Arch. Pharm. Res.
(2019) 42:862–878
https://doi.org/10.1007/s12272-019-01184-3
REVIEW
Interactions of ginseng with therapeutic drugs
Min‑Koo Choi1 · Im‑Sook Song2
Received: 15 July 2019 / Accepted: 26 August 2019 / Published online: 6 September 2019
© The Pharmaceutical Society of Korea 2019
Abstract Ginseng is the most frequently used herbal
medicine for immune system stimulation and as an adju-
vant with prescribed drugs owing to its numerous pharma-
cologic activities. It is important to investigate the beneficial
effects and interaction of ginseng with therapeutic drugs.
This review comprehensively discusses drug metabolizing
enzyme- and transporter-mediated ginseng–drug interaction
by analyzing in vitro and clinical results with a focus on
ginsenoside, a pharmacologically active marker of ginseng.
Impact of ginseng therapy or ginseng combination therapy
on diabetic patients and of ginseng interaction with anti-
platelets and anticoagulants were evaluated based on gin-
seng origin and ginsenoside content. Daily administration of
Korean red ginseng (0.5–3 g extract; dried ginseng > 60%)
did not cause significant herb–drug interaction with drug
metabolizing enzymes and transporters. Among various
therapeutic drugs administered in combination with gin-
seng, adjuvant chemotherapy, comprising ginseng (1–3 g
extract) and anticancer drugs, was effective for reducing
cancer-related fatigue and improving the quality of life and
emotional scores. Limited information regarding ginseno-
side content in each ginseng product and plasma ginsenoside
concentration among patients necessitates standardization
of ginseng product and establishment of pharmacokinetic–
pharmacodynamic correlation to further understand benefi-
cial effects of ginseng–therapeutic drug interactions in future
clinical studies.
* Im‑Sook Song
isssong@knu.ac.kr
1 formulations have accounted for approximately 13.8% and
College of Pharmacy, Dankook University, Cheon‑an 31116,
Republic of Korea
2 respectively (Wu et al. 2016). For example, Danshen extract
College of Pharmacy and Research Institute
of Pharmaceutical Sciences, Kyungpook National University,
Daegu 41566, Republic of Korea
13
Vol:.(1234567890)
Online ISSN 1976-3786
Print ISSN 0253-6269
Keywords Korean ginseng · Ginsenoside · Herb–drug
interaction · Adjuvant chemotherapy
Introduction
Herbal medicine is increasing being used owing to the effi-
cacy and low toxicity of traditional plants. Panax ginseng
root has been extensively used for more than 2000 years in
East Asian countries because of its ability to restore vital-
ity and stimulate the immune system (Lee and Kim 2014;
Ru et al. 2015). Ginseng is frequently used owing to its
therapeutic anti-oxidative, anti-inflammatory, anti-diabetic
properties (Choi 2008) as well as its chemopreventive and
adjuvant therapeutic potential (Lu et al. 2009).
In the USA, approximately 76% adult population con-
sumed herbal supplements in 2017, which increased from
64% over the last 9 years (Council for Responsible Nutrition
2018). Nearly 25% herbal supplemental users regularly take
prescribed drugs, which have increased the possibility of
herb–drug interaction (Na et al. 2011). Similarly, in seven
European countries, herbal medicine was used by 9.6–22.7%
individuals across all age groups, and the concomitant use of
therapeutic drugs has been reported in approximately 20%
children and 60% adults (Jeurissen et al. 2018). Owing to the
rapid increasing use of herbal medicine and ease of consum-
ing herbal medicine formulations, adverse drug reactions
or herb–drug interactions resulting from co-administration
of therapeutic drugs with herbal medicine have also rap-
idly increased (Wu et al. 2016). In China, herbal medicine
17.3% of the total adverse drug reactions in 2010 and 2013,
(oral administration, 3 g/day for 10 days) decreased fexofen-
adine plasma exposure via P-glycoprotein (P-gp) induction
Interactions of ginseng with therapeutic drugs 863

(Qiu et al. 2014). Co-administration of Schisandrae fruc-
tus extract (oral administration, 600 mg/day for 2 weeks)
increased plasma concentration of talinolol and tacrolimus
possibly by inhibiting P-gp (Xin et al. 2007; Wu et al. 2016).
Plasma concentration of cyclosporine, warfarin, oral contra-
ceptives, theophylline, etc. decreased owing to the induc-
tion of cytochrome P450 (CYP) 3A4, CYP2C9, CYP1A2
enzymes and P-gp (Henderson et al. 2002).
The most frequently reported herb–drug interaction cases
include herbal medicine modulation by drug-metabolizing
enzymes and transporters and the causative pharmacokinetic
effects of co-administered therapeutic drugs that are sub-
strates for drug-metabolizing enzymes and transporters (Na
et al. 2011; Lee et al. 2018), because they are key regula-
tors that determine the pharmacokinetics and control the
therapeutic efficacy or adverse reaction of substrate drugs
(Seong et al. 2018). Therefore, in vivo results from animal
and clinical studies conducted on ginseng–drug interaction
and related ginsenoside concentrations will be focused in
this review. Based on the therapeutic benefits of ginseng,
the pharmacokinetic and pharmacodynamics interactions
between ginseng and therapeutic drugs, including antican-
cer, antiplatelet, anticoagulative, and antidiabetic drugs,
which can be combined in clinical settings are discussed.
Ginsenosides
Ginsenosides are the major active pharmacological com-
ponents of ginseng and unique to ginseng species. Ginse-
nosides, also known as steroid-like saponins, are classified
into two types according to their hydroxylation position on
the core triterpene saponin structure: 20(s)-protopanaxadiol
(PPD)-type and 20(s)-protopanaxatriol (PPT)-type ginse-
nosides (Won et al. 2019). Ginsenosides found in ginseng
products were subclassified by their sugar moiety at C3,
C6, and C20 positions (Fig. 1). These PPD-type ginseno-
sides Rb1, Rb2, and Rc undergo further hydrolysis by the

Fig. 1  Structure and metabolic pathway of PPD- and PPT- type ginsenosides. Metabolic pathway represents deglycosylation at C3, C6, or C20
position, catalyzed by beta-glucosidase secreted by the intestinal microflora. PPD: 20(s)-protopanaxadiol; PPT: 20(s)-protopanaxatriol; CK:
compound K, Glc: glucose; Arap: arabopyranose; Araf: arabinofuranose; Rha: rhamnose; Xyl: xylose. The content of ginsenosides in three gin-
seng products (6-year-old Fresh Panax ginseng, red ginseng extract, and white ginseng extract) was given

