, bile,
sensitive and suitable for the measurement of plasma subcutis, conjunctiva, and epithelia of the oral cavity,
Rg3, Rh2 and Ppd concentrations. Another method esophagus, and nasal cavity; the concentration was low
based on LC-MS and MS-MS was also established to in muscle and endocrine organs and very low in the
determine Rg3 and its metabolites in rat plasma, urine brain. Rg1 also was metabolized rapidly. Intact Rg1 was
and feces samples[33]. This method offered a excreted in mouse urine and feces in very small
satisfactory sensitivity for the determination of R-Rg3 amounts, but the metabolite concentration was high.
in plasma, with good precisions and accuracy[45]. Five metabolites could be detected; two of them were
In addition, a method of isotope labeling was used ginsenoside Rh1 and 25-OH-Rh1. Intact cells were used
in the pharmacokinetics studies of ginsenoside Rb2[24]. to study the metabolism of ginsenoside Rh2[28]. Odani et
This method of specific position labeling of Rb2 may be al. reported that the amount of Rg1 and Rb1 absorbed
applicable to other ginsenosides. Micro-detection of from the gastrointestinal tract of rat were 1.9% and
ginsenosides by EIA (enzyme immunoassay) method 0.1%, respectively [ 2 9 , 3 0 ] . Rb 2 was detected to

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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 were recovered for i.v. and oral administration from the
the urine (0.4%) and bile (1.1%) in oral administration entire gastrointestinal tract, respectively. Following oral
of a single dose (100mg·kg-1) in rats[31]. By HPLC administration, dose-normalized AUC was increased at
analysis, Rb1 and Rg1 in the same serum were the 20 mg/kg dose, compared with those at lower doses.
determined after administering saponins of Panax Subsequently, the absolute oral bioavailability was
notoginseng (PNS) to rats. The decline of Rb1 in serum increased about 8-20 times[26]. Additionally, another
could be described by a two-compartment model. The study after oral administration of Rb1 and C-K revealed
half-life of α phase was 23.40 min and that of β phase that intact Rb1 was not detectable in serum for 24 h by
was 17.96 h. Rb1 was absorbed from the digestive tract HPLC analysis, whereas the level of C-K in the serum
and the bioavailability via P.O. was 4.35%. The reached maximum at 8 h (about 8.5 μg·mL-1) after Rb1
pharmacokinetics of Rg1 in rats also could be described administration, and at 2 h (about 10 μg·mL-1) after C-K
by a two- compartment model. The half-lives of Rg1 administration, respectively[27].
were 24.23 min for α phase and 14.13 h for β phase[47]. After the oral administration of ginseng total
After iv infusion of Shenmai injection to volunteers, the saponin (1 g·kg-1·d-1) to rats, C-K was detected about
concentration- time curves of Rg1 and Re fitted to the 0.9 μg·mL-1 in blood at 6 h and 5.1μg·mL-1 at 24 h, 3.8
two-compartment model[46]. μg·mL-1 in urine at 0-24 h and 3.7μg·mL-1 at 24-48 h.
Aqueous humor, cornea and iris-ciliary body of Ppd was detected about 0.6 μg·mL-1 in blood at 24 h,
rabbit were collected at a range of time following and not detected in urine. Ppt was detected about 0.4
topically applying S-Rg3 eyeointment. The result μg·mL-1 in blood at 6 h and 0.7 μg·mL-1 at 24 h, and not
showed that the pharmacokinetics of S-Rg3 in rabbit detected in urine. Their intestinal absorption is
eye were described by one-compartment model [48]. An time-dependently enhanced. After the oral
average half-life of 18.5 min was obtained after Rg3 administration of ginseng extract (150 mg·kg-1·d-1) in
was intravenously dosed at 5 mg·kg-1. However, Rg3 human, C-K was detected about 0.2 μg·mL-1 in urine at
was not detected in rat plasma collected after oral 16-24 h[35].
administration at 100 mg·kg-1[33]. The pharmacokinetics In summary, the simultaneous monitoring of all
of R-Rg3 in healthy volunteers showed that after oral compounds including naturally occurring ginsenosides
administration, the absorption of R-Rg3 was rapid in and their degradation products is not practical due to
man, and its elimination was rapid after oral the limitation of techniques and cost. However, the
administration of R-Rg3[34]. current studies about have offered a lot of information.
An average half-life of 16 min in plasma was Based on this, the diagnostic compounds may be
obtained after intravenous administration Rh2 to male identified in the near future, which can be used as
Sprague-Dawley rats. No Rh2 was detected in plasma markers of pharmacokinetics properties of ginseng or
samples following oral administration, and only a small its products.
amount was found in the feces samples after
oraladministration. Three metabolites of Rh2 were Drug–drug interactions and influence on
detected in the feces samples. Oxygenation and cytochrome P450
deglycosylation were found to be the major metabolic
pathways of Rh2. Intense metabolism, rather than There are two types of drug–drug interactions
excretion, appears to be the reason for the fast clearance based on pharmacokinetics and pharmacodynamics.
of this ginsenoside[49]. The oral bioavailability of Rh2 in Adverse events are generally linked to the association
dog was relative high for male (17.6%) and female of concomitant drugs able to induce or inhibit drug
(24.8%) dogs, respectively[50]. However, a similar metabolizing enzymes or transporters and drugs with a
method did not detected Rh2 and Ppd in dog plasma[44]. narrow therapeutic window[51]. In the last decades, the
About 24.4%-26.2% and 54.3%-81.7% of C-K consumption of herbal medicine has increased by

