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Ginseng: Pharmacological Action And Phytochemistry Prospective
By Sowon Lee Sowon Lee Scilit Preprints.org Google Scholar View Publications 1, Mihwa Kwon Mihwa Kwon Scilit Preprints.org Google Scholar View Publications 1, Min-Koo Choi Min-Koo Choi Scilit Preprints.org Google Scholar View Publications 2, * and Im-Sook Song Im-Sook Song Scilit Preprints.org Google Scholar View Publications 1, *
We aimed to investigate the effects of red ginseng extract (RGE) on the expression of efflux transporters and to study the pharmacokinetics of representative substrate. For this, rats received single or repeated administration of RGE (1.5 g/kg/day) for 1 and 2 weeks via oral gavage. mRNA and protein levels of multidrug resistance-associated protein2 (Mrp2), bile salt export pump (Bsep), and P-glycoprotein (P-gp) in the rat liver were measured via real-time polymerase chain reaction and Western blot analysis. Ginsenosides concentrations from the rat plasma were also monitored using a liquid chromatography–tandem mass spectrometry (LC–MS/MS) system. Plasma concentrations of ginsenoside Rb1, Rb2, Rc, and Rd following repeated administration of RGE for 1 and 2 weeks were comparable but significantly higher than those after single administration of RGE. These dosing regimens did not induce significant biochemical abnormalities in the liver, kidneys, and lipid homeostasis. In the RGE repeated oral administration groups, the mRNA and protein levels of Mrp2 significantly decreased. Accordingly, we investigated the changes in the pharmacokinetics of methotrexate, a probe substrate for Mrp2, following intravenous administration of 3 mg/kg methotrexate to rats in the RGE 1-week repeated oral administration group, compared to that in the control group. Biliary excretion, but not urinary excretion, of methotrexate decreased in the RGE repeated administration group, compared to that in the control group. Consequently, the plasma concentrations of methotrexate slightly increased in the RGE repeated administration group. In conclusion, repeated administration of RGE for 1 week resulted in a decrease in Mrp2 expression without inducing significant liver or kidney damage. Pharmacokinetic herb–drug interaction between RGE and methotrexate might occur owing to the decrease in the mRNA and protein levels of Mrp2.
Ginseng (the roots and rhizomes of Panax ginseng C.A. Meyer) has been extensively used for more than 2000 years in East Asian countries [1, 2]. Red ginseng extract (RGE) is produced from 6-year-old fresh ginseng by steaming and drying, which leads to biochemical transformation of various ginsenosides [3]. Ginsenosides are considered the major active pharmacological constituents of ginseng. They have been shown to exhibit anti-neoplastic, anti-hypertensive, anti-diabetic, anti-inflammatory, anti-oxidant, anti-allergic, neuroprotective, and immunological effects [4, 5, 6, 7].
A Traditional Herb, Conveniently Packaged For Modern Lifestyles
Similar to other herbal medicines, ginseng products are frequently co-administered with prescribed Western medications. Accordingly, the potential for pharmacokinetic herb–drug interactions between ginseng and concomitantly administered drugs should be evaluated since they may result in toxicity or treatment failure [8]. Ginseng could alter the activity of cytochrome P450 (CYP) enzymes, the most important drug-metabolizing enzymes, which can affect the pharmacokinetics and efficacy of the co-administered drug. Administration of Panax ginseng for 4 weeks (1.5 g/day) resulted in slight inhibition of CYP2D6 activity, with no significant effects on CYP3A4, CYP1A2, and CYP2E1 in elderly subjects [9]. Two-week red ginseng treatment (10 mL of concentrated red ginseng extracts, dried ginseng 64%) weakly inhibited CYP2C9, CYP2D6, and CYP 3A4 activity, whereas it weakly induced CYP2D6 activity [10].