13
864
intestinal microbiota via β-glucosidase; consequently, they
are biotransformed into Rd → F2 or Rg3 → compound K or
Rh2 → PPD (Fig. 1) (Dong et al. 2017b; Park et al. 2017a).
Re and Rg1 belong to PPT-type ginsenosides and are hydro-
lyzed into Rh1 or F1 → PPT (Won et al. 2019) (Fig. 1).
These PPD- and PPT-type ginsenosides and glycosylated
metabolites are considered as major active pharmacological
constituents of ginseng (Ru et al. 2015; Kim et al. 2017b).
Therefore, numerous studies have described the immuno-
logical, antioxidant, anticoagulant, anticancer, antidiabetic,
and neuroprotective effects of ginseng and its associated gin-
senosides (Yun et al. 2001; Choi 2008; Gui et al. 2016; Kim
et al. 2017b; Park et al. 2017b; Lee et al. 2018).
Various ginsenosides generally showed low oral bioavail-
ability in rats and human. For example, the oral bioavail-
ability of Rb1 was 1.2–4.4% and that of Rh2 was 4.0–6.4%.
Other ginsenosides including Rg1, Rd, Rh1, and Re showed
low oral bioavailability of < 10% (Won et al. 2019). Owing
to the low oral bioavailability and low intestinal perme-
ability of these ginsenosides (Choi et al. 2018), the plasma
ginsenoside concentrations are also considerably low. The
maximum plasma concentrations of Rb1, Rb2, Rc, and Rd—
major ginsenosides found in rat plasma—were < 10 ng/mL
in rats following oral administration of 1.5 g/kg Korean red
ginseng extract (Lee et al. 2018). The maximum plasma con-
centrations of Rb1, Rb2, Rc, and Rd were also < 5 ng/mL
following oral administration of Korean red ginseng extract
(dried ginseng > 60%) in healthy Korean subjects (Choi et al.
2018). Because these ginsenosides had long elimination
half-lives (> 30 h), the plasma concentrations of Rb1, Rb2,
Rc, and Rd after repeated administration for 2 weeks were
significantly higher than those after a single oral administra-
tion at the same dose. The accumulation factor, calculated
by dividing the area under the plasma concentrations (AUC)
value of repeated administration by the AUC value of sin-
gle administration, was 4.5–6.7 (Choi et al. 2018). Deglyco-
sylated ginsenosides Rd, Rg3, Rh2, compound K, PPD, and
PPT are also found in human plasma following repeated oral
administration of Korean red ginseng extract for 2 weeks (Jin
et al. 2019a). In human plasma, Rd and Rg3 were present at
a concentration of 2.2–8.7 ng/mL, whereas Rh2, compound
K, PPD, and PPT, which are usually absent in red ginseng
extract, were present at a concentration of 6.1–81.6 ng/mL.
In human plasma, the concentration of compound K was
the highest (­ Cmax 81.6 ng/mL), followed by Rb1, Rb2, PPD,
and PPT in that order (12.7 ng/mL, 6.9 ng/mL, 6.1 ng/mL,
and 7.9 ng/mL, respectively) (Jin et al. 2019a). However, the
plasma concentrations of compound K have been reported
to show large inter-subject variability due to the variability
in the metabolism of compound K from ginseng product
mediated by gut microbiota (Kim 2018; Choi et al. 2018;
Jin et al. 2019a). Genetic variants of multidrug resistance-
related protein 4 (MRP4; ABCC4) rs1751034 TT and
13
M.-K. Choi, I.-S. Song
rs1189437 TT were associated with increased exposure of
compound K and decreased exposure of PPD in Chinese
healthy subjects who were orally administered compound
K (100–400 mg). Genetic variants of pregnane X receptor
(PXR; NR1I2) rs1464602 and rs2472682 were associated
with decreased plasma concentrations of compound K. The
results suggested that genetic polymorphisms in MRP4
and PXR also contributed to the inter-subject variability
of compound K (Zhou et al. 2019b). Because Compound
K is reported as a major active component among various
ginsenosides, red ginseng has been fermented using lactic
acid bacteria to enhance compound K in the ginseng prod-
uct (Choi et al. 2016). As results, the plasma concentration
of compound K in subjects who were orally administered
3 g fermented Korean red ginseng (­ Cmax 254.5 ng/mL) as
substantially higher and less variable than that in subjects
who received non-fermented Korean red ginseng extract
­(Cmax 8.4–24.8 ng/mL) (Kim 2013; Choi et al. 2016). Taken
together, limited information regarding plasma ginsenoside
concentration is available because studies on the pharma-
cokinetics of these ginsenosides garnered lesser interest
than pharmacological in vivo and in vitro studies. However,
understanding the pharmacokinetics of ginsenosides found
in human plasma is very important for designing an optimal
dose regimen, establishing pharmacokinetic–pharmaco-
dynamic relationship, and understanding the mechanisms
underlying herb–drug interaction between ginseng products
and concomitantly administered therapeutic drugs.
Another complication arises from varied ginsenoside
compositions depending on ginseng origin [i.e., Panax
notoginseng, Panax ginseng (Korean ginseng), and Panax
quinquefolium (American ginseng)] and preparation pro-
tocols (i.e., fresh ginseng, red ginseng and white ginseng)
(Fig. 1). The concentration of some ginsenosides including
Rg2, Rg3, Rh1, and Rh2 increases after prolonged steam-
ing, whereas that of others (Rb1, Rb2, Rd, Rd, Re, and Rg1)
decreases. In Table 1, the characteristics of ginsenosides in
Panax notoginseng, Korean red ginseng, Korean ginseng,
and American ginseng are arranged as PPD to PPT ratio,
Rb1/Rg1 ratio, and individual contents that are known to
exert antiplatelet and anticoagulant effects. The PPD to PPT
ratio is the highest in Korean red ginseng, but it decreases
in Korean ginseng and American ginseng and is the lowest
in steamed Panax notoginseng. In Panax ginseng, the pro-
portion of PPD-type ginsenosides (2.57–6.67%) is higher
than that of PPT-type ginsenosides (1.23%). In Korean gin-
seng, Rb1 and Rb2 are predominant PPD-type ginsenosides
and Rg1 and Re are predominant PPT-type ginsenosides
(Chen et al. 2008). The concentration of ginsenoside Rb1
(1.51%), Re (0.89%), and Rd (0.77%) in American gin-
seng is approximately 3, 6, and 5 times higher than that in
Korean ginseng and account for > 70% of the total ginseno-
sides. In American ginseng, the Rb1/Rg1 ratio is the highest
Interactions of ginseng with therapeutic drugs 865

Table 1  Comparison of ginsenosides among Panax notoginseng, Panax ginseng, and Panax quinquefolium
Composition Steamed Panax Raw Panax Korean Red gin- Panax ginseng Panax quinque- References
notoginseng notoginseng seng extract (Korean ginseng) folium
(American gin-
seng)

Total ginsenoside 50–100 mg/g 50–100 mg/g 30–50 mg/g 20–40 mg/g 40–60 mg/g Lau et al. (2003),
Major ginsenoside R1, Rg1, Rb1, Rd R1, Rg1, Rb1, Rd Rb1, Rb2, Rc, Rd, Rb1, Rb2, Rc, Rb1, Re, Rg1, Rc, Awang and Li,
Rf, Rg1, Rg2, Rg1, Rg1, Re Rd (2008), Lee and
Rg3, Re, Rh1 Kim (2014),
Dong et al.
PPD to PPT ratio 0.9 0.8–2.94 4.2–4.8 2.0–5.4 < 2.0
(2017b), Choi
Rb1/Rg1 1.0 0.56–3.61 0.9–6.6 0.9–2.8 15.3 et al. (2018)
Rb1 15.1 mg/g 26.1 mg/g 4.6–29 mg/g 4.7 mg/g 15.1–49.6 mg/g
Rb2 – – 2.5–3.8 mg/g 0.9 mg/g 0.6 mg/g
Rg1 14.4–18.7 mg/g 19.8–27.6 mg/g 0.7–4.6 mg/g 1.7–5 mg/g 1.3 mg/g

