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Pharmacokinetic Drug Interactions with Panax ginseng

  • Meenakshi R. Ramanathan
  • Scott  R. PenzakEmail author
Review Article

Abstract

Panax ginseng is widely used as an adaptogen throughout the world. The major active constituents of P. ginseng are ginsenosides. Most naturally occurring ginsenosides are deglycosylated by colonic bacteria to intestinal metabolites. Ginsenosides along with these metabolites are widely accepted as being responsible for the pharmacologic activity and drug interaction potential of ginseng. Numerous preclinical studies have assessed the influence of various ginseng components on cytochrome P450 (CYP), glucuronidation, and drug transport activity. Results from these investigations have been largely inconclusive due to the use of different ginseng products and variations in methodology between studies. Drug interaction studies in humans have been conflicting and have largely yielded negative results or results that suggest only a weak interaction. One study using a midazolam probe found weak CYP3A induction and another using a fexofenadine probe found weak P-gp inhibition. Despite several case reports indicating a drug interaction between warfarin and P. ginseng, pharmacokinetic studies involving these agents in combination have failed to find significant pharmacokinetic or pharmacodynamic interactions. To this end, drug interactions involving P. ginseng appear to be rare; however, close clinical monitoring is still suggested for patients taking warfarin or CYP3A or P-gp substrates with narrow therapeutic indices.

Keywords

Warfarin International Normalize Ratio Ginsenosides Fexofenadine Premature Ejaculation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Key Points

The major active components of P. ginseng that are believed to be involved in drug interactions are the ginsenosides and their glycosylated intestinal metabolites.

Data from in vitro drug interaction studies are inconsistent with regard to P. ginseng’s ability to modulate cytochrome P450, glucuronidation, or drug transport proteins.

Clinical pharmacokinetic studies in humans suggest the drug interaction potential with P. ginseng is low. At least one study suggests it is a mild-moderate inducer of CYP3A4, and it may also decrease the anticoagulant activity of warfarin via an unknown mechanism.

1 Introduction

The use of complementary and alternative medications (CAM), including herbal remedies continues to be prevalent in the United States and Europe. Total estimated retail sales of herbal supplements in the United States was over 6.4 billion dollars in 2014, representing a 6.8% increase over the previous year [1]. The use of herbal supplements is common in Europe as well. In a survey that included six European countries, nearly 19% of respondents claimed to have taken at least one plant food supplement (PFS) in the previous year with at least some degree of regularity [2]. Among the 40 top-selling herbal supplements in the United States in 2014, Panax ginseng, achieved nearly 5.7 million dollars in sales [1]

Ginseng refers to any one of 11 species of perennial plants that belong to the genus Panax and the family Araliaceae [3]. P. ginseng is also known as Korean ginseng or Asian ginseng; it should not be confused with Siberian ginseng or American ginseng, which also belong to the Araliaceae family but are from a different genus. Depending on how it is processed, ginseng can be classified into 3 types: (1) fresh (unprocessed) ginseng, (2) white ginseng (peeled and then dried), and (3) red ginseng (peeled and then steamed). When administered orally, ginseng is promoted as an adaptogen, which is defined as a natural substance that assists the body in coping with stress and normalizing bodily processes. It is used to stimulate immune function, improve cognitive function, physical stamina, concentration, work efficiency, and memory. Additional purported uses of ginseng include depression, chronic fatigue syndrome, diabetes mellitus, various forms of cancer, and numerous other maladies [4]

The most abundant components of commercially active ginseng are the ginsenosides Rb1, Rb, Rc, Rd, Re, Rf, and Rg1 [5]. Most of these ginsenosides are poorly absorbed after oral ingestion due to the presence of bulky sugar moieties and high molecular weights [6]. The majority of these ginsenosides undergo deglycosylation by colonic bacteria to intestinal metabolites including 20(S)-protopanaxatriol type (ppt) and 20(S)protopanaadiol type (ppd) and Compound K [7]. The metabolites are the primary compounds that appear in systemic circulation after oral administration of ginsenosides; they are also widely accepted as being responsible for the pharmacologic activity and drug interaction potential of ginseng [8, 9]. Of note, fermented red ginseng, which increases the concentration of certain ginsenoside metabolites, was developed to enhance the oral absorption of P. ginseng components and increase its pharmacologic efficacy [10].

Panax ginseng, like other CAMs in the United States, is regarded as a dietary supplement (i.e., food product) and is not subject to intense regulatory oversight by the United States Food and Drug Administration (FDA) [11]. As a result, the content of herbal preparations may vary significantly between manufacturers or even within lots produced by the same manufacturer [12]. Recently, the USP Dietary Supplement Verification Program was enacted to evaluate the integrity of dietary supplements. Products that meet the program’s standards are labeled with a USP Verified logo that can be included on labels, promotional materials, and packaging. In Europe, the marketing of PFSs is dependent upon national legislation, which differs significantly across the 27 European Union Member States. Because the legal status of PFSs varies between countries, the market environment for these items is complex and at times confusing [2].

Ginseng is typically administered orally (although topical administration is used for certain conditions such as premature ejaculation) in several forms, including the fresh cut root, capsules, alcohol extracts, powder, and teas. The pharmacologic activity of ginseng is believed to be due to ginsenosides, and percent ginsenoside content is widely used for standardizing ginseng products [3]. Data from a number of preclinical studies suggest that several ginsenosides and their deglycosylated metabolites are involved in the modulation of cytochrome P450 (CYP) enzymes, organic anion transporting polypeptide 1B1 (OATP1B1), P-glycoprotein (P-gp), and uridine diphosphate glucuronosyltransferases (UGTs), although not all study results have been in agreement [13, 14, 15, 16, 17, 18]. It is also possible that additional compounds present in P. ginseng may contribute to CYP modulation and that other metabolic enzymes and/or transporters such as breast cancer-related protein (BCRP), multidrug resistant proteins (MRPs), and organic anion transporters (OATs) may be altered by P. ginseng administration as well. The ability of ginseng to modulate the activity of uptake and efflux transporters, CYP, and UGTs likely explains its involvement in drug interactions, although other unidentified mechanisms may also contribute.