Besides inhibition or induction of CYP, the modulation of drug-transporters is also an important mechanism for herb–drug interaction [11, 12, 13]. Drug efflux transporters such as multidrug resistance-associated protein (Mrp), bile salt export pump (Bsep), and P-glycoprotein (P-gp) play important roles in the efflux of their substrates from the cells, thereby protecting the cells against these high concentrations of substrates, reducing intestinal absorption, or facilitating excretion of the substrate drugs [14]. Moreover, alteration of efflux transporter activity or expression could affect the tissue distribution, systemic disposition, and intestinal absorption of substrate drugs, thereby affecting their efficacy [15, 16]. Despite the growing understanding of the role of the transport system in the pharmacokinetics, drug response, and herb–drug interactions, the effects of red ginseng on the efflux transporters have not yet been fully elucidated. A clinical study reported that red ginseng exhibited limited effects on P-gp function following 2-weeks repeated administration of red ginseng product in humans [10].
Therefore, in the present study, we investigated the effects of single or repeated administration of RGE on efflux transporters and examined the potential changes in the pharmacokinetics of their substrate drugs. Of these, Mrp2 drew our interest because it is mainly involved in the pharmacokinetics and renal and biliary elimination of its substrate anions as well as amphipathic drugs that conjugate with glucuronide, sulfate, and glutathione (GSH) [17, 18]. For example, numerous anionic drugs such as methotrexate, SN38, cisplatin, vinblastine, and sulfinpyrazone are mainly eliminated from the body by Mrp2 [19, 20]. GSH facilitates the biliary excretion of amphipathic drugs via Mrp2 through the conjugation reaction and also acts as a regulator of redox homeostasis [21]. RGE has been shown to be effective in reducing oxidative stress through the Nrf2 signaling pathway [7, 22]. Nrf2 is a transcriptional factor that regulates Mrp2 expression [21], suggesting herb–drug interaction between red ginseng and Mrp2 substrates.
Recommended Souvenir From Korea, Jung Kwan Jang Red Ginseng
To measure ginsenoside concentrations, we developed analytical methods for quantification of 14 ginsenosides in diluted RGE and rat plasma samples with slight modification of a previously described method [23]. Among the 14 ginsenosides tested, eight ginsenosides (Rb1, Rb2, Rc, Rd, Rg3, Re, Rh1, and Rg1) could be quantitated in the diluted RGE. Peaks of the other six ginsenosides (Rh2, F2, compound K, protopanaxadiol, F1, and protopanaxatriol) were not detected since these ginsenosides are minor components and are biological metabolites of Rb1, Rb2, Re, or Rg1 that could be produced via metabolism in the gut microflora [24, 25]. The contents of ginsenosides could differ depending on the preparation procedure for RGE (steaming and drying conditions); however, the contents of major ginsenosides, such as Rb1, Rb2, Rc, and Rg3, were comparable to previously reported values [26, 27]. Ginsenoside contents in RGE used in this study are summarized in Table 1. Rb1 content was the highest (0.19%), and Rb2, Rc, and Rg3 contents were 0.09%, 0.1%, and 0.13%, respectively. Rd, Re, and Rh1 contents in RGE were in the range of 0.05–0.06%.
After RGE was orally administered to rats at single or multiple doses for 1 or 2 weeks, the plasma concentrations of ginsenosides were also monitored. Among the 14 ginsenosides monitored, only four ginsenosides (Rb1, Rb2, Rc, and Rd) could be quantitated (Table 2); however, the other 10 ginsenoside peaks were not detected in rat plasma. The representative multiple reaction monitoring (MRM) chromatograms for the four identified ginsenosides (Rb1, Rb2, Rc, and Rd) and five unidentified ginsenosides (Rg3, compound K, Re, Rh1, and Rg1) are shown in Figure 1. Plasma concentrations of ginsenosides Rb1, Rb2, and Rc following single oral administration (SA) of RGE were comparable to each other and greater than the plasma concentrations of Rd (Table 2). Repeated administration of RGE for 1 week (1WRA) resulted in an increase in plasma ginsenoside concentrations, compared to those in the SA group; however, they were not significantly different from those in the 2WRA group (Table 2). The results suggested that ginsenosides accumulated in the plasma because of their long elimination half-life (t
). For example, Rb1 is the most abundant and stable ginsenoside with a long elimination half-life of 58.47 h [28, 29]. The results also suggested that the steady-state plasma concentrations were reached within 1 week and maintained up to 2 weeks. Although the steady-state plasma concentrations of ginsenosides did not match with the order of ginsenoside contents in RGE (Table 1 and Table 2), the major components in RGE (Rb1, Rb2, and Rc) existed in the rat plasma at the highest concentration levels. Thus, it was suggested that Rb1, Rb2, and Rc could permeate the intestinal membrane despite their hydrophilicity and large molecular size based on their multiple glycoside conjugation [3, 30].