(Table 1), and the ginsenoside concentrations are as follows:
Rb1 > Re > Rg1 = Rc > Rd. Contrastingly, the Rb1/Rg1 ratio
is the lowest in Panax notoginseng. Therefore, for achiev-
ing better reproducibility and reliable clinical evidence, it
is important to standardize ginsenoside concentration using
a pharmacologically effective ginsenoside in in vitro and
in vivo studies with ginseng product.
Effect of ginseng on drug‑metabolizing enzyme
and transporters
In vitro study
Drug-metabolizing enzymes and transporters play cru-
cial roles in the pharmacokinetics, safety, and efficacy of
therapeutic drugs by modulating the absorption, distribu-
tion, metabolism, and excretion (ADME) properties of their
substrate drugs. For example, bioavailability, metabolism,
and elimination of the major active components should be
investigated in herbal medicine. The possible interactions
of herbal medicines with co-administered drugs should be
monitored and classified according to the pharmacokinetic
fold change in the affected therapeutic drugs based on the
values of I­ C50 or E
­ C50 (i.e., half maximal concentration of
inhibition or induction of enzyme activity or expression) of
Panax ginseng product (Seong et al. 2018).
Seong et al. 2018 reported in vitro inhibitory and induc-
ible effects of red ginseng on drug-metabolizing enzymes
and transporters, to evaluate the potential of ginseng product
as a perpetrator of pharmacokinetic drug interactions, and
the results are shown in Table 2. In vitro drug interaction
studies suggest that ginseng product does not cause clini-
cally relevant drug–drug interaction with drug-metabolizing
enzymes, including CYP1A2, CYP2B6, CYP2C8, CYP2C9,
CYP2C19, CYP2D6, CYP3A4, UDP-glucuronosyltrans-
ferase (UGT)1A1, UGT1A4, UGT1A9, and UGT2B7,
or with drug transporters, including organic cation trans-
porter (OCT)1, OCT2, organic anion transporter (OAT)1,
OAT3, organic anion transporting polypeptide (OATP)1B1,
OATP1B3, P-gp, and breast cancer resistant protein (BCRP)
(Table 2).
Contrary to the case of ginseng product, individual ginse-
nosides modulate drug-metabolizing enzymes or transport-
ers. For example, ginsenoside Rb1 significantly inhibited
CYP2C9, UGT1A9, OATP1B1, and OATP1B3 with ­IC50
values of 2.4 µM, 21.3 µM, 33.2 µM, and 4.8 µM, respec-
tively, whereas other CYP and UGT enzymes as well as
other transporters remained unaffected (Table 2). In hepato-
cyte induction experiments, Rb1 either did not induce or
inhibited mRNA expression of CYP and UGT enzymes as
well as of P-gp and BCRP transporters (Table 2).
Ginsenoside Rg3 inhibited UGT1A3, UGT1A9, and
UGT2B7 with I­C 50 values of 20.9 µM, 15.1 µM, and
23.1 µM, respectively. Ginsenoside Rh2 inhibited UGT1A3
with ­IC50 value of 37.9 µM (Kim et al. 2016a). ­IC50 values
for individual ginsenosides are relatively high considering
the plasma ginsenoside concentrations in humans; therefore,
the possibility of ginsenoside–drug interaction is remote.
However, OATP1B1 and OATP1B3 transporters were
strongly inhibited by ginsenosides. Ginsenosides Rb1, Rc,
and Rd (PPD-type ginsenoside) inhibited OATP1B1 and
OATP1B3 with ­IC50 values of 0.2–4.6 µM. Rg1, and ginse-
noside Re (PPT-type ginsenoside) also inhibited OATP1B1
and OATP1B3 with I­ C50 values of 39.4–133 µM (Jiang et al.
2015). Although the clinical herb–drug interaction of gin-
seng or ginsenoside associated with OATP1B1 or OATP1B3
has not yet been investigated, caution should be taken with
long-circulating PPD-type ginsenoside following the admin-
istration of high-dose Korean red ginseng or PPD-type gin-
senoside. Regarding this issue, a case of drug-induced liver
injury (DILI) in patient (82-year-old, male) who took ator-
vastatin (80 mg), atenolol (50 mg), and aspirin (100 mg)
after concomitant ginseng intake was reported based on

13
 866

Table 2  Summaries of in vitro system to evaluate the effect of Panax ginseng on the activities of drug-metabolizing enzyme and transporters
System Substrate Metabolite IC50 (µg/mL) (Seong et al. 2018)

13
Fresh ginseng Red ginseng extract White ginseng extract Rb1

CYPs
CYP1A2 Human liver micro- Phenacetin acetaminophen NI NI NI NI
CYP2A6 somes Coumarin OH-coumarin NI NI NI NI
CYP2B6 Bupropion OH-bupropion 112 NI NI NI
CYP2C8 Paclitaxel OH-paclitaxel NI NI NI NI
CYP2C9 Diclofenac OH-diclofenac NI NI NI 2.4
CYP2C19 Omeprazole OH-omeprazole NI NI NI NI
CYP2D6 Dextromethorphan Dextrorphan NI NI NI NI
CYP3A4 Midazolam OH-midazolam NI NI NI NI
UGTs
UGT1A1 Human liver micro- SN-38 SN-38-glucuronide NI NI NI NI
UGT1A3 somes Chenodeoxycholic Chenodeoxycholate- NI NI NI NI
acid glucuronide
UGT1A4 Trifluoperazine Trifluoperazine- NI NI NI NI
glucuronide
UGT1A6 N-acetylserotonin N-acetylserotonin- NI NI NI NI
glucuronide
UGT1A9 Mycophenolic acid Mycophenolic acid- NI NI NI 21.3
glucuronide
UGT2B7 Naloxone Naloxone-glucuronide NI NI NI NI
Transporters
OCT1 Overexpressed system N-methyl-4-phe- NI NI NI NI
in HEK293 cells nylpyridinium
OCT2 N-methyl-4-phe- NI NI NI NI
nylpyridinium
OAT1 p-amino hippuric NI NI NI NI
acid
OAT3 Estrone-3-sulfate NI NI NI NI
OATP1B1 Estrone-3-sulfate NI NI NI 33.2
OATP1B3 Estradiol-17-beta- 104 62 104 4.8
d-glucuronide