Patients most vulnerable to experiencing drug interactions involving P. ginseng include those receiving polypharmacy with concurrent proprietary medications. Such patients typically include the elderly and those with chronic medical conditions for which P. ginseng has been suggested as an effective treatment modality; these conditions include Alzheimer’s, diabetes mellitus, several types of cancer, depression, anxiety, and various other conditions [4]. Because P. ginseng is purported to alter the pharmacokinetics of certain prescription medications, it is important for clinicians to be aware of data either supporting or refuting such claims. To this end, the purpose of this review is to evaluate documented and potential drug interactions between P. ginseng and various prescription medications, the purported mechanism by which these interactions occur, and appropriate measures to address and/or avoid these interactions when possible.

2 Preclinical Drug Interaction Studies with P. ginseng

2.1 Pharmacokinetic Studies

2.1.1 Cytochrome P450 (CYP)

A number of in vitro studies, including those conducted in cellular systems, and liver or intestinal microsomes (of human or animal origin) have attempted to assess the impact of ginseng components and or their metabolites on one or multiple CYP enzymes (Table 1) [13, 15, 16, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30]. Unfortunately, much of the data from these investigations is conflicting and inconsistent. Of the 15 studies included in Table 1, nine assessed the influence of various ginsenosides on CYP3A4 activity using probe substrates, or changes in CYP3A4 mRNA [15, 21, 22, 23, 24, 25, 26, 28, 29, 30]. Results from these studies report CYP3A4 inhibition, induction, or no effect. Data are similarly conflicting for other tested CYP isoforms such as CYP1A2, CYP2C9, CYP2C19, and CYP2D6 [15, 16, 19, 20, 24, 25, 26, 28]. There are many reasons for disparity among these results. These may include: (1) use of concentrations of ginsenosides and other ginseng constituents in in vitro experiments that are much higher than those achieved in humans taking recommended P. ginseng doses, and differences in incubation periods, durations of exposure and various other methodological approaches; (2) assumptions regarding the concentrations of phytochemicals that are achieved at enzymatic sites in the liver and/or intestines after oral P. ginseng administration; (3) differences in phytochemicals found among P. ginseng products arising secondary to differences in cultivation conditions such as temperature, soil, moisture, length of cultivation, and harvest season [31]. (4) Routine use of different in vitro models among studies including Supersomes (microsomes derived from baculovirus-infected insect cells that express CYP cDNAs), Baculosomes, human hepatocytes, HepG2 cells, rat liver microsomes, and others. To this end, due to conflicting data from in vitro studies assessing the CYP-mediated drug interaction potential of P ginseng, it is not possible to readily extrapolate results from these studies to the clinical setting.
Table 1

Effect of Panax ginseng on cytochrome P450 activity and/or expression in vitro

In vitro system

P. ginseng component(s)

Outcome measurement

Results

References

Recombinant human CYP isoforms

Rb1, Rb2, Rc, Rd, Re, Rf, Rg1, eleutherosides B and E

CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 catalytic activity

Rd weakly inhibited the activity of CYP3A4 and CYP2D6 > CYP2C19 and CYP2C9

Rc increased CYP2C9 activity, and Rf increased the activity of CYP3A4

[15]

Human recombinant CYP1A1, CYP1A2, and CYP1B1

Standardized P. ginseng extract and the individual ginsenosides: Rb1, Rb2, Rc, Rd, Re, Rf, and Rg1

CYP1A1, CYP1A2, and CYP1B1 activity as assessed by 7-ethoxyresorufin O-dealkylation

P. ginseng extract decreased CYP1A1, CYP1A2, and CYP1B1 activities in a concentration-dependent manner

Individually or as a mixture, Rb1, Rb2, Rc, Rd, Re, Rf, and Rg1 did not alter CYP1A1, CYP1A2, or CYP1B1 activity

[19]

Supersomesa (in vitro fluorometric microtitre plate assay)

P. ginseng extractum

CYP2C9, CYP2C19, CYP2D6, and CYP3A4 activity using marker substrates

Potent inhibition (74-100%) of CYP2C9, CYP2C19, CYP2D6, CYP3A4

[20]

Human hepatocytes; HepG2 cells

Ginseng

Inducibility of CYP3A4 mRNA

No significant enhancement of CYP3A4 mRNA content (155 ± 83% of control)

[21]

Human liver microsomes

Rb1, Rb2, Rc, and Rd

CYP2C9 and CYP3A4 catalytic activity using marker substrates

Rd significantly inhibited CYP2C9 and CYP3A4

Rb1, Rb2, Rc had limited inhibitory activity activities on CYP2C9 and CYP3A4

[22]

Caco-2 monolayers, Baculosomes, rat liver microsomes

Kaempferol from ginseng

CYP3A4-mediated metabolism of cortisol

Kaempferol significantly inhibited the CYP3A4-mediated metabolism of cortisol

[23]

Primary cultures of rat hepatocytes

P. ginseng extract [4% (w/w) total ginsenosides]

CYP2B1 and CYP3A23, gene expression

Neither CYP2B1, CYP3A23, or CYP1A2 mRNA expression was altered

[13]

Human liver microsomes

Rb1, Rb2, Rc, and Rd

CYP2C19 and CYP2D6 catalytic activity using marker substrates

Rd weakly inhibited CYP2C19 and CYP2D6; Rb1, Rb2, Rc produced negligible inhibitory effects on CYP2C19 and CYP2D6

[16]

Human liver microsomes and cDNA-expressed human CYP3A4

Rb1; Rh1 and F1 [two hydrolysis products of 20(S)-protopanaxatriol]

CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4 catalytic activity using probe-specific substrates

No significant effect of Rb1 on any CYP activity

Rh1 and F1 competitively inhibited CYP3A4; F1 weakly inhibited CYP2D6; Rh1 weakly stimulated CYP2E1 activity

