A Comprehensive In Vivo and In Vitro Assessment of the Drug Interaction Potential of Red Ginseng

Seong, Sook Jin; Kang, Woo Youl; Heo, Jae-Kyung; Jo, Jungjae; Choi, Won Gu; Liu, Kwang-Hyeon; Lee, Sangkyu; Choi, Min‐Koo; Han, Yong‐Hae; Lee, Hye Suk; Ohk, Boram; Lee, Hae Won; Song, Im‐Sook; Yoon, Young‐Ran

doi:10.1016/j.clinthera.2018.06.017

Cited by 28 publications

(23 citation statements)

References 31 publications

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“…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.…”

Section: Resultsmentioning

confidence: 99%

Effects of Red Ginseng Extract on the Pharmacokinetics and Elimination of Methotrexate via Mrp2 Regulation

et al. 2018

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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.

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Section: Resultsmentioning

confidence: 99%

Effects of Red Ginseng Extract on the Pharmacokinetics and Elimination of Methotrexate via Mrp2 Regulation

et al. 2018

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“…Nevertheless, in a previous study, single or repeated administration of red ginseng solution (>60% dried ginseng, three pouches/day once or for 2 weeks; equivalent to 85 mg total ginsenosides) did not have clinically significant inhibitory effects on the pharmacokinetics of pitavastatin, a selective substrate for OATP1B1 [14]. Furthermore, the clinically relevant pharmacokinetic ginseng or ginsenosides-valsartan interaction may not be caused based on the maximum concentrations of ginsenosides Rb1, Rb2, and Rc (6.2-12.7 nM) in human blood after repeated administration of red ginseng extract at high daily dose (3 g/day) [14,41]. In addition, 82-year-old male patient who took atorvastatin (80 mg), atenolol (50 mg), and aspirin (100 mg) reported drug-induced liver injury after concomitant ginseng intake.…”

Section: Discussionmentioning

confidence: 84%

“…For example, Rb1, the most abundant ginsenoside in RGE, was found to significantly inhibit CYP2C9 (IC 50 value of 2.4 µM), UDP-glucuronosyltransferase (UGT) 1A9 (IC 50 value of 21.3 µM), organic anion transporting polypeptide 1B1 (OATP1B1) (IC 50 value of 33.2 µM), and OATP1B3 (IC 50 value of 4.8 µM). Other CYP enzymes, UGT enzymes, and transporters were not affected [14]. Ginsenosides could be grouped as protopanaxadiol (PPD)-type ginsenosides and protopanaxatriol (PPT)-type ginsenosides based on their hydroxylation site and their structure effected differentially on the UGT1A9 metabolic activity.…”

Section: Introductionmentioning

confidence: 98%

“…In case of ginseng interactions, it was reported that no herb-drug interaction between single oral dose of Korean red ginseng extract (RGE) (0.5-2.0 g/kg) and the probe substrates for five cytochrome P450 (CYP) enzymes (i.e., CYP1A2, 2C9, 2C19, 2D6, 3A) in mouse [12]. Repeated oral administration of RGE (0.5 g/kg for 2 weeks in mice and 85 mg total ginsenosides for 2 weeks in human) did not alter the metabolic activity of above 5 CYP enzymes in the mouse liver [13] and could not induce clinically significant interaction in human [14,15]. In a study conducted by Malati et al [16], Korean ginseng (0.5 g capsule twice daily for 28 days) induced CYP3A activity and decrease plasma concentration of midazolam following oral administration of 8 mg midazolam.…”

Section: Introductionmentioning

confidence: 99%

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Herb–Drug Interaction of Red Ginseng Extract and Ginsenoside Rc with Valsartan in Rats