BCRP Overexpressed system Estrone-3-sulfate NI NI NI NI

P-gp in LLC-PK1 cells Digoxine NI NI NI NI

IC50: Half maximal inhibitory concentration; NI: No significant inhibition

CYP cytochrome P450, UGT​ UDP-glucuronosyltransferase, OCT organic cation transporter, OAT organic anion transporter, OATP organic anion transporting polypeptide, P-gp P-glycoprotein,
BCRP breast cancer resistance protein
M.-K. Choi, I.-S. Song
Interactions of ginseng with therapeutic drugs 867
the thorough medication history and the close examination.
After the cessation of both atorvastatin and ginseng product,
the patient’s symptoms was resolved within 2 months (Laube
and Liu 2019). The inhibition of CYP3A4 and/or OATP1B1
activities by ginseng and causative impaired elimination of
atorvastatin could be suspected for the patient’s hepatotoxic-
ity (Laube and Liu 2019).
In vivo animal study
In in vivo pharmacokinetic herb–drug interaction study, a
single dose of Korean red ginseng extract was administered
to experimental animals to investigate whether Korean red
ginseng could directly affect the pharmacokinetic properties
of substrate drugs by inhibiting the critical pharmacokinetic
pathway including drug-metabolizing enzymes and trans-
porters. Contrastingly, repeated administration of Korean
red ginseng extract was performed to investigate whether
Korean red ginseng extract treatment could regulate the
expression of drug-metabolizing enzymes and transporters
(Jin et al. 2019b).
Jo and Lee (Jo and Lee 2017) reported no herb–drug
interaction between single oral dose of Korean red gin-
seng extract (0.5–2.0 g/kg) and 5 Cyp enzymes (i.e.,
Cyp1a, Cyp2b, Cyp2c, Cyp2d, and Cyp3a). Repeated oral
administration of Korean red ginseng extract (0.5 g/kg
for 2 weeks; equivalent to 4.05 mg ginsenoside/kg) did
not alter the metabolic activity of Cyp1a, Cyp2b, Cyp2c,
Cyp2d, and Cyp3a in the mouse liver (Kim et al. 2012).
Another study revealed that oral administration of etha-
nol extract of ginseng (30 mg/kg for 10 days; equivalent
to 8.13 mg ginsenoside/kg) to rats increased the mRNA
expression of Cyp2d1 and Cyp3a2 in rat liver (Bogacz
et al. 2016). The discrepancy between the two studies
can be explained from different ginsenoside concentra-
tions and compositions of the ginseng product used.
This treatment also increased the mRNA expression of
hepatocyte nuclear factor (Hnf)1α but not of Hnf4α in
the liver (Bogacz et al. 2016), which is one of the master
transcription factor that differentially regulates numerous
drug-metabolizing enzymes and transporters (Shih et al.
2001; Maher et al. 2006; Martovetsky et al. 2013).
Repeated administration of ginseng extract report-
edly regulates the expression of drug transporters in a
tissue-specific manner. The expression of Oat1 and Oat3
in the kidney and the expression of P-gp in the liver was
increased by the repeated administration of Korean red
ginseng extract in a dose dependent manner (30–300 mg/
kg for 2 weeks; equivalent to 13 mg ginsenoside/kg) in
mice, which was accompanied with the dose dependent
decrease of fexofenadine AUC (Kim et al. 2018). Repeated
administration of Ginseng radix extract (150 mg/kg/day)
for 2 weeks reduced fexofenadine bioavailability by 16.1%
in rats, which could be explained by reduced fexofenadine
absorption caused via induction of intestinal P-gp expres-
sion (Zhang et al. 2009). However, repeated red ginseng
extract treatment did not modulate Bsep and P-gp expres-
sion in the liver but decreased Mrp2 mRNA and protein
expression (Lee et al. 2018). Intestinal Oct1 expression
increased but hepatic Oct1 expression decreased in rats
owing to repeated administration of Korean red ginseng
extract (1.5 g/kg for 7 days). Although intestinal Cyp3a
decreased owing to repeated administration of Korean
red ginseng extract (1.5 g/kg for 7 days), hepatic Cyp3a
remained unaffected (Jin et al. 2019b). It is speculated
that ginsenoside concentrations in the intestine and liver
were considerably different because of its low bioavail-
ability; thus, different ginsenoside concentrations could
differentially modulate the metabolizing enzymes and
transporters depending on the tissue type. It could be also
speculated that the increase in mRNA levels of Hnf-1α in
the liver resulting from oral administration of red ginseng
extract at high doses (30 mg/kg for 10 days) (Bogacz et al.
2016) differentially regulates drug-metabolizing enzymes
and transporters depending on the tissue type, which in
turn complicates in vivo ginseng–drug interaction.
In vivo human study
Several studies performed to investigate ginseng–drug inter-
actions and results are briefly summarized in Table 3. Gurley
et al. (Gurley et al. 2002, 2005) investigated metabolic activity
changes in CYP1A2, CYP2E1, CYP3A4, and CYP2D6 fol-
lowing oral administration of 0.5 g Korean ginseng powder
twice daily for 4 weeks in young and elderly heathy subjects.
No significant change was reported in CYP-mediated metabo-
lism in both populations.
In a study conducted by Malati et al. (2012), Korean gin-
seng (0.5 g capsule twice daily for 28 days) induced CYP3A
activity following oral administration of 8 mg midazolam,
and the geometric least square mean ratio for AUC (GMAR)
(90% confidence intervals) was 0.66 (0.55–0.78). Of the six
studies enlisted in Table 3, this is the only significant result
on CYP3A4 induction following repeated administration of
Korean ginseng.
Kim et al. (2016b) investigated the effects of Korean red
ginseng extract on the activities of CYP enzymes in 15 healthy
volunteers, by administering them with a modified Inje cock-
tail (Ryu et al. 2007). Korean red ginseng extract (64% dried
ginseng, once daily for 2 weeks) weakly inhibited CYP2C9
and CYP3A4 and weakly induced CYP2D6, with no clini-
cally significant interactions observed between red ginseng and
CYP enzymes (Kim et al. 2016b) (Table 3). In another study
by Kim et al. (2016c) involving 2-week treatment with concen-
trated fermented red ginseng liquid (> 3% dried ginseng, once
daily for 2 weeks), no significantly different drug interactions
13
 Table 3  Clinical studies to evaluate the effect of ginseng on the activities of drug-metabolizing enzyme and transporters
868

Subject character- Age Ginseng dose regimen Phenotype assessment Results References
istics

13
Healthy, young 25.0 ± 3.9 Panax ginseng 0.5 g, tid/day (75 mg ginse- CYP3A4 ([OH-midazolam]/[midazolam] at No significant difference in CYP3A4, Gurley et al. (2002)
12 (M6:F6) noside/day) for 4 weeks 1-h plasma) CYP1A2, CYP2E1, and CYP2D6
CYP1A2 ([paraxanthine]/[caffeine] at 6-h between control and ginseng groups
plasma) Panax ginseng had little effect on CYP-
CYP2E1([OH-chlorozoxazone]/[chlorozo- mediated metabolism
xazone] at 2-h plasma)
CYP2D6([OH-debrisoquin]/[debriso-
quin + OH-debrisoquin] for 8-h urine
recovery)
Healthy, elderly 67.0 ± 5.2 Panax ginseng 0.5 g, tid/day (75 mg ginse- CYP3A4 ([OH-midazolam]/[midazolam] at No significant difference in CYP3A4, Gurley et al. (2005)
12 (M6:F6) noside/day) for 4 weeks 1-h plasma) CYP1A2, CYP2E1, and CYP2D6
CYP1A2 ([paraxanthine]/[caffeine] at 6-h between control and ginseng groups
plasma) Panax ginseng had little effect on CYP-
CYP2E1([OH-chlorozoxazone]/[chlorozo- mediated metabolism
xazone] at 2-h plasma)
CYP2D6([OH-debrisoquin]/[debriso-
quin + OH-debrisoquin] for 8-h urine
recovery)
a
Healthy 32.3 ± 6.7 Panax ginseng 0.5 g, bid/day (50 mg gin- CYP3A4 (AUC of midazolam) Significant increase in CYP3A4 activity in Malati et al. (2012)
12 (M8:F4) senoside/day) for 4 weeks P-gp (AUC of fexofenadine) ginseng group
No significant difference in P-gp activity in
ginseng group
b
Healthy 24.5 ± 1.9 Korean red ginseng extract (100 mg ginse- CYP1A2 (GMMR of paraxanthine/caf- Korean red ginseng weakly inhibited Kim et al. (2016b)
14 (M14:F0) noside/day) for 2 weeks feine) CYP2C9 and CYP3A4 activities and
CYP2C9 (GMMR of EXP3174/losartan) weakly induced CYP2D6 activity
CYP2C19 (GMMR of OH-omeprazole/ Korean red ginseng had little effect on
omeprazole) CYP1A2, CYP2C19, and P-gp function
CYP2D6 (GMMR of dextrorphan/dex-
tromethorphan)
CYP3A4 (GMMR of OH-midazolam/
midazolam)
P-gp (GMAR of fexofenadine)
Healthy 25.6 ± 2.6 Fermented red ginseng extract (ginsenoside CYP1A2 (GMAR of paraxanthine and Korean red ginseng weakly inhibited Kim et al. (2016c)
15 (M15:F0) content not specified) for 2 weeks caffeine) CYP1A2, CYP2C9, and CYP3A4 activi-
CYP2C9 (GMAR of EXP3174 and losar- ties.
tan) Korean red ginseng had little effect on
CYP2C19 (GMAR of OH-omeprazole and CYP2C19, CYP2D6, and P-gp function
omeprazole)
CYP2D6 GMAR of dextrorphan and dex-
tromethorphan)
CYP3A4 (GMAR of OH-midazolam and
midazolam)
P-gp (GMAR of fexofenadine)
M.-K. Choi, I.-S. Song
 Interactions of ginseng with therapeutic drugs 869

were reported between fermented red ginseng and CYP probe

Daily intake of Korean red ginseng extract comprises 100 mg of total ginsenosides including 29.02 mg Rb1, 4.63 mg Rb2, 15.68 mg Rc, 8.58 mg Re, 4.59 mg Rg1, 15.04 mg Rh1, and