[24]

Human liver microsomes

 

CYP1A2, CYP2C89, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 catalytic activity using probe-specific substrates

Ginsenosides F1, Rh1 (bur not ginseng extract) inhibited CYP3A4 at 10 µM

[25]

Baculosomes (cDNA-expressed CYP enzymes)

Saponins: Rb1, Rb3, Rd, Rg3, Rh2, C-K, Re, Rg2, Rg1

Sapogenins: PPD, 20(R)-PPD, PPT, 20(R)-25-OH-PPD, 20(R)-25-OH-PPT, 25-OCH3-PPD

Activity of CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4

Rb1, Rg3, and C-K moderately inhibited CYP1A2; other tested compounds weakly inhibited CYP1A2

Rg3, Rh2, and C-K, and all sapogenins moderately inhibited CYP2C19 with greater inhibition (P < 0.05) observed versus CYP2C9 and CYP3A4; the sapogenins weakly inhibited CYP1A2 and CYP2D6

Rg3 potently inhibited CYP2D6

[26]

HepG2 cells

Rb1, Rg1

CYP1A1 expression determined via mRNA levels

CYP1A1 mRNA was significantly increased by Rb1 and Rg1 in a time- and concentration-dependent manner

[27]

HepG2 cells

Saponins: Rb1, Rb3, Rd, Rg3, Rh2, C-K, Re, Rg2, Rg1

Sapogenins: PPD, 20(R)-25-OH-PPD, 25-OCH3-PPD, 20(R)-25-OH-PPT

CYP1A1, CYP1A2, and CYP3A4 mRNA expression

CYP1A1 mRNA expression was significantly increased by 8 components (P < 0.05): Rg3, C-K, Rg1, 25-OH-PPD, 25-OCH3-PPD, 25-OH-PPT

Deglycosylated ginsenosides were more potent inducers of CYP1A1, CYP1A2, and CYP3A4 than glycosylated ginsenosides

[28]

PXR-CYP3A stable translation cell lines

13 ginsenosides including F2, Rg1, protooanaxatriol, panaxotriol, Rg2, pseudoginsenoside F11

Screening for PXR receptor activation, and influence of Rg1 on CYP3A4 mRNA expression

F2 and protooanaxatriol had moderate inductive effects on PXR

Panaxotriol, Rg2, pseudoginsenoside F11, Rg1, and Rb3 had inhibitory effects on PXR

Rf1, Rg3, Rh2, and protopanaxadiol did not alter PXR

Rg1 produced a concentration-dependent down-regulated CYP3A4 mRNA expression

[29]

Supersomesa (fluorometric CYP3A4 inhibition assay)

Ginseng (Eleutherococcus senticosus); Eleutheroside E (0.44%), and B (0.25%)

CYP3A4-mediated metabolism of 7-benzyloxy-4-trifluoromethyl-coumarin (BFC), midazolam, and docetaxel

Ginseng did not significantly alter CYP3A4-mediated metabolism of any of the tested substrates

[30]

CYP cytochrome P450, mRNA messenger RNA, PXR pregnane-X receptor

aSupersomes are recombinant complementary DNA-expressed CYP enzymes prepared from a baculovirus-infected insect cell system

In addition to the use of in vitro models, animal models have also been used to assess the influence of P. ginseng on CYP activity [13, 32, 33, 34, 35, 36, 37]. Nearly 30 years ago, Lee et al. noted that a single dose of an ethanol extract of P. ginseng (10–30 mg/kg) produced a modest increase in CYP activity in adult male rats [32]. Using the same dose of P. ginseng, Yu et al. assessed its impact on CYP2B1, CYP3A23, and CYP1A2 in adult male Sprague-Dawley rats [13]. P. ginseng given as a single 30 mg/kg oral dose or as a 100 mg/kg oral or intraperitoneal dose once daily for 4 days, did not alter hepatic CYP2B1, CYP3A23 (a human CYP3A ortholog), or CYP1A2 mRNA expression. In another study in rats, Shenmai injection (SMI) (Radix ginseng, which is the dried root of P. ginseng) produced statistically significant increases (P < 0.05) in the area under the concentration-versus-time curve (AUC) values for probe substrates midazolam and diclofenac, indicating that SMI inhibited CYP3A1/2 and CYP2C6, respectively [33]. However, it should be noted that the observed increases in AUC, with both single and multiple SMI doses, ranged between 15 and 34%. This degree of inhibition is considered weak and likely of limited clinical relevance if extrapolated to humans.

In another study, the influence of Panax notoginseng saponins (PNS), which, like P. ginseng contains various ginsenosides, was assessed in male Wistar rats for its influence on CYP1A2, CYP2C9, CYP2D6, and CYP3A4 activity using specific probe drugs [34]. CYP protein content was measured via western blotting. PNS appeared to induce CYP1A2 activity as indicated by reduced exposure and increased apparent oral clearance (Cl/F) of the CYP1A2 probe medication, caffeine. CYP1A2 protein level was also found to be significantly increased (P < 0.05) by PNS. Conversely, PNS did not alter the protein content or catalytic activity of the other CYP enzymes. However, the methodology and results of this study have recently been called into question, based on the fact that the CYP isoforms reported in this study are only expressed in humans and not wild-type rats [35]. These concerns notwithstanding, another team of investigators reported similar results in rats with regard to the influence of PNS of CYP1A2 [36]. PNS significantly induced CYP1A2 activity and mRNA expression as determined via probe drug (caffeine) administration and PCR. PNS was also found to increase the activity and mRNA expression of CYP2E1 [36]. In contrast to the studies by Liu et al. and Chen et al., Yin and colleagues found that notoginsenoside R1, a major component of Panax notoginseng, inhibited CYP1A2 in rats as determined by significant increases in the AUC and maximum concentration (C max) of the probe substrate caffeine (43 and 41%, respectively; P < 0.05 for both comparisons) [37]. In contrast, R1 did not produce any significant changes in CYP2D1, CYPC211, or CYP3A1/2 activity.