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unprecedented proportions. effect on the drug efflux pump in multidrug resistant


Although herbal remedies are often promoted as mouse lymphoma, and increased drug accumulation
natural and therefore harmless, they are not free from and tumor antigen expression at low concentrations[61].
adverse effects. It has been well documented that they Using rhodamine 123 as an artificial substrate, Rg3
are associated with clinically significant drug-drug promoted accumulation of rhodamine 123 in
interactions (DDI) via the inhibition of cytochrome drug-resistant KBV20C cells in a dose-dependent
P450 isoforms (CYPs), and with adverse events that manner, but it had no effect on parental KB cells.
include all levels of severity, organ systems, and age Additionally Rg3 inhibited 3H-vinblastine efflux and
groups[52-54]. A recent survey in China indicated that reversed MDR to doxorubicin, COL, VCR, and VP-16
75% of respondents had used traditional Chinese in KBV20C cells. The further study showed that
medicine (TCM) during the past year in treatment of inhibition of drug efflux by Rg3 was due to neither
diseases[55]. A similar survey in USA also showed that repression of MDR1 gene expression nor Pgp level.
in 1997, 42.1% U.S. households used unconventional Photo-affinity labeling study revealed that Rg3
therapy including herbal medicine, and an estimated 15 competed with anticancer drug for binding to Pgp
million adults took prescription medications thereby blocking drug efflux[62]. In addition, Rh2 can act
concurrently with herbal remedies and/or high-dose either additively or synergistically with chemotherapy
vitamins (18.4% of all prescription users)[56]. There are drugs to hypersensitize multidrug-resistant breast
also several surrey indicating that ginseng is one of the cancer cells to paclitaxel[63].
most commonly used herbs[57-59]. This means that Besides Pgp, Fuchikami et al. examined the effects
numerous persons are at risk for potential of herbal extracts used in dietary supplements on the
herb-prescription drug interactions. function of organic anion transporting polypeptide B
(OATP-B; OATP2B1), which is expressed on human
The in vitro study of influence on transporters intestinal epithelial cells, and is considered to be
The transporters are known to be important in the involved in the intestinal absorption of various drugs.
transport of many xenobiotics into/out of cells. Among Specifically, the effects of extracts of Siberian ginseng
these transporters, P glycoprotein (Pgp) is a drug on uptake of estrone-3-sulfate, a typical OATP-B
transporter responsible for the efflux of xenobiotics out substrate, by human embryonic kidney 293 cells stably
of cells that influence the pharmacokinetics of expressing OATP-B were evaluated. The extracts of
numerous drugs. On one hand, Pgp is distributed within Siberian ginseng moderately inhibited estrone-3-sulfate
a lot of organs and tissues implicated in the absorption uptake. These results suggested that co-administration
or excretion of xenobiotics, and drug–drug interactions of ginseng-derived products may decrease the
with this protein may increase the bioavailability of absorption of orally administered substrates of
simultaneously administered active drugs. On the other OATP-B[64].
hand, Pgp is linked to the integrity of blood–tissue In a recent study, Caco-2 cells were used as
barriers, such as the blood–brain barrier or placenta, models to evaluate the effect of purified kaempferol
and a partial blockage of Pgp could be responsible for a from ginseng on Pgp-mediated efflux of the human
new drug distribution in the organism with possible immunodeficiency virus (HIV) protease inhibitor
increase of drug rates in organs behind these barriers. ritonavir. In addition, the inhibitory effect of
Therefore, concomitant administration of substrates and kaempferol on CYP3A4-mediated metabolism was
Pgp inhibitors would modify drug pharmacokinetics by determined by using cortisol as a model compound.
increasing bioavailability and organ uptake, leading to Kaempferol exhibited a remarkable inhibition of
more adverse drug reactions and toxicities[60]. Pgp-mediated efflux of ritonavir by increasing its
Molnar et al. reported that ginsenosides Rg1, Re, cellular uptake in these models. There was a significant
Rc, and Rd were found to have a moderate inhibitory decrease in the Apical to Basal/Basal to Apical