M male, F female, tid ter in die, three times a day; bid bis in die, twice a day, GMMR Geometric least square mean metabolic ratio, GMAR Geometric least square mean AUC ratio, CYP
Daily intake of Korean red ginseng extract comprises 85 mg of total ginsenosides including 23.0 mg Rb1, 11.4 mg Rb2, 13.0 mg Rc, 6.6 mg Rd, 6.2 mg Re, 2.8 mg Rg1, 8.0 mg Rh1, and
Seong et al. (2018)
drugs, with a weak inhibition of CYP1A2, CYP2C9, and
CYP3A4 (Table 3). Seong et al. (2018) also reported no clini-
References

cally significant inhibitory effects between Korea red ginseng

and CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4,
and OATP1B1 probe substrates following single or multiple
administration of Korean red ginseng extract (> 60% dried gin-
seng had no clinically significant effect on
CYP2C9, CYP2C19, CYP2D6, CYP3A4,

CYP1A2, CYP2C9, CYP2C19, CYP2D6,

Repeated administration of Korean red gin-
seng, once daily for 2 weeks) (Table 3). Because these clini-
ginseng had little effect on CYP1A2,

cal studies conducted using Korean red ginseng product had

Single administration of Korean red

CYP3A4, and OATP1B1 function

similar ginsenoside content and origin, clinical results were
consistent. In summary, Korean red ginseng did not exhibit
significant pharmacokinetic herb–drug interaction with drug-
and OATP1B1 function

metabolizing enzymes and transporters, regardless of a single

or repeated administration. This could be attributed to the low
absorption and low plasma concentration of ginsenosides, con-
sistent with the in vitro prediction in a previous study (Choi
et al. 2018; Seong et al. 2018).
Results

Daily intake of Panax ginseng root powder comprises 50 mg of total ginsenosides including 14.78 mg Rb1 and 13.6 mg Rb2

Effect of ginseng on therapeutic drugs

CYP2C19 (GMAR of OH-omeprazole and
CYP2C9 (GMAR of EXP3174 and losar-

CYP3A4 (GMAR of OH-midazolam and

CYP1A2 (GMAR of paraxanthine and

CYP2D6 (GMAR of dextrorphan and

Anticancer drugs
OATP1B1 (GMAR of pitavastatin)

Numerous in vitro and in vivo animal studies have proved

the effect of ginseng or ginsenosides on increased cytotox-
Phenotype assessment

icity of chemotherapeutic agents including 5-fluoroura-

dextromethorphan)

cil, irinotecan, mitomycin C, docetaxel, and cisplatin at a

omeprazole)

concentration range of 0.1–300 µg/mL (Chen et al. 2014).

midazolam)
caffeine)

Repeated oral dose of PPD (70 mg/kg) for 6 weeks increased

the plasma exposure of calcitriol in prostate tumor bearing
tan)

mice, which is attributed to the decreased Cyp3a activity that

are responsible for the metabolism of calcitriol. The results
Korean red ginseng extract (85 mg ginse-

suggested enhanced efficacy of calcitriol with a co-treatment

of PPD (Ben-Eltriki et al. 2019).
A critical concern in the above mentioned in vitro and
in vivo animal studies was the relatively high concentra-
Single dose and for 2 weeks

tion of ginseng extract and ginsenoside because this con-

centration is not likely achievable in humans owing to the
Ginseng dose regimen

maximum plasma ginsenoside concentration reportedly

being < 100 ng/mL (Chen et al. 2008; Choi et al. 2018).
noside/day)

Therefore, it is critical to identify individual ginsenosides

that shows anti-tumor efficacy at a low dose. Ginsenoside
Rg3 is effective against various human cancer cells, and
cytochrome P450, P-gp P-glycoprotein

when used at doses of 3–20 mg/kg in combination with

c

anticancer drugs, including cyclophosphamide and gem-

citabine, it improves survival rate in tumor-bearing animal
24.9
Age

models (Chen et al. 2014). Rg3 suppresses tumor growth and

inhibits tumor angiogenesis by inhibiting vascular endothe-
Table 3  (continued)

lial growth factor-dependent pathway (Xu et al. 2016). Rg3

Subject character-

also induces apoptosis and cell cycle arrest at G0/G1 phase

14.45 mg Rg3
15 (M15, F0)

14.1 mg Rg3

and decreases drug resistance by inactivating nuclear fac-

Healthy

tor kappa light chain enhancer of activated B cells (NF-kB)