As with in vitro drug metabolism studies, a number of limitations are also present in studies that use animal models to assess the drug interaction potential of P. ginseng. These include the use of different brands of P. ginseng, which contain diverse and variable constituents, the use of different doses and treatment durations of P. ginseng, and metabolic differences between rats and humans: most notably the fact that CYP2C9, CYP2C19, CYP2D6, and CYP3A4 are human-specific forms of the CYP superfamily and are not expressed in wild-type animals [38, 39]. To this end, drug interaction studies with P. ginseng that are conducted in the preclinical setting (in vitro and in the rat model) are not likely to provide metabolic drug interaction data that can be easily extrapolated to humans.

2.1.2 Glucuronidation (UGT-Mediated Metabolism)

A small number of studies conducted in vitro have attempted to characterize components of P. ginseng on UGT activity [40, 41, 43]. Because UGTs are involved not only in drug metabolism, but also in the conjugation of endogenous substances such as bilirubin, thyroid hormones, bile acids, fat soluble vitamins, and steroid hormones, modulation of UGTs may produce metabolic disorders secondary to an excess or dearth of these compounds [40]. He et al. examined the inhibitory potential of ppt on the UGT isoforms UGT1A1 and UGT2B7 [41]. In addition, in vitro inhibition kinetic parameters (K i) were used to predict the magnitude of any observed drug–drug interactions in vivo. Results showed that ppt inhibited the UGT1A1-mediated and UGT2B7-mediated glucuronidation of 4-methylumbelliferone (4-MU) in a dose-dependent manner. These results suggest that medications metabolized by these UGT isoforms may experience elevated concentrations in the presence of ginseng-containing products. Noted substrates for UGT1A1 and UGT2B7 include bilirubin, levothyroxine, and estradiol; and diclofenac, naloxone, valproic acid, and zidovudine, respectively [42]. A separate study using human liver microsomes did not find significant inhibition of UGT1A4, UGT1A6, and UGT1A9 when incubated with P. ginseng ≥5% total ginsenosides [43].

In addition to in vitro studies assessing the influence of ginsenosides in combination on UGT activity, several studies have attempted to characterize the impact of specific ginsenosides on the activity of several UGT isoforms [17, 44]. Fang et al. examined the influence of the ginsenoside Rg3 on the activity of UGT1A7, 1A8, 2B7, and 2B15 using an in vitro probe reaction involving recombinant UGT isoform-catalyzed 4-MU glucuronidation [17]. Using a mathematical in vitro–in vivo extrapolation approach, the investigators predicted that Rg3 administration in vivo would result in AUC increases of 2.2 and 6.3% for coadministered substrates that are 100% metabolized by UGT1A7 and 1A8, respectively. Predicted AUC increases for UGT2B7 and UGT2B15 were greater at 26.3 and 25%, respectively. These predicted increases in UGT1A7 and 1A8 substrate concentrations are so small that they are unlikely to be clinically relevant. This is particularly true, considering that most substrate medications for UGT isoforms are not solely metabolized by a single enzyme (a UGT isoform or otherwise); hence, the predicted increases in UGT1A7 and UGT1A8 substrate concentrations are probably overestimations if extrapolated to humans. While the possibility of clinically relevant UGT2B7 and UGT2B15 inhibition by Rg3 is greater compared to UGT1A7 and UGT1A8, the predicted AUC increase in substrates of these UGT isoforms of approximately 25% still barely qualifies as “weak” inhibition (1.25–2.0 increase in AUC) [45]. Inhibitory interactions of this magnitude are unlikely to be clinically relevant except possibly for medications with narrow therapeutic ranges such as morphine (UGT2B7), carvedilol (UGT2B7), carbamazepine (UGT2B7), cyclosporine A (UGT2B7), and tamoxifen (UGT2B15) [42]. However, it must be reiterated that all of these medications undergo at least one additional route of metabolism, strongly suggesting that weak inhibition of UGT2B7 or UGT2B15 by Rg3 is probably not likely to produce clinically relevant drug interactions even with medications with narrow therapeutic ranges, especially when such medications are metabolized by multiple metabolic pathways.

Although of scientific interest, it is important to note that studies that attempt to isolate the impact of a specific ginsenoside (i.e., Rg3) or ginsenoside metabolite (i.e., ppt; ppd; Compound K and others) on the activity of a UGT or CYP isoform are not representative of a “Real life” situation in which an individual ingests P. ginseng. In such cases, individuals are exposed to numerous phytochemicals in ginseng and their intestinal and hepatic metabolites, some of which may produce additive, synergistic, or antagonistic effects on Phase 1 and/or Phase 2 metabolic activity. Assessing the capability of the ginsenosides or their metabolites to modulate drug metabolism in a vacuum so to speak, is not likely to produce a realistic picture of the drug interaction potential of P. ginseng supplementation in a clinical setting.

2.1.3 Drug Transport

In addition to studies assessing P. ginseng’s ability to modulate Phase 1 and Phase 2 drug metabolism, P. ginseng and/or its constituents has also been evaluated for its potential to influence a variety of drug transport proteins including P-gp, BCRP, OATP1B1, OATP1B3, and others (Table 2) [23, 25, 46, 47, 48, 49, 50].
Table 2

Effect of Panax ginseng on drug transport in vitro

Transport protein

In vitro model

P. ginseng component(s)

Outcome measurement

Main results

References

P-glycoprotein

Acute myelogenous leukemia sublines, which overexpress P-gp and MRP

Total saponins, PPD ginsenosides, PTG ginsenosides, Rb1, Rb2, Rc, Rg1, and Re

Ability to reverse resistance doxorubicin and daunorubicin-resistance in acute myelogenous leukemia sublines

PPD showed cytotoxicity in both sublines, indicative of P-gp inhibition

[46]