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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 reduced in the ginseng group as compared with the
of kaempferol. When tested with the Vivid CYP3A4 placebo group. Peak INR and peak plasma warfarin
assay kit, kaempferol caused substantial inhibition of level were positively correlated. Because of the narrow
cortisol metabolism, compared with the control[65]. therapeutic index of warfarin, keeping its anticoagulant
effect in a target range is crucial[67].
The in vivo study of Ginseng-drug interactions However, in another trail in 12 healthy male
Numerous persons have taken ginseng or its subjects, INR and platelet aggregation were not
derived products. However, they are not free from affected by treatment with ginseng. Ginseng did not
adverse effects, and there are a number of reports about affect the apparent volumes of distribution or protein
ginseng-prescription drug interactions. Therefore, it is binding of warfarin enantiomers. Although ginseng
vital to evaluate whether ginseng, one of the most diminished the urine excretion rate (UER) of
commonly used herbal products, and its active S-7-hydroxywarfarin, the metabolite from S-warfarin,
components possess the potential to exert drug co-administration of warfarin with ginseng did not
interactions. However, data suggest that the ginsenoside affect the pharmacokinetics or pharmacodynamics of
composition varies widely among commercially either S-warfarin or R-warfarin[68]. A similar study in
available ginseng products[23]. This variability makes it male rats showed no significant impact of ginseng on
difficult to evaluate the safety and efficacy of ginseng the pharmacokinetics/pharmacodynamics of warfarin
products. when they are concomitantly administered[69].
There are several clinical studies about the A clinical study with class IV cardiac function
interactions of ginseng with prescription drugs. showed that the co-administration of Red Ginseng
However, the reported ginseng-drug interactions in the improved the hemo-dynamical and biochemical indexes
clinical trials are somewhat contradictory, as these of digoxin, Red Ginseng and digoxin had synergism for
studies have shown that ginseng may have no treatment of congestive heart failure[70]. However, in
significant effects, or have statistically significant other cases, the apparent interaction may be misleading.
interactions. It has been shown that when Siberian ginseng was used
in combination with digoxin, the interaction resulted in
Interactions with warfarin, digoxin and elevated plasma digoxin levels[71], but in this particular
albendazole sulfoxide case there was evidence that the increased levels of
The interactions are particularly important if a digoxin were due to interference with the assay rather
drug has a narrow therapeutic index, such as warfarin. than as a result of PK effects[72].
A case report describes a probable interaction between A recent study with rat suggested that Panax
warfarin and a ginseng product (Ginsana)[66]. The ginseng increased the intestinal elimination of the
International Normalized Ratio (INR) of the patient benzimidazole derivative albendazole sulfoxide
was 3.1 four weeks before he started taking ginseng. (ABZSO)[73]. An upper small intestine segment was
Two weeks after the patient started taking ginseng, isolated and perfused in situ with saline, while ABZSO
hisINR declined to 1.5. Ginseng was discontinued, and solution was administered intravenously. Systemic
the INR returned to 3.3 in two weeks. co-administration of ginseng increased significantly the
In a randomized, double-blind, placebo-controlled clearance of ABZSO. The increase in ABZSO
trial, the interactions between American ginseng and elimination could be the result of the effect of ginseng
warfarin was evaluated. The peak INR statistically on metabolic pathways.
significantly decreased after 2 weeks of ginseng
administration compared with placebo. The INR area In vivo study of DDI via the influence on
under the curve (AUC), peak plasma warfarin level, cytochrome P450
and warfarin AUC were also statistically significantly