istics

(Chen et al. 2014). These findings were substantial clinical

b
a

13
870
evidence for Rg3 efficacy and the basis for the development
of ginsenoside Rg3 capsule (20 mg; Shenyi®, China). Rg3
(20 mg twice daily for 30 days) administered in combina-
tion with gemcitabine and cisplatin in advanced esophageal
cancer patients increased 1-year survival rate and reduced
drug-associated adverse events; this adjuvant triple therapy
substantially improved quality of life as opposed to chemo-
therapy using gemcitabine and cisplatin alone (Chen et al.
2014). Meta-analysis of 20 clinical studies involving admin-
istration of Rg3 (20 mg twice daily 6–24 weeks) combined
with chemotherapy for non-small cell lung cancer patients
indicated that Rg3 enhances response rate, prolongs overall
survival rate, reduces treatment-related toxicity, and pro-
motes and improves quality of life (Xu et al. 2016).
Ginseng product is also frequently administered as
a health supplement along with cancer chemotherapy.
Because many anticancer drugs are substrates for CYP3A4
and P-gp, ginseng–anticancer drug interaction has been
focused on CYP3A4 and P-gp. No significant in vivo phar-
macokinetic interactions between ginseng and CYP3A4 and
P-gp function have been reported, except for the findings
reported by Gurley et al. (Table 3). However, two contro-
versial ginseng–drug interaction cases with regard to cancer
therapy have been reported (Table 4). Both cases deduced
that decrease in CYP3A4 activity or induction of CYP3A4
can be attributed to imatinib-associated liver toxicity or
gefitinib resistance, respectively (Hwang et al. 2008; Bilgi
et al. 2010). However, the underlying mechanisms related to
CYP3A4 activity and the associated controversies need to
be carefully validated.
In order to improve the clinical interpretation of the
in vivo pharmacokinetic interactions between herbal medi-
cines and chemotherapy, a novel algorithm-assisted infor-
mation system has been developed and visualized by the
grading colors according to the risk categories (Ziemann
et al. 2019). In this system, cyclosporine, cyclophospha-
mide, docetaxel, imatinib, irinotecan, and tamoxifen were
indicated as possible interaction with ginseng mediated by
CYP3A4 and/or P-gp (Ziemann et al. 2019). However, only
3 clinical trials and 1 case report on pharmacokinetic inter-
actions between ginseng and anticancer drugs were included
in this algorithms. Prediction of pharmacokinetic interac-
tion potential from in vitro cell system could be restricted
because of lack of information on the plasma concentration
of active components of ginseng, ginsenosides (Ziemann
et al. 2019). Further studies for determining plasma ginse-
noside concentrations and the used of standardized ginseng
product may be useful for the extrapolation of clinical gin-
seng–drug interactions.
Clinical studies on pharmacodynamic interactions
between ginseng and anticancer drugs have been focused on
the effect of ginseng in adjuvant chemotherapy for reducing
cancer-related fatigue (CRF) and for improving quality of
13
M.-K. Choi, I.-S. Song
life (Table 4). High dose of Korean ginseng and American
ginseng (over 1000 mg/day for > 4 weeks) in combination
with conventional chemotherapy significantly improves
CRF without causing any critical adverse event in patients
with different cancer types and stages (Table 4). Two clini-
cal studies involving administration of Korean red ginseng
and fermented red ginseng at 3000 mg/day in combination
with platinum-based chemotherapy also improved CRF
score (Table 4). The patients showed significantly improved
emotional symptoms and quality of life scores and reduced
anticancer drug-related toxicity. During the study period,
high-dose ginseng administration was tolerated by cancer
patients. However, in both cases, survival rates and tumor
markers did not significantly change after administration of
adjuvant therapy with a high dose of ginseng (Kim et al.
2017a; Jiang et al. 2017). An interesting results on the inter-
action between cisplatin and ginsenoside Rb1 have been
reported in A549 lung cancer bearing mice (Zhou et al.
2019a). The intervention of cisplatin (2 mg/kg, intraperito-
neal injection) significantly decreased the plasma exposure
of Rd, Rg3, and F2, metabolites of Rb1, but did not affect
the plasma concentrations of Rb1, suggesting the inhibi-
tion of gut metabolism from Rb1 to Rd, Rg3, and F2 from
Rb1 by cisplatin treatment (Zhou et al. 2019a). The results
were supported by the decreased deglycosylation of Rb1 but
increased intestinal permeability of Rb1 by cisplatin (Zhou
et al. 2019a). Taken together, the beneficial anti-proliferative
effect of ginseng needs further validation in cancer treatment
considering the effect of platinum-based chemotherapy on
the inhibited gut metabolism, narrowed intestinal absorptive
area, increased efflux ratio of ginsenoside, and as enhanced
intestinal permeability (Zhou et al. 2019a).
Antiplatelet drugs
Lau et al. (2009) reported the different antiplatelet effects
of Panax notoginseng, Korean ginseng, and American gin-
seng. Platelet inhibition percentage following treatment with
these ginseng products (3 mg/mL) was compared with that
following treatment with 200 µM aspirin (positive control);
similarly, steamed Panax notoginseng showed an equivalent
effect with aspirin, and the effect decreased in the order of
raw Panax notoginseng, Korean red ginseng, Korean gin-
seng, and American ginseng. Ginsenosides Rg1 and Rg2
were reported as the main antiplatelet components (Teng
et al. 1989; Kuo et al. 1990).
Ginsenosides Rg1 and Rg3 inhibited thrombin-induced
human platelet aggregation in a dose-dependent manner
(Kwon 2018). Difference in antiplatelet effects depend on
the origin of ginseng can be attributed to the different gin-
senoside contents of ginseng since ratios of Rb1/Rg1 and
PPD/PPT are the lowest in Panax notoginseng but the high-
est in American ginseng (Table 1). The concentrations of
 Table 4  Clinical studies evaluating the effect of ginseng on anticancer drugs
Study
Pharmacokinetics interac-
tion: possibly via CYP3A
induction
Pharmacokinetics interac-
tion: possibly via CYP3A
or P-gp inhibition
Adjuvant chemotherapeu-
tic agent: cancer-related
fatigue (CRF)
13
Subject characteristics Age Ginseng dose regimen Phenotype assessment Results References
(+Combination drugs)
Case report 36-year-old (F) Complementary herbal Chest CT scan Initial 9 weeks of gefitinib Hwang et al. (2008)
Stage IV lung adenocarci- medicines including along with ginseng, pri-
noma ginseng gefitinib, 250 mg/ mary mass and metastasis
day PO increased 4 weeks of gefi-
tinib with discontinuation
of complementary herbal
medicines, primary mass
and metastasis markedly
decreased
Continuation of gefitinib for
30 weeks, primary mass
Interactions of ginseng with therapeutic drugs
and metastasis further
decreased
Case report 26-year-old (M) Energy drink containing Liver toxicity 7 years of imatinib mainte- Bilgi et al. (2010)
Chronic myelogenous ginseng nance and follow-up
leukemia Imatinib, 400 mg/day PO Imatinib-associated liver
toxicity was induced dur-
ing 3 months of imatinib
therapy along with ginseng
After treatment of liver
toxicity, imatinib was
restarted at the same dose
without recurrence of liver
toxicity
282 American ginseng, 750, Multidimentional fatigue No significant improvement Arring et al. (2018)
(M96:F186) 1000, and 2000 mg for symptom inventory at a dose of 750 mg
8 weeks Decreasing CRF at doses of
1000 and 2000 mg
364 American ginseng, 2000 mg Multidimentional fatigue Improved fatigue score at Barton et al. (2013)
(M80:F284) for 8 weeks symptom inventory ginseng dose of 2000 mg
40 Panax ginseng, 1252.5 mg Visual analogue scale of Significantly improved Jeong et al. (2010)
(M16:F24) for 2 weeks global fatigue fatigue score
30 Panax ginseng, 800 mg for Functional assessment of Significantly improved Yennu et al. (2016)
(M15:F15) 4 weeks chronic illness therapy fatigue score
fatigue
15 52.4 ± 9.9 Methylphenidate 10–40 mg/ Change in fatigue score in Significant reduction in Chang et al. (2018)
(M7:F8) day + American gin- numerical rating scale fatigue
seng 2000 mg/day for
30.5 ± 7.8 days
871
 Table 4  (continued)
872

Study Subject characteristics Age Ginseng dose regimen Phenotype assessment Results References
(+Combination drugs)

13
Adjuvant chemotherapeutic Epithelial ovarian cancer 55.9 ± 12.1 6 cycles of taxane and Genotoxicity-binucleated No difference in binucleated Kim et al. (2017a)
agent: genotoxicity and patients platinum-based chemother- cells index and micronu- cell index after ginseng
HRQL 30 apy + 1Korean red ginseng clei yield treatment
3000 mg/day for 3 months HRQL–Functional scale, Significant reduction in
symptom scale micronuclei yield after
Brief fatigue inventory ginseng treatment
Anxiety and depression Significantly improved
scale HRQL score
Significantly improved
fatigue score
Significantly improved anxi-
ety and depression score
Non-small cell lung cancer 58.6 ± 19.3 Gemcitabine 1 g/m2 Chemotherapy toxicity Significantly decreased leu- Jiang et al. (2017)
patients and cisplatin 25 mg/ evaluation kopenia, thrombocytope-
60 (M42:F18) m2 chemotherapy every Comparison of tumor nia, nausea, and vomiting
3 weeks + fermented red marker No difference in tumor
ginseng 3000 mg/day for Anxiety and depression marker after ginseng treat-
60 days scale ment
Functional assessment of Significantly improved anxi-
chronic illness therapy ety and depression score
fatigue Significantly improved
fatigue score
a
Korean red ginseng 1 g contains ginsenoside Rb1 (5.61 mg/g), Rb2 (2.03 mg/g), Rc (2.20 mg/g), Rd (0.39 mg/g), Re (1.88 mg/g), Rf (0.89 mg/g), Rg1 (3.06 mg/g), Rg2 (0.15 mg/g), Rg3
(0.17 mg/g), and Rh1 (0.30 mg/g)
M male, F female, HRQL health-related quality of life, CT computed tomography
M.-K. Choi, I.-S. Song
Interactions of ginseng with therapeutic drugs 873