P-glycoprotein

Caco-2 cells

MDR1 (now called ABCB1) MDKC cells

Kaempferol

Cellular uptake of the P-gp substrate ritonavir in Caco-2 cells

Remarkable inhibition of ritonavir up take by P-gp (suggestive of P-gp inhibition by kaempferol)

[23]

P-glycoprotein

Baculovirus expression system

Ginseng extract and Rb1, Rb2, Rc, Rg1, Rd, Re, and Rf

Verapamil-stimulated, vanadate-sensitive ATPase activity

Ginseng extract and Rh1 stimulated ATPase activity, indicating P-gp inhibition

[25]

P-glycoprotein

Caco-2 cells

Rb1, Rb2, Rc, Rd, Re, F1, F2, Rg1, Rh1, Ro, ginsenoside C-K, PPD, and 20S protopanaxatriol (PPT)

Rhodamine123 and digoxin transport (both P-gp substrates)

Ginsenoside C-K, PPD, and PPT significantly enhanced rhodamine123 retention, and decreased digoxin efflux, indicative of potent P-gp inhibition

[47]

P-glycoprotein

MRP1

Caco-2 cells

Shenfu formula (P. ginseng and Aconitum carmichaeli)

Rhodamine 123 efflux by P-gp and MRP1; change in MDR1 mRNA; P-gp-mediated efflux of Aconitum carmichaeli

P. ginseng induced P-gp activity in Caco-2 cells via increased MDR1/P-gp expression; P. ginseng also facilitated the P-gp-mediated efflux

[48]

BCRP

Human breast carcinoma cells

Rg3, Rh2, PPD, Rg1, Rh1, PPT

Cytotoxicity of mitoxantrone to human breast carcinoma cells that overexpress BCRP

Rh2, PPD, PPT significantly increased mitoxantrone toxicity (suggestive of BCRP inhibition)

[49]

OATP1B3, OATP1B1,

Oatp1b2

HEK293 cells

Ginsenoside Rg1, Re, notoginsenoside Rg1

Uptake of E217βG by OATP1B3 and OATB1B1

Rb1, Rc, and Rd potently inhibited OATP1B3, and to a lesser extent, OATP1B1

Rg1, Re, and notoginsenoside R1 were weak inhibitors of MRP2, BCRP, and BSEP (IC50 values >100 μM)

[50]

P-gp P-glycoprotein, MRP multidrug resistance protein, PPD protopanaxadiol ginsenosides, PTG protopanaxatriol ginsenosides, MDR1 multidrug resistance protein 1, PPT 20S protopanaxatriol, MRP1 multidrug resistance protein 1, mRNA messenger RNA, BCRP breast cancer resistance protein, OATP human organic anion transporting polypeptide, Oatp rat organic anion transporting polypeptide, BSEP bile salt export pump, IC 50 50% inhibitory concentration, E 2 17βG estradiol 17β-d-glucuronide

The most-studied transport protein in combination with P. ginseng or its components is P-gp (Table 2) [23, 25, 46, 47, 48]. These investigations assessed the influence of a number of ginsenosides on P-gp activity or expression using Caco-2 cells, transfected MDKC cells, and acute myelogenous leukemia sublines. Three studies showed P-gp inhibition secondary to PPD, ginseng extract and Rh1, and C-K, PPD, and PPT, respectively [25, 46, 47]. Conversely, Qing et al. reported that P. ginseng induced P-gp expression and facilitated the P-gp-mediated efflux of Aconitum carmichaeli [48]. Similarly, a study in Sprague-Dawley male rats showed that long-term administration (14 days) of P. ginseng by gavage significantly reduced the fexofenadine AUC0–12 by approximately 50% (P < 0.005), suggesting that P. ginseng induced P-gp [51]. However, fexofenadine is transported by several other proteins (i.e., Oatp, Bcrp, and Octp) so it is difficult to identify the precise mechanism by which this interaction occurred [52]. Of note, long-term P. ginseng did reduce the oral bioavailability of fexofenadine by 16% (P < 0.05), which suggests that at least part of the observed interaction could be explained by induction of intestinal P-gp [51].

In addition to the efflux transporter P-gp, hepatic uptake transporters have also been assessed for their potential role in drug interactions involving P. ginseng. Jiang recently found that Rb1, Rc, and Rd potently inhibited OATP1B3 (IC50 values, 0.2–0.5 µM for inhibiting the transport of the OATP1B3 substrate, E217βG) and to a slightly lesser extent, inhibited OATP1B1 (IC50 values, 1.4–4.6 µM for inhibiting the transport of the OATP1B1 substrate, E217βG) [50]. Based on the poor systemic availability of many ginsenosides and their metabolites, it is unlikely that clinically significant interactions will occur secondary to OATP1B3 or OATP1B1 inhibition after oral P. ginseng dosing. However, as discussed by Jiang et al. in China there are herbal injections containing P. ginseng (i.e., ShenMai and ShenFu) that yield plasma ginsenoside concentrations that are quite high (i.e., C max of Rb1 = 26.3 ± 2.6 µM) after intravenous administration of a standard dose of a P. ginseng-containing product called XueShuanTong [50]. The authors also note that the (PPD-type) ginsenosides that inhibit OATP1B1 and OATP1B3 likely have additive inhibitory effects in vivo following intravenous administration. Substrates of OATP1B1 and OATP1B3 whose concentrations may be increased after intravenous administration of P. ginseng-containing injections include rosuvastatin, atorvastatin, pravastatin, enalapril, repaglinide, valsartan, and olmesartan [53]. Elevated plasma concentrations of these agents could result in toxicities normally associated with these drugs.

To date, relatively few preclinical studies have characterized the influence of P. ginseng and its components on drug transporters, and of the studies that have been conducted, data are conflicting. Perhaps the most compelling in vitro data are those that suggest that intravenous P. ginseng formulations may inhibit the hepatic uptake transporters OATP1B1 and OATP1B3 potentially resulting in clinically relevant interactions. Carefully conducted studies in humans are necessary to further assess this putative interaction.