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Metabolizing enzyme-based drug interactions intestinal and hepatic P450 activities. The majority of
constitute the major proportion of clinically important naturally occurring ginsenosides including Rb1, Rb2,
drug interactions. The inhibition of CYPs activities may and Rg1 is poorly absorbed[24-32]. They have been found
result in clinically significant DDI[74]. to be deglycosylated by colonic bacteria followed by
There are several in vivo studies about the effects transit to the systemic circulation[20]. Thus, every orally
of ginseng, ginseng extracts, or naturally occurring administered component and their degradation products
ginsenosides on CYPs activities. However, the reported in gastrointestinal tract are possible of exerting an
effects of ginseng on CYPs activities in the clinical influence on intestinal CYPs. However, the influence
trials are somewhat contradictory, as these studies have on hepatic CYPs should be subject to the precondition
shown that ginseng may have no significant effects, or that the ginsenosides can be absorbed from the
have statistically significant inhibition of some CYPs gastrointestinal tract and enter systemic circulation.
activities.
In a recent clinical trial, single timepoint, In vitro study of influence on cytochrome P450
phenotypic metabolic ratios were used to determine Metabolism of compounds represents a key
whether long-term supplementation of St John's wort, process by which drugs are cleared from the body. They
garlic oil, Panax ginseng, and Ginkgo biloba affected are mainly eliminated by cytochrome P450 (CYPs or
CYP1A2, CYP2D6, CYP2E1 or CYP3A4 activity in P450) enzymes (Phase I metabolism) and by
twelve healthy aged volunteers[75]. The results showed conjugating enzymes (Phase II metabolism), such as
that P. ginseng inhibition of CYP2D6 was statistically UDP-glucuronosyl transferases and N-acetyl
significant, but the magnitude of the effect did not transferases[80-82]. These enzymes add functional groups
appear to be clinically relevant. In addition, long-term to make lipophilic molecules more hydrophilic and
ginseng supplementation has been shown to produce hence easier to eliminate. CYPs, a superfamily of
modest increases in nifedipine plasma concentrations, heme-containing isoenzymes located primarily in
implying an inhibitory effect on CYP3A4[76]. hepatocytes, are responsible for the oxidative
By contrast, another clinical trial in 12 normal metabolism of the majority of drugs and xenobiotics[83].
volunteers indicate that standardized extracts of In liver, the most important CYPs from the
Siberian ginseng (SG) at generally recommended doses viewpoint of drug metabolism are CYP1A2, CYP2A6,
for over-the-counter use are unlikely to alter the CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4,
disposition of co-administered medications primarily which represent about 70% of the total CYPs enzymes
dependent on the CYP2D6 or CYP3A4 pathways for and are responsible for the oxidation of more than 90%
elimination[77]. In addition, in a 12 healthy volunteers clinical drugs[84,85]. In intestine, CYP3A4 is the
trail, a long-term supplementation (28 days) of Panax predominant CYP, while only a very limited number of
ginseng did not significant effect on CYP3A4, other CYPs including CYP2C9, CYP2C19, and
CYP1A2, CYP2E1, and CYP2D6 activity[78]. Further, CYP1A1 are expressed[86,87]. Intestinal CYPs also have
health subjects received Panax ginseng standardized been shown to contribute significantly to the
extracts for 14 days, and Panax ginseng did not metabolism of several drugs, including nifedipine and
significantly alter the urinary 6-β-OH-cortisol/cortisol midazolam[88,89]. The inhibition of CYPs activities may
ratio, the marker of CYP3A activity[79]. result in clinically significant DDI[90].
There are some in vitro studies about the effect of
In vitro study of drug-drug interactions via ginseng, ginseng extracts or naturally occurring
influence on cytochrome P450 ginsenosides on CYPs activities. Henderson et al.
Because ginseng products are orally administered achieved the evaluation of the effects of seven naturally
in most cases, the influence of ginsenosides on CYPs occurring ginsenosides Rb1, Rb2, Rc, Rd, Re, Rf, and
activities in vivo includes the influence on both Rg 1 and eleutherosides B and E (active