individual components are more important than the total
ginsenoside content in ginseng product.
The importance of Panax notoginseng ginsenosides (R1,
Rg1, Rb1, Rd, and Re) in cardiovascular diseases, and the
interaction between aspirin and Panax notoginseng has
been investigated in rats. Because of a very short half-life
of aspirin and rapid transformation of salicylate from aspi-
rin, Tian et al. (2017) compared salicylate concentrations
following co-administration of aspirin and Panax notogin-
seng (30.25 mg/kg as total ginsenosides) with that following
administration with aspirin alone. Plasma concentration of
salicylate increased by twofolds following co-administration
with Panax notoginseng. Intestinal permeability of aspirin
and salicylate was significantly increased by the presence
of Panax notoginseng ginsenosides in Caco-2 cells, sug-
gesting that pharmacokinetic interactions between aspirin
and Panax notoginseng could occur during absorption (Tian
et al. 2017). Aspirin increases plasma concentrations and
intestinal permeability of ginsenosides R1, Rg1, Rb1, Re,
and Rd when concomitantly administered, and the mecha-
nisms underlying increased absorption were that Panax
notoginseng ginsenosides increase membrane fluidity and
that aspirin and salicylate open up the tight junction of cells
(Tian et al. 2018). These results suggest likely clinical phar-
macodynamics and pharmacokinetic interactions between
Panax notoginseng and aspirin, but associated clinical evi-
dence remains unavailable.
Anticoagulant drugs
Warfarin is the most common oral anticoagulant used for
preventing thromboembolic disorders. It has a narrow
range between therapeutic and toxic doses, suggesting that
inappropriate interventions could result in unexpected clini-
cal outcomes (Leite et al. 2016; Choi et al. 2017). Some
studies produced superficial results, and other articles which
reported cases of interactions between warfarin and ginseng
did not provide relevant clinical outcome-related informa-
tion or quantify the clinical significance (Leite et al. 2016;
Agbabiaka et al. 2017).
Recently, interactions between ginseng and warfarin
have been reported to decrease warfarin efficacy owing to
its pharmacokinetic alterations. The concomitant use of con-
centrated ginseng extract interrupted the warfarin-caused
increase in the international normalized ratio (INR) in a
time-dependent and dose-dependent manner (Dong et al.
2017a). A well-established K-carrageenan-induced rat tail
thrombosis model demonstrated that ginsenoside caused
dose-dependent antagonism of the anti-coagulation effect
of warfarin after repeated co-administration of concentrated
ginseng extract (30, 100, 300 mg/kg for 3 weeks) and war-
farin; consequently, decreased plasma concentrations of
warfarin and increased warfarin metabolism in turn reduced
warfarin efficacy owing to CYP3A4 and CYP2C9 upregula-
tion (Dong et al. 2017a).
Several clinical studies also focus on this issue (Table 5).
American ginseng exhibited herb–drug interaction with
warfarin, causing a reduction in the anti-coagulative effect
exerted by warfarin (Yuan et al. 2004). However, other three
studies (Jiang et al. 2004; Lee et al. 2008, 2009) involving
Korean ginseng had little effect on warfarin pharmacoki-
netics and efficacy, despite the study subjects being admin-
istered a high ginsenoside dose (100 mg/day for 6 weeks)
(Table 5). Therefore, similar to the case of aspirin, the ginse-
noside composition and concentration seems to be important
and should be studied further.

Table 5  Clinical studies investigating the herb–drug interaction between warfarin and ginseng
Subject characteristics Age Ginseng dose Duration Results References

Healthy 30.2 ± 7.2 Warfarin 5 mg 4 weeks American ginseng reduced the Yuan et al. (2004)
20 (M9:F11) American ginseng 0.5 ga anti-coagulation effect of
warfarin
Healthy 20–40 Warfarin 25 mg 2 weeks Korean ginseng had little effect Jiang et al. (2004)
12 (M12:F0) Korean ginseng 0.5 gb on warfarin INR and warfarin
metabolism
Cardiac valve replacement < 50: 8 Warfarin 40.60 ± 14.53 mg/ 6 weeks Korean red ginseng had little Lee et al. (2009)
patients 50–60: 9 week effect on the anti-coagulation
25 (M4:F21) > 60: 8 Korean red ginseng 1.0 gc effect of warfarin
Ischemic stroke patients 62.75 ± 7.71 Warfarin 2–5 mg 2 weeks Korean ginseng had little effect Lee et al. (2008)
25 (M13F12) Korean ginseng 1.5 gd on warfarin INR and warfarin
metabolism

M male, F female
a
American ginseng root powder contains 26 mg of total ginsenosides. Rb1:Rb2:Rc:Re:Rg1 = 9.6 mg:1 mg:3.05 mg:8.4 mg:1.75 mg
b
Korean ginseng root powder contains 8.93 mg of ginsenoside Rg1
c
Korean red ginseng extract from the 6-year-old root of Korean ginseng contains 100 mg ginsenosides
d
Korean ginseng root powder contains 3 mg and 1.5 mg of Rb1 and Rg1, respectively

13
874 M.-K. Choi, I.-S. Song

Antidiabetic drugs
Anti-diabetic effect of ginseng and its related mechanisms
have been investigated to prove the beneficial hypoglyce-
mic effects of ginseng products and ginsenosides on diabetic
animals and patients. The therapeutic potential of several
ginseng products from Asian ginseng, American ginseng,
Korean red ginseng, black ginseng, and fermented ginseng
has been proved using in vitro cells systems and diabetic
animals (Yuan et al. 2012; Li and Gong 2015). The mecha-
nisms underlying the modulation of glucose metabolism by
ginseng products in diabetic patients would likely be pertur-
bation of hepatic glucose production and enhancement of
glucose uptake in peripheral tissues via glucose transporter

Table 6  Studies investigating the antidiabetic effect of ginseng

Subject characteristics Age Ginseng dose Duration Results References

Ginseng without standard diabetic drugs

DM patients 59.7 ± 7.0 Ginseng 0.2 g/day 8 weeks FBG ↓, HbA1c ↓, OGGT ↓ Sotaniemi et al. (1995)
36 (M16:F20)
DM patients 51.6 ± 10.9 Korean red ginseng 2.7 g/day 24 weeks FBG ↔, HbA1c ↔ Choi et al. (1997)
31 (M15:F16)
DM patients 64.0 ± 7.0 American ginseng 3.0 g/day 8 weeks FBG ↓, FPI ↔, HbA1c ↔ Shishtar et al. (2014)
24 (M13:F11) Insulin resistance ↔
DM patients 51.0 ± 8.5 Panax ginseng powder 2.2 g/ 12 weeks FBG ↓, HbA1c ↔ Ma et al. (2008)
20 (M12:F8) day Insulin resistance ↓
DM patients 64.0 ± 8.7 Korean red ginseng 6.0 g/day 12 weeks FBG ↔, HbA1c ↔, OGGT Vuksan et al. (2008)
19 (M11:F8) ↓, FPI ↓, Insulin resistance ↓
Pre-DM and DM patients 46.0 ± 3.0 Korean red ginseng 3 g/day 4 weeks FBG ↔, FPI ↔ Reeds et al. (2011)
15 (M1:F14) for 2 weeks; 8 g/day for HbA1c ↔
2 weeks
DM patients 56.0 ± 7.2 Fermented Korean red gin- 12 weeks FBG ↓, HbA1c ↓ Kim et al. (2011)
38 (M23:F15) seng 0.78 g/day FPI ↔
DM patients 52.7 ± 11.0 Ginsam 1.5–3.0 g/daya 8 weeks FBG ↓, HbA1c ↓ Yoon et al. (2011)
72 (M44:F28) FPI ↔, Insulin resistance ↓
DM patients 58.8 ± 1.7 Korean red ginseng 5.0 g/day 12 weeks FBG ↔, HbA1c ↔ Bang et al. (2014)
41 (M28:F13) FPI ↔, Insulin resistance ↓
DM patients 53.2 ± 1.8 Fermented Korean red gin- 4 weeks FBG ↓, HbA1c ↔ Oh et al. (2014)
42 (M28:F14) seng 2.7 g/day PPG ↓, AUC​glucose ↓
Impaired fasting glucose 50.5 ± 12.4 Ginseng extract 0.96 g/day 8 weeks Insulin resistance ↓ Park et al. (2014)
11 (M6:F5)
Co-medication of ginseng with diabetic drugs
Pre-DM and DM patients 62.9 ± 12.0 PQS 1.8 g/day + standard 4 weeks FBG ↔, FPI ↔ Zhang et al. (2007),
84 (M51:F33) diabetic ­medicationb Insulin resistance ↔ Shishtar et al. (2014)
No combination effect
DM patients 88.1 ± 17.2 American ginseng extract 12 weeks FBG ↑, HbA1c ↔ Mucalo et al. (2014)
74 (M28:F46) 3.0 g/day + usual diabetic No combination effect
medication (control usual
diabetic medication)
Streptozotocin-induced – Korean red ginseng 2.0 g/ 7 weeks FBG ↓, HbA1c ↔ Nam et al. (2018)
diabetic rats kg/day + metformin 50 mg/ Beneficial effect of
kg/day (control metformin KRG + metformin combina-
50 mg/kg/day) tion
Diabetic db/db mice – Compound K 10 mg/kg + met- 8 weeks Beneficial effect of compound Yoon et al. (2007)
formin 150 mg/kg K + metformin combination
Ginsenoside Re
Pre-DM and DM patients 46.0 ± 3.0 Re 0.2 g/day for 2 weeks; 4 weeks FBG ↔, FPI ↔ Reeds et al. (2011)
15 (M1:F14) 0.5 g/day for 2 weeks HbA1c ↔
DM diabetes mellitus, M male, F female, FBG Fasting blood glucose, FPI Fasting plasma inulin, HbA1c Hemoglobin A1C, OGGT​Oral glucose
tolerance test, PPG Postprandial blood glucose, AUC​glucose Area under plasma concentration of glucose
a
Ginsam: Vinegar extract of Korean ginseng
b
PQS: Extract of American ginseng saponin