2.1.4 Additional Preclinical Pharmacokinetic Studies

Due to the potential of P. ginseng to produce cardiac effects, Ryu et al. conducted two separate studies in Sprague-Dawley rats that examined the influence of red ginseng on the pharmacokinetics of losartan and amlodipine [54, 55]. Red ginseng produced a negligible increase in the AUC of intravenous losartan and no change in the losartan active metabolite, E-3174 [54]. Similarly, after single intravenous or oral doses, amlodipine AUC values were not significantly changed after 2 weeks of oral red ginseng administration [55].

Due to case reports of an interaction between warfarin and ginseng, Zhu et al. examined the influence of ginseng decoction on warfarin pharmacokinetics and pharmacodynamics in rats [56]. Warfarin and ginseng were coadministered for 5 days to male Sprague-Dawley rats. None of warfarin’s pharmacokinetic parameter values (AUC, Cl/F, T ½, and C max) were altered by concurrent ginseng administration [56]. Similarly, there were no significant changes in the prothrombin time vs. time curve, indicating that ginseng did not alter the anticoagulant effect of warfarin.

3 Clinical Pharmacokinetic Interaction Studies with P. ginseng

3.1 CYP Probe Investigations

Several investigations have assessed the pharmacokinetic interaction potential of P. ginseng in humans (Table 3) [57, 58, 59, 60, 61, 62, 63]. Gurley et al. used an orally administered probe-drug cocktail to examine the influence of P. ginseng on the metabolic activity of CYP3A4, CYP1A2, CYP2E1, and CYP2D6 using 1-hydroxymidazolam/midazolam serum ratios (1-h post 8 mg midazolam dose), paraxanthine/caffeine serum rations (6 h post 100 mg caffeine dose), 6-hydroxychlorzoxazone/chlorzoxazone serum rations (2-h post 500 mg chlorzoxazone dose) and debrisoquine urinary recovery ratios (8 h post 5 mg debrisoquine dose), respectively [57]. A probe drug cocktail with these medications was administered to 12 elderly (ages 60–76) healthy volunteers before, and after 28 days of supplementation with P. ginseng, 500 mg three times daily, standardized to 5% ginsenosides. P. ginseng administration produced a statistically significant decrease (P = 0.003) in debrisoquine urinary recovery ratios of 7%; however, the magnitude of this effect was not deemed to be clinically relevant. Conversely, no modulatory effects were identified for P. ginseng on CYP3A, CYP1A2, or CYP2E1.
Table 3

Pharmacokinetic drug interaction studies of Panax ginseng in humans

P. ginseng formulation

Coadministered (test) drug(s)

Sample size and study population

Study design

Primary results and conclusion

Reference

P. ginseng standardized to 5% ginsenosides

Midazolam

Caffeine

Chlorzoxazone

Debrisoquine

12 healthy volunteers; ages 60–76 years

P. ginseng 500 mg 3 times daily for 28 days with phenotyping at baseline and post-ginseng administration

No effect on midazolam, caffeine, or chlorzoxazone PK, indicating no change in CYP3A, CYP1A2, or CYP2E1 activity

Decrease in debrisoquine urinary recovery ratios of 7% (P = 0.003) indicating weak inhibition of CYP2D6 that is unlikely to be clinically relevant

[59]

P. ginseng standardized to 4% ginsenosides

Cortisol

20

Cortisol phenotyping (urinary 6β-hydroxycortisol:cortisol ratio) at baseline and after P. ginseng 100 mg twice daily for 14 days

No change in urinary 6β-hydroxycortisol:cortisol ratio

[60]

P. ginseng standardized to 5% ginsenosides

Midazolam

Fexofenadine

12 healthy subjects

P. ginseng 500 mg twice daily for 28 days with phenotyping at baseline and post-ginseng administration

No effect on fexofenadine PK indicating no change in P-gp activity

Significant reductions in geometric mean ratios (post-ginseng/pre-ginseng) for midazolam AUC0–∞ (0.66 [0.55–0.78]), C max (0.71 [0.53–0.90]), and T ½ (0.74 [0.56–0.93]), indicating CYP3A induction by P. ginseng

65

P. ginseng standardized to 5% ginsenosides

LPV-r

12 healthy subjects

Subjects received LPV-r (400/100 mg) for 29.5 days. On day 16, subjects received P. ginseng 500 mg twice daily for 14 days in combination with LPV/r. LPV and ritonavir PK was assessed on day 15 (no concurrent P. ginseng) and after 2 weeks of P. ginseng coadministration (day 30)

No significant changes in any PK parameter values for LPV-r were noted, indicating that CYP3A inhibition by ritonavir likely preventing any potential CYP3A induction by P. ginseng

[62]

Fermented red ginseng (one pouch = 70 mL, >3% dried ginseng)

Caffeine

Losartan

Dextromethorphan

Omeprazole

Midazolam

Fexofenadine

15 healthy subjects

Subjects received fermented red ginseng one pouch once daily for 14 days with phenotyping at baseline and post-ginseng administration

No effect on caffeine, losartan, dextromethorphan, omeprazole, or midazolam PK, indicating no change in CYP1A2, CYP2C9, CYP2D6, CYP2C19 or CYP3A activity

Significant increases in geometric mean ratio (post-ginseng/pre-ginseng) for fexofenadine AUC0–∞ (1.32 [1.11–1.57]), indicating weak (1.25 to <twofold increase) P-gp inhibition

67

Korean ginseng containing 0.5 mg P. ginseng root and 8.93 mg ginsenosides as ginsenoside Rg1)

Warfarin

12 healthy subjects

A single 25 mg warfarin dose was given before and after 7 days of Korean ginseng administration; S-warfarin and R-warfarin PK (and INR) were assessed at both points

No changes were observed in S-warfarin and R-warfarin PK or INR after 7 days of Korean ginseng administration

[64]

Asian ginseng (commission E recommended daily doses)