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

components of the ginseng root) on the catalytic which were not treated with calf serum or subjected to
activity of cDNA expressed CYPs (CYP1A2, CYP2C9, acid hydrolysis, inhibited CYP1 catalytic activity in an
CYP2C19, CYP2D6 and CYP3A4) in in vitro enzyme-selective and extract-specific manner, but the
experiments. Of the components tested, three effects were not due to Rb1, Rb2, Rc, Rd, Re, Rf, or
ginsenosides (Rd, Rc, and Rf) modified the activity of Rg1[93]. In addition, using primary cultures of human
the recombinant enzymes. Rd produced weak inhibitory hepatocytes from 17 individuals, Raucy assessed the
activity against the surrogate substrates for CYP3A4 inducibility of CYP3A4 mRNA by prototypical
and CYP2D6 and even weaker inhibitory activity inducers, dietary flavonoids, and botanicals. Ginseng
against the surrogate substrates for CYP2C19 and produced about 1.5 times of control CYP3A4
CYP2C9. Rc produced an weak increase in the activity mRNA[94].
of CYP2C9 and Rf produced an increase in the activity Utilizing the probe reaction of CYP3A activity,
of CYP3A4. The authors suggest that the ginsenosides testosterone 6β-hydroxylation, and rat liver microsomes,
and eleutherosides tested are not likely to inhibit the Liu et al. found that ginsenosides from the
metabolism of co-administered medications in which 20(S)-protopanaxadiol and 20(S)-protopanaxatriol
the primary route of elimination is via cytochrome family including naturally occurring ginsenosides
P450; the potential of ginsenosides to enhance the including Rb1, Rb2, Rc, Re, Rg1 and one of the
catalysis of certain substrates requires further intestinal bacterial metabolites of ginsenosides, C-K,
investigation[91]. In a study in human liver microsomes, had no inhibitory effect, had no inhibitory effect,
Rd was found inhibitory potency on both CYP2C9- and whereas Rg2, 20(S)-panaxatriol (Pt) and another
CYP3A4-mediated index reactions with IC50 values of intestinal bacterial metabolite, Ppt, exhibited potent
105 and 62 μmol/L, respectively. Rb1, Rb2, and Rc had inhibition against rat CYP3A activity with the
limited inhibitory activities on both enzyme reaction inhibition constants (Ki) of about 86.4, 1.7, and 3.2
systems[92]. μmol·L-1, respectively [95]. Using a “cocktail” approach
In another in vitro study, the effect of a including four probe drugs caffeine, dapsone,
standardized Panax ginseng (or Asian ginseng) extract chlorzoxazone and omeprazole by HPLC determination,
(G115), a standardized Panax quinquefolius (or North Fan et al studied the influence of ginsenosside Re on
American ginseng) extract (NAGE), and individual CYP1A2, 3A4, 2E1, and 2C19 in rats. The results
ginsenosides (Rb1, Rb2, Rc, Rd, Re, Rf, and Rg1) on suggested that Re could induce CYP1A2 and 3A4, and
CYP1 catalytic activities, were examined. G115 and did not influence on CYP2E1 and 2C19[96]. Tawab et al.
NAGE decreased human recombinant CYP1A1, reported that two hydrolysis products of naturally
CYP1A2, and CYP1B1 activities in a occurring ginsenosides in gastrointestinal tract, namely
concentration-dependent manner. Except for the Rh1 and F1 can enter systemic circulation[29]. Liu and
competitive inhibition of CYP1A1 by G115, the mode co-workers found that Rh1 and F1 exhibited moderate
of inhibition was the mixed-type in the other cases. competitive inhibition of the activity of CYP3A4. F1
NAGE was 45-fold more potent than G115 in inhibiting also exhibited weaker inhibition of the activity of
CYP1A2. Compared with G115, NAGE also CYP2D6. Rh1 exhibited weak stimulation rather than
preferentially inhibited 7-ethoxyresorufin inhibition of the activity of CYP2E1[97].
O-dealkylation activity in human liver microsomes. Rb1, Based on the previous studies, Liu et al. further
Rb2, Rc, Rd, Re, Rf, and Rg1, either individually or as a conducted a systematic study about influence of a set of
mixture and at the levels 100 μg·mL-1 of NAGE or ginsenosides on CYPs activities, and found that
G115, did not influence CYP1 activities. However, at a naturally occurring ginsenosides, including Rb1, Rb2,
higher ginsenoside concentration (50μg·mL-1), Rb1, Rb2, Rc, Re, and Rg1, exhibited no inhibition on CYPs
Rc, Rd, and Rf inhibited these activities. The findings activities, and another naturally occurring ginsenoside
indicate that standardized NAGE and G115 extracts, Rd exhibited weak inhibition on CYP1A2, CYP2C9,