Ginseng: Health Benefits, Facts, And Research
Because of the potential of drug interactions between herbal medicines and efflux transporters, we measured the mRNA expression of efflux transporters, such as Bsep, P-gp, Mrp1, and Mrp2 in the liver
To measure ginsenoside concentrations, we developed analytical methods for quantification of 14 ginsenosides in diluted RGE and rat plasma samples with slight modification of a previously described method [23]. Among the 14 ginsenosides tested, eight ginsenosides (Rb1, Rb2, Rc, Rd, Rg3, Re, Rh1, and Rg1) could be quantitated in the diluted RGE. Peaks of the other six ginsenosides (Rh2, F2, compound K, protopanaxadiol, F1, and protopanaxatriol) were not detected since these ginsenosides are minor components and are biological metabolites of Rb1, Rb2, Re, or Rg1 that could be produced via metabolism in the gut microflora [24, 25]. The contents of ginsenosides could differ depending on the preparation procedure for RGE (steaming and drying conditions); however, the contents of major ginsenosides, such as Rb1, Rb2, Rc, and Rg3, were comparable to previously reported values [26, 27]. Ginsenoside contents in RGE used in this study are summarized in Table 1. Rb1 content was the highest (0.19%), and Rb2, Rc, and Rg3 contents were 0.09%, 0.1%, and 0.13%, respectively. Rd, Re, and Rh1 contents in RGE were in the range of 0.05–0.06%.
After RGE was orally administered to rats at single or multiple doses for 1 or 2 weeks, the plasma concentrations of ginsenosides were also monitored. Among the 14 ginsenosides monitored, only four ginsenosides (Rb1, Rb2, Rc, and Rd) could be quantitated (Table 2); however, the other 10 ginsenoside peaks were not detected in rat plasma. The representative multiple reaction monitoring (MRM) chromatograms for the four identified ginsenosides (Rb1, Rb2, Rc, and Rd) and five unidentified ginsenosides (Rg3, compound K, Re, Rh1, and Rg1) are shown in Figure 1. Plasma concentrations of ginsenosides Rb1, Rb2, and Rc following single oral administration (SA) of RGE were comparable to each other and greater than the plasma concentrations of Rd (Table 2). Repeated administration of RGE for 1 week (1WRA) resulted in an increase in plasma ginsenoside concentrations, compared to those in the SA group; however, they were not significantly different from those in the 2WRA group (Table 2). The results suggested that ginsenosides accumulated in the plasma because of their long elimination half-life (t
). For example, Rb1 is the most abundant and stable ginsenoside with a long elimination half-life of 58.47 h [28, 29]. The results also suggested that the steady-state plasma concentrations were reached within 1 week and maintained up to 2 weeks. Although the steady-state plasma concentrations of ginsenosides did not match with the order of ginsenoside contents in RGE (Table 1 and Table 2), the major components in RGE (Rb1, Rb2, and Rc) existed in the rat plasma at the highest concentration levels. Thus, it was suggested that Rb1, Rb2, and Rc could permeate the intestinal membrane despite their hydrophilicity and large molecular size based on their multiple glycoside conjugation [3, 30].
Ginseng: Health Benefits, Facts, And Research
Because of the potential of drug interactions between herbal medicines and efflux transporters, we measured the mRNA expression of efflux transporters, such as Bsep, P-gp, Mrp1, and Mrp2 in the liver
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