Warfarin

24 healthy subjects

A population PK-PD modeling approach was used to assess S-warfarin and anticoagulant response (prothrombin complex activity) before and after “pre-treatment” with Asian ginseng (P. ginseng)

The ratio of S-warfarin apparent oral clearance compared to control was 1.14 ± 0.04 after Asian ginseng administration; this increase in clearance was statistically, but unlikely clinically significant

[65]

PK pharmacokinetic(s), CYP cytochrome P450, P-gp P-glycoprotein, AUC 0–∞ area under the plasma concentration-versus-time curve from time zero to infinity, C max maximum concentration, T ½ terminal half-life, LPV-r lopinavir-ritonavir, INR international normalized ratio, PK/PD pharmacokinetic/pharmacodynamic

We also determined the influence of P ginseng (500 mg twice daily for 28 days) on CYP3A activity in 12 healthy volunteers, 8 males, 18–50 years) using midazolam as a probe [59]. The GMR (90% CI), post-ginseng/pre-ginseng, for midazolam AUC from zero to infinity (AUC0–∞) was significantly reduced at 0.66 (0.55–0.78). Geometric mean ratios for C max and T ½ were also reduced at 0.74 (0.56–0.93), and 0.71 (0.53–0.90), respectively. These results suggest that P. ginseng has the ability to induce CYP3A. This degree of reduced exposure may be clinically inconsequential for most medications; however, for CYP3A4 substrates with narrow therapeutic indices such as cyclosporine, tacrolimus, irinotecan, sildenafil, and sirolimus, reductions of this magnitude may place patients at risk for therapeutic failure.

A separate group of investigators examined the potential of P. ginseng to induce 3A4 by measuring the urinary metabolic ratio of cortisol and 6-hydroxycortisol in 20 healthy volunteers given ginseng extract (4% ginsenosides, 100 mg twice daily) for 24 days [58]. Results from this study indicated that P. ginseng did not induce CYP3A4, although the capability of urinary cortisol metabolic ratios to accurately predict CYP3A4 activity is uncertain [64]. A third study, conducted in healthy volunteers found a modest increase (29%; P value not reported) in maximum nifedipine C max in healthy volunteers following 18 days of ginseng administration at 200 mg per day [65].

Recently, a study using a probe cocktail approach was used to assess the impact of fermented red ginseng on the activity of CYP1A2, CYP2C9, CYP2C19, and CYP3A [61]. Healthy volunteers (20–55 years) received probe cocktails before and after 2 weeks of fermented red ginseng administration given as one pouch (70 mL) daily. The cocktail drugs and their respective CYP enzymes were caffeine 200 mg (CYP1A2), losartan 50 mg (CYP2C9), omeprazole 20 mg (CYP2C19), dextromethorphan 30 mg (CYP2D6), and midazolam 7.5 mg (CYP3A). Geometric mean ratios (GMR)s were not significantly different pre- and post-fermented red ginseng administration (90% confidence interval [CI] of GMRs included the value of 1.0) except for midazolam, which showed mild CYP3A inhibition, unlikely to be clinically relevant (GMR: 0.816 [90% CI: 0.673–0.990]).

In an effort to expand beyond interaction studies using P. ginseng and probe cocktails, we assessed the influence of P. ginseng on the pharmacokinetic profile of the HIV protease inhibitor and CYP3A4 substrate lopinavir, when administered in combination with the CYP3A4 inhibitor, ritonavir as the combination product, Kaletra® to 12 healthy volunteers (8 males, 18–50 years) [60]. The same P. ginseng formulation and dosage regimen was employed as the P. ginseng/midazolam interaction study described above [59]. The GMR (90% CI), post-ginseng/pre-ginseng, for LPV AUC0–∞ was 0.95 (0.85–1.05). Geometric mean ratios for C max and T ½ were 0.94 (0.84–1.04), and 1.19 (0.92–1.46), respectively. None of these changes were statistically significant (P > 0.05 for all comparisons). The lack of an observed effect of P. ginseng on lopinavir pharmacokinetics is likely the result of concurrent CYP3A4 inhibition by ritonavir, which obviated the induction effects of P. ginseng on lopinavir metabolism through CYP3A4. These data suggest that the presence of a CYP3A4 inhibitor, such as RTV, can nullify the induction properties of P. ginseng. It is unclear whether this observation can be extrapolated to all situations where an antiretroviral medication (such as an HIV protease inhibitor or elvitegravir) is coadministered with a CYP3A4 inhibitor (used as a “Boosting” agent) such as ritonavir or cobicistat; however, it stands to reason that this is most likely the case.

3.2 Drug Transport-Mediated Interactions Involving P. ginseng

We recently assessed the influence of P. ginseng 500 mg twice daily for 28 days on the pharmacokinetics of a single dose of the P-gp substrate, fexofenadine 120 mg in 12 healthy volunteers (8 males) [59]. The P. ginseng product used in this investigation was standardized to 5% ginsenosides. The GMR (90% CI), post-ginseng/pre-ginseng, for fexofenadine AUC0–∞ was 0.91 (0.69–1.14). The primary conclusion from these data was that P. ginseng did not alter the P-gp-mediated transport of fexofenadine. However, as noted earlier, use of fexofenadine as a P-gp probe is limited by the fact that it is a substrate for transporters other than P-gp, such as the OATPs [66, 67, 68]. Nonetheless, what can be concluded from this study is that P. ginseng did not appear to modulate any of the transport proteins involved in fexofenadine disposition (unless multiple transporters were equally altered by P. ginseng in opposite directions, which seems unlikely). Additional studies in humans using another P-gp probe, such as digoxin, would help to solidify the conclusion that P. ginseng does not modulate P-gp in humans. Until such information is available, current data in humans suggest that the possibility of drug interactions involving P-gp and P. ginseng are low.