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

CYP2D6, and CYP3A4. Their degradation products changeable in dependence of host conditions, including
Rg2, S-Rg3, and Rh2 also exhibited no inhibition on diet, health, and even stress. The bacterial
P450 activities, except the weak inhibition of S-Rg3 on ginsenoside-hydrolyzing potentials also exhibit a high
CYP2D6 and of Rh2 on CYP3A4. However, the degree of inter-individual variability in humans and
intestinal metabolites of ginsenosides including C-K, experimental mice[20]. Moreover, substantial variability
Ppd and Ppt demonstrate a wide range of inhibition of in ginsenoside content has been reported among
CYPs -mediated metabolism. C-K, Ppd and Ppt, all commercial ginseng preparations[23]. These reports
exhibited moderate inhibition against the activity of imply that the clinically significant effects of ginseng
CYP2C9 in human liver microsomes. Ppd and Ppt were on CYPs activity might be individual-dependent and
found to have strongly competitive inhibition against product-dependent, which might be responsible for the
CYP3A4 in both human liver microsomes and inconsistency of those clinical studies[98].
cDNA-expressed CYP3A4. There is no
mechanism-based inhibition of P450 induced by Discussion
naturally occurring ginsenosides or their degradation
products[98]. Ginseng, the king of traditional Chinese medicines,
These results suggested that the degradation of is the most famous Asian herb, and has been in
ginsenosides in gastrointestinal tract may play an medicinal use for thousands of years. Materia Medica
important role in the influence on CYPs. of Divine Plowman written in China about 2,000 years
ago records ginseng as the highest quality herb.
Prediction of drug-drug interactions via Ginseng has been used widely in Asia, Europe and
influence on cytochrome P450 America.
There are some in vitro studies about the effect of The main active agents in Panax ginseng are
ginseng, ginseng extracts or naturally occurring ginsenosides, which are triterpene saponins. The
ginsenosides on CYPs activities. Some studies majority of published research on the medicinal activity
suggested naturally occurring ginsenosides have no or of Panax ginseng has focused on ginsenosides. These
limited influence on CYPs activities. However, Liu et are the compounds to which some ginseng products are
al found that the deglycosylation products of naturally now standardized. Research reviews[101, 102] postulate
occurring ginsenosides including Rh1, F1, C-K, Ppd and that extracts of Panax ginseng affect the
Ppt demonstrate a wide range of inhibition of hypothalamus-pituitary-adrenal axis and the immune
CYPs-mediated metabolism. Among these, Ppt and Ppd, system, which could account for many of the
exhibited potent inhibition against CYP3A4 activity; documented effects. Animal models and in vitro studies
Rh1, F1 exhibited moderate inhibition against CYP3A4 mentioned that Panax ginseng enhances phagocytosis,
activity; and C-K, Ppd and Ppt also exhibited moderate natural killer cell activity, and the production of
inhibition against CYP2C9 activity. These results interferon; improves physical and mental performance
demonstrate that ginseng-derived products might have in mice and rats; causes vasodilation; increases
potential for significant ginseng-drug resistance to exogenous stress factors; and affects
interactions[95,97,98]
. hypoglycemic activity.
Both the content and activity of CYPs exhibit a The chemical constituents of ginseng root have
high degree of inter- and intra-individual variability[99]. been investigated since the beginning of the 20th
The genetic polymorphism of CYPs is extensive, and century, and several classes of compounds have been
the rate of metabolism for a certain drug can even differ isolated: triterpene saponins; essential oil-containing
1000-fold between phenotypes [100]. In addition, human polyacetylenes and sesquiterpenes; polysaccharides;
intestinal bacteria exhibit a high degree of peptidoglycans; nitrogen-containing compounds; and
intra-individual variability, as which are very various ubiquitous compounds such as fatty acids,

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

carbohydrates, and phenolic compounds. protopanaxatriol, with the exceptions of 20R