Jeon

Lee

et al. 2020

Molecules

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The purpose of this study was to investigate the herb–drug interactions involving red ginseng extract (RGE) or ginsenoside Rc with valsartan, a substrate for organic anion transporting polypeptide (OATP/Oatp) transporters. In HEK293 cells overexpressing drug transporters, the protopanaxadiol (PPD)-type ginsenosides- Rb1, Rb2, Rc, Rd, Rg3, compound K, and Rh2-inhibited human OATP1B1 and OATP1B3 transporters (IC50 values of 7.99–68.2 µM for OATP1B1; 1.36–30.8 µM for OATP1B3), suggesting the herb–drug interaction of PPD-type ginsenosides involving OATPs. Protopanaxatriol (PPT)-type ginsenosides-Re, Rg1, and Rh1-did not inhibit OATP1B1 and OATP1B3 and all ginsenosides tested didn’t inhibit OCT and OAT transporters. However, in rats, neither RGE nor Rc, a potent OATP inhibitor among PPD-type ginsenoside, changed in vivo pharmacokinetics of valsartan following repeated oral administration of RGE (1.5 g/kg/day for 7 days) or repeated intravenous injection of Rc (3 mg/kg for 5 days). The lack of in vivo herb–drug interaction between orally administered RGE and valsartan could be attributed to the low plasma concentration of PPD-type ginsenosides (5.3–48.4 nM). Even high plasma concentration of Rc did not effectively alter the pharmacokinetics of valsartan because of high protein binding and the limited liver distribution of Rc. The results, in conclusion, would provide useful information for herb–drug interaction between RGE or PPD-type ginsenosides and Oatp substrate drugs.

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“…Recent studies identified that CYP450 enzymes such as CYP2D6 and CYP3A4 were involved in the metabolism of Aconiti Lateralis Radix Praeparata-red ginseng herbal formulation. Compounds such as Ginsenosides Rc, Rf, and Rb2 induced CYP3A4 metabolic enzymes [15,16], while diester alkaloids of Aconiti Lateralis Radix Praeparata were identified as substrates of CYP3A4 metabolic enzymes [17]. However, several Ginsenoside components or in vitro studies have not been able to fully elucidate the effects of Aconiti Lateralis Radix Praeparata and its combination with red ginseng on CYP450 enzymes.…”

Section: Introductionmentioning

confidence: 99%

HPLC‐MS/MS Analysis of Aconiti Lateralis Radix Praeparata and Its Combination with Red Ginseng Effect on Rat CYP450 Activities Using the Cocktail Approach

Wang

Huang

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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Red ginseng is often combined with Aconiti Lateralis Radix Praeparata to reduce alkaloids-related toxicity of the latter. Such herb-pairing also results in better therapeutic effect in heart failure, as compared to the singular use of either herb. The purpose of this study was to investigate the effect of Aconiti Lateralis Radix Praeparata and its combination with red ginseng on the activities of CYP450 enzymes in rats. A sensitive and reliable HPLC-MS/MS method was established and validated for the simultaneous determination of eight probe drugs, phenacetin (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), dapsone (CYP3A4), 7-hydroxycoumarin (CYP2A6), bupropion (CYP2B6), and amodiaquine (CYP2C8), in rat plasma using diazepam as internal standard (IS). The chromatographic separation was performed on a Waters XBridge™ C18 column (2.1 mm × 100 mm, 3.5 μm) using a gradient elution with the mobile phase consisting of acetonitrile and water (containing 0.1% formic acid) at a flow rate of 0.3 mL/min. The method was successfully applied in evaluating the effect of Aconiti Lateralis Radix Praeparata and red ginseng on the activities of CYP450 enzymes. The pharmacokinetic results of the eight probe drugs suggested that Aconiti Lateralis Radix Praeparata may inhibit the activity of CYP2A6, CYP2C19, CYP2B6, CYP1A2, CYP3A4, and CYP2C9 enzymes in rats. Comparison between the two groups, Aconiti Lateralis Radix Praeparata combined with red ginseng and Aconiti Lateralis Radix Praeparata, indicated that red ginseng may inhibit the activity of CYP2D6 and CYP2B6 enzymes while inducing the activity of CYP1A2, CYP3A4, and CYP2C9 enzymes.

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A Comprehensive In Vivo and In Vitro Assessment of the Drug Interaction Potential of Red Ginseng

Cited by 28 publications

References 31 publications

Effects of Red Ginseng Extract on the Pharmacokinetics and Elimination of Methotrexate via Mrp2 Regulation

Effects of Red Ginseng Extract on the Pharmacokinetics and Elimination of Methotrexate via Mrp2 Regulation

Herb–Drug Interaction of Red Ginseng Extract and Ginsenoside Rc with Valsartan in Rats

HPLC‐MS/MS Analysis of Aconiti Lateralis Radix Praeparata and Its Combination with Red Ginseng Effect on Rat CYP450 Activities Using the Cocktail Approach

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