3.3 P. ginseng Interactions with Warfarin

A number of pharmacokinetic studies and case reports have focused on the putative interaction between P. ginseng and warfarin [62, 63, 69, 70]. A highly cited case report by Janetzky and Morreale reported a potential interaction between warfarin and Ginsana® (P. ginseng) [69]. The patient had a mechanical heart valve and was stabilized on warfarin therapy for 5 years. After 2 weeks of self-administration of Ginsana, the patient’s international normalized ratio (INR) decreased from the target range (3.0–4.0) to 1.5. After cessation of the P. ginseng product, the patient’s INR returned to its therapeutic range under warfarin anticoagulation. In a separate case report, a patient stabilized on warfarin for 3 months experienced a thrombosis on a mechanical bileaflet aortic valve after taking a commercial ginseng product. The thrombosis was attributed to inadequate anticoagulation (INR: 1.4) secondary to a drug interaction between ginseng and warfarin [72]. The publication of these two case reports led to the aforementioned study in rats that failed to show a pharmacokinetic or pharmacodynamic interaction between warfarin and a ginseng decoction [56]. In addition to this animal study, pharmacokinetic and pharmacodynamic studies in humans have further explored the putative interaction between P. ginseng and warfarin [62, 63, 71].

The influence of Korean ginseng (0.5 g P. ginseng root and 8.93 mg ginsenosides as ginsenoside Rg1) was assessed on the pharmacokinetics and pharmacodynamics of S- and R-warfarin in 12 healthy male subjects [62]. Subjects received a single dose of warfarin 25 mg before and after Korean ginseng (Golden Glow®), 2 capsules 3 times daily for 7 days. S- and R-warfarin AUC0–∞ values were non-significantly reduced by 11.6 and 10.6%, respectively, after Korean ginseng administration (P > 0.05). Similarly, INR values were not significantly changed after Korean ginseng administration. In an attempt to further characterize the influence of P. ginseng on warfarin pharmacokinetics, the same researchers conducted a study using a population pharmacokinetic-pharmacodynamic modeling approach [63]. In this investigation, Asian ginseng (P. ginseng) accounted for only a 2% variability in the apparent oral clearance (CL/F) of S-warfarin. Asian ginseng did, however, account for a 14% increase in CL/F of S-warfarin (P < 0.05). Although this difference was statistically significant, there was no change in prothrombin time, and thus the change in S-warfarin was deemed clinically inconsequential (<20%). A limitation of this study is that P. ginseng was only administered for 7 days, which may not have been sufficient for induction of enzymatic and/or transport proteins involved in warfarin disposition. However, given that no other studies reported significant changes in warfarin pharmacokinetics or pharmacodynamics with P. ginseng given for longer periods (up to 6 weeks), this observation may not be of particular relevance.

As part of a double-blind, placebo-controlled crossover study with a 3-week washout period, Lee et al. examined the influence of 6 weeks of Korean red ginseng extract (1 g) in combination with warfarin in 25 patients with cardiac valve replacement [71]. The primary outcome of this study was change in INR at 3 weeks and 6 weeks in the ginseng versus placebo arms. The results indicated no significant change in INR for any of the comparisons. In another study that focused on warfarin pharmacodynamics in the presence of P. ginseng, Lee characterized the effect of P. ginseng in 25 patients newly diagnosed with ischemic stroke [72]. The study was conducted in parallel, with 12 subjects receiving P. ginseng (aqueous extracts 0.5 g) 3 times daily for 2 weeks in combination with warfarin, and a second group of 13 subjects receiving warfarin alone. No significant differences were observed in peak INR or INR AUC between the study groups.

In summary, a small number of case reports have suggested an interaction between P. ginseng and warfarin [69, 70]. However, studies in animals, healthy volunteers, and patients undergoing warfarin anticoagulation have failed to observe an interaction. As such, it appears that any interaction between P. ginseng and warfarin is rare. Also, the purported mechanism of such an interaction is not readily apparent, as P. ginseng does not appear to modulate CYP2C9, which is the primary isoform involved in the metabolism of S-warfarin—the more potent isomer of the racemic warfarin mixture [61]. Hence, in those cases where P. ginseng appears to reduce the anticoagulant activity of warfarin, the mechanism of such an interaction is unclear. At least one group of researchers has suggested that the vitamin K content of ginseng products be assessed; insinuating that perhaps the presence of vitamin K in select ginseng products could be responsible for reducing the anticoagulant activity of warfarin [71]. Close monitoring of INR is suggested for those patients on warfarin who wish to take concurrent P. ginseng products.

4 Conclusions

Panax ginseng preparations contain numerous components that are inconsistent between brands, dosage formulations, and strengths. Because each of these P. ginseng components (primarily ginsenosides) is capable of exerting distinct pharmacological actions, it is difficult to consistently predict the drug interaction potential of such an herbal product. This is exemplified by the various in vitro effects of ginseng products on metabolic and transport proteins (Tables 1, 2). Nonetheless, drug interaction studies in humans have generally yielded negative results or results that suggest a relatively minor interaction. Perhaps the most clinically relevant effect of P. ginseng is its induction effects on CYP3A4 where it produced a 34% decrease in the AUC of the CYP3A4 substrate midazolam in healthy volunteers [59]. This degree of reduced exposure may not be important for many medications, but for medications with narrow therapeutic indices, reductions of this magnitude may place patients at risk for therapeutic failure. Although P. ginseng has been studied frequently in combination with warfarin, the possibility of a clinically relevant interaction is likely minimal.

Clinicians caring for patients who wish to take supplemental P. ginseng should record the name of the ginseng product, including the manufacturer and lot number in the patient’s medical record; start and stop dates should also be recorded. If an unexpected toxicity arises or a previously tolerated drug is now producing side effects, a potential interaction with P. ginseng should be considered and evaluated.

Notes

Compliance with Ethical Standards

Funding

No external source of funding or writing assistance was received in the production of this manuscript.

Conflict of Interest

Meenakshi Ramanathan and Scott Penzak have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Department of PharmacotherapyUniversity of North Texas System College of PharmacyFort WorthUSA

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