The biologically active constituents in Panax ginsenoside Rg3, Rh4, and koryoginsenoside R2.
ginseng are the complex mixture of triterpene saponins Ginseng is specified in the German, Swiss, Austrian,
known as ginsenosides, which are mainly triterpenoid and French pharmacopeias, among others. The Swiss
dammarane derivatives. Ginsenosides Rx according to pharmacopeia demands a total ginsenoside content,
their mobility on thin-layer chromatography plates, calculated as ginsenoside Rg1, of not less than 2.0%.
with polarity decreasing from index "a" to "h". The root According to the German pharmacopeia, the total
contains 2-3% ginsenosides of which Rg1, Rc, Rd, Rb1, ginsenoside content should be not less than 1.5%. Both
Rb2, and Rb0 are quantitatively the most important. At pharmacopeias use a spectrophotometric method for
least 30 ginsenosides have been isolated and quantification. However, a draft for the European
characterized. [101-105] pharmacopeia demands the content of ginsenosides Rg1
By applying various chemical and spectroscopic and Rb1 to be not less than 0.3%, measured with an
methods, researchers have found that the genuine HPLC method. HPLC separations such as the one
aglycones were protopanaxadiol and protopanaxatriol, published by Samukawa and co-authors enable the
which both have a dammarane skeleton. On acid separation of additional ginsenosides; 22 ginsenosides
treatment of protopanaxadiol and protopanaxatriol, a can be separated in a single run (Fig 5).
tertiary hydroxyl group attached to C-20 participates in In fact, the pharmacokinetics, metabolism and
ring closure with a double bond in the side chain. Total drug-drug interactions of these compounds were only
of 31 ginsenosides have been isolated from the roots of studied for a part ginsenosides. Because of complex
white and red ginseng. They can be categorized in three of metabolism process, the determination of
groups depending on their aglycones: protopanaxadiol- ginsenosides and their metabolites in biological
type ginsenosides, protopanaxatriol- type ginsenosides, samples can be not separated in a single run.
and oleanolic acid-type saponins. All dammarane Therefore, we will face many difficult challenges in
ginsenosides isolated from ginseng root (white ginseng) this field.
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 active mechanism of ginseng. To clarify the ADME


properties of Ginseng, the major active components,
The study about pharmacokinetic properties of ginsenosides, are mainly focused on biotransformation
ginseng is in favor of understanding the safety and includes in vitro and in vivo metabolism of multiple

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

components. In addition, some of ginsenosides are 13. Hasegawa H, Sung JH, Benno Y. Role of human intestinal
Prevotella oris in hydrolyzing ginseng saponins. Planta Med
transformated in gastrointestinal tract by gastric acid 1997; 63(5): 436-440.
14. Bae EA, Park SY, Kim DH. Constitutive beta-glucosidases
and microflora. hydrolyzing ginsenoside Rb1 and Rb2 from human intestinal
The inconsistency of detected ginsenosides with bacteria. Biol Pharm Bull 2000; 23(12): 1481-1485.
real active components due to the lack of knowledge of 15. Lee DS, Kim YS, Ko CN, Cho KH, Bae HS, Lee KS, Kim JJ,
Park EK, Kim DH. Fecal metabolic activities of herbal
active mechanisms, variability of component contents components to bioactive compounds. Arch Pharm Res. 2002;
and so on, make the evaluation of ginseng 25(2): 165-169.
16. Karikura M, Miyase T, Tanizawa H, Takino Y, Taniyama T,
pharmacokinetics more difficult than that of the so Hayashi T. Studies on absorption, distribution, excretion and
called western drugs, a single component. In this metabolism of ginseng saponins. V. The decomposition
chapter, the studies of naturally occurring ginsenosides products of ginsenoside Rb2 in the large intestine of rats. Chem
Pharm Bull (Tokyo). 1990; 38(10): 2859-2861.
and their metabolites by in vitro and in vivo methods 17. Bae EA, Choo MK, Park EK, Park SY, Shin HY, Kim DH.
determining pharmacokinetic properties, such as Metabolism of ginsenoside R(c) by human intestinal bacteria
and its related antiallergic activity. Biol Pharm Bull 2002
physicochemical properties of ginsenosides, Jun;25(6):743-7
metabolizing enzymes, transporters and deglycosy- 18. Wang Y, Liu TH, Wang W, Wang BX. Research on the
transformation of ginsenoside Rg1 by intestinal flora.
lation in gastrointestinal tract, as well as
Zhongguo Zhong Yao Za Zhi 2001;26(3):188-190. [Article in
ginsenoside-drug interactions are summarized. Chinese]
19. Bae EA, Han MJ, Choo MK, Park SY, Kim DH. Metabolism of
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