13
Interactions of ginseng with therapeutic drugs 875
4 (GLUT4). Recently, PPD-type ginsenosides (Rb1, Rb2,
Rc, Rg3, and compound K) and PPT-type ginsenosides
(Re, Rg1, and PPT) suppressed hepatic gluconeogenesis
via adenosine monophosphate (AMP)-activated protein
kinase (AMPK) (Lee et al. 2012; Ryu et al. 2013; Meng
et al. 2017). Enhancement of GLUT4 expression following
treatment with ginseng or ginsenosides in turn increased
glucose uptake in adipocytes or skeletal muscle cells (Yuan
et al. 2012).
Despite increasing evidence for various therapeu-
tic effects of ginseng products on diabetic animals, the
hypoglycemic effect of ginseng product remains non-
conclusive (Table 6). A double blind, placebo-controlled
study of 36 diabetic patients who received 0.2 g/day gin-
seng root powder for 8 weeks showed reduction in fast-
ing blood glucose (FBG) and hemoglobin A1c (HbA1c)
levels and an improvement in glucose response to oral
glucose tolerance test (OGGT) (Sotaniemi et al. 1995).
However, 31 diabetic patients who underwent long-term
treatment for 24 weeks with 2.7 g/day Korean red ginseng
showed no changes in FBG and HbA1c levels (Choi et al.
1997). Clinical studies, shown in Table 6, varied with
regard to ginseng treatment (i.e., dose, formulation, ori-
gin, and treatment period) and showed partially improved
clinical outcomes for FBG level and insulin resistance but
was unsuccessful at reducing HbA1c level to the control
level. The discrepancy between animal and human stud-
ies as well as among human studies could be attributed to
different ginsenoside exposures resulting from different
ginseng treatments. However, plasma ginsenoside con-
centrations that exert a hypoglycemic effect have not yet
been investigated.
In numerous animal studies showing anti-diabetic
effect of red ginseng extract, red ginseng extract dose
ranges from 200 mg/kg to 2.0 g/kg (i.e., 3–15 mg/kg of
total ginsenosides) (Xin et al. 2007; Martovetsky et al.
2013; Nam et al. 2018). In human studies, 2.7–6.0 g/
day Korean red ginseng extract, usually containing
50–100 mg ginsenosides/day, was administered to dia-
betic patients for 4–24 weeks (Table 6). On the basis of
the abovementioned ginseng dose and ginsenoside con-
tent, the maximum plasma concentration of Rb1 was
36.6 ng/mL after administration of a single oral dose of
2 g/kg red ginseng extract to streptozotocin-induced dia-
betic rats (Nam et al. 2018). However, in humans, plasma
Rb1 concentration was 2.2 ng/mL after a single dosage of
Korean red ginseng extract, which increased to 12.2 ng/
mL after repeated administration for 2 weeks (Choi et al.
2018). After establishing plasma ginsenoside concentra-
tions, it can be suggested that the anti-diabetic effect of
ginseng is reproducible or comparable with that reported
in other clinical studies. Another study reported that the
total ginsenoside content in American ginseng root and
Korean red ginseng exhibiting positive glycemic control
was 1.9–3.2% (Awang and Li 2008). Ginsenoside Rb2
is the most effective in decreasing blood glucose levels
in streptozotocin-induced diabetic rats (Yokozawa et al.
1985); however, Rb2 content in American ginseng root
and Korean red ginseng was reportedly 0.06% and 0.25%,
respectively (Awang and Li 2008).
In two clinical studies involving co-administration of
ginseng product with other antidiabetic drugs, no addi-
tional combination effect of ginseng could be found com-
pared with the standard anti-diabetic drug used as con-
trol (Table 6). Contrarily, high-dose Korean red ginseng
and compound K in combination with metformin showed
beneficial effects on FBG in diabetic animals (Table 6).
Reeds et al. (2011) studied the effect of ginsenoside Re
in previously diagnosed diabetic patients and prediabetic
subjects but did not report optimistic clinical outcomes
(Table 6). As previously mentioned, determining an
optimal dose for ginseng or a single ginsenoside based
on plasma ginsenoside concentration may be useful for
future clinical studies.
Conclusions and perspectives
This comprehensive review on the pharmacokinetic interac-
tions of ginseng revealed that daily administration of Korean
red ginseng (0.5–3 g extract; dried ginseng, > 60%) did not
cause significant herb–drug interaction with drug-metab-
olizing enzymes (e.g., CYPs) and drug transporters (e.g.,
P-gp and OATP1B1). Among different therapeutic drugs co-
administered with ginseng, adjuvant chemotherapy, com-
prising ginseng (1–3 g extract) and anticancer drugs, facili-
tates reduction in CRF and improves the quality of life and
emotional scores. It is important to understand the effects of
ginseng therapy or ginseng combination therapy on diabetic
patients and of ginseng interaction with aspirin or warfarin
because these effects may vary depending on the composi-
tion of specific ginsenosides, including Rb1/Rg1 ratio and
Re or Rb2 content, as well as the origin and preparation
method of ginseng products.
Although many in vitro cell studies and in vivo animal
studies have reported potential ginseng–drug interactions
and beneficial effects of ginseng, such results could neither
reflect the actual overall effect of herb–drug interactions in
an in vivo system nor extrapolate the therapeutic benefit
of ginseng in clinical settings. Individual case reports of
herb–drug interaction could not be extrapolated to clinical
settings owing to differences in dosage, origins, and formu-
lations of ginseng product in several cases. Therefore, clini-
cal results of a standardized ginseng product created using a
pharmacologically effective component and various ginseno-
sides along with their pharmacokinetic–pharmacodynamic
13
876
correlation are of utmost necessity to serve as reproducible
and reliable clinical evidence.
Compliance with ethical standards
Conflict of interest The authors declare no conflict of interest.
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