Tolerability and pharmacokinetics of ginsenosides Rb1, Rb2, Rc, Rd, and compound K after single or multiple administration of red ginseng extract in human beings

Choi, Min‐Koo; Jin, Sojeong; Jeon, Ji‐Hyeon; Kang, Woo Youl; Seong, Sook Jin; Yoon, Young‐Ran; Han, Yong‐Hae; Song, Im‐Sook

doi:10.1016/j.jgr.2018.10.006

Cited by 44 publications

(42 citation statements)

References 30 publications

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“…However, the maximum plasma concentrations (C max ) of Rb1, Rb2, and Rc in rats were in the range of 5.3-15.8 nM following repeated administration of RGE (1.5 g/kg/day) for 7 days ( Figure 6) and C max of Rb1, Rb2, and Rc in human were 6.2-12.7 nM following repeated administration of RGE (3 g/day) for 14 days [31]. The selected RGE dose in this study is in the range of effective dose without significant toxicity and showed similar plasma concentrations of Rb1, Rb2, and Rc (5.3-15.8 nM in rats and 6.2-12.7 nM in human subjects) [19,33]. In numerous animal studies, the RGE dose has ranged from 200 mg/kg to 2.0 g/kg (i.e., 3-15 mg/kg of total ginsenosides) [36,37].…”

Section: Discussionmentioning

confidence: 66%

“…At first, the inhibitory effect of ginsenoside Rb1, Rb2, and Rc on the OATP1B1 and OATP1B3-mediated valsartan uptake was measured. Ginsenoside Rb1, Rb2, and Rc was selected considering its stability and high plasma concentation in rat plasma (based on Figure 6) and in human plasma [31,33] as well as its low IC 50 value for OATP1B3 inhibition (2.28 µM, 1.76 µM, and 1.36 µM, respectively, Figure 3). As shown in Figure 7, Rb1, Rb2, and Rc inhibited both OATP1B1 and OATP1B3-mediated valsartan uptake in a concentration dependent manner and yielded IC 50 values of 8.8-24.1 µM for OATP1B1 and 1.9-5.1 µM for OATP1B3.…”

Section: Effect Of Ginsenoside Rc On the Pharmacokinetics Of Valsartamentioning

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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Section: Discussionmentioning

confidence: 66%

Section: Effect Of Ginsenoside Rc On the Pharmacokinetics Of Valsartamentioning

confidence: 99%

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

Jeon

Lee

et al. 2020

Molecules

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“…Moreover, the compound K plasma concentrations increased or maintained at 2-4 h after sharply decreasing in the 0-2 h period, and then showed a slow decrease over the 4-48 h time period in both rats and mice ( Figure 7A,B). This pattern could be attributable to the continuous reabsorption of compound K. The lipophilicity (LogP value 3.85 for compound K; 5.53 for PPD) and moderate permeability (0.5-2 × 10 −6 cm/s for compound K; 1.15 × 10 −6 cm/s for PPD) of compound K and PPD in Caco-2 cells also support the possibility of compound K and PPD reabsorption [3,7,14,15].…”

Section: Discussionmentioning

confidence: 75%

“…in their fecal microbiota showed 6-fold higher metabolic activity of compound K than the subject group that had a smaller proportion of Bacteroides sp. Choi et al [7] reported that inter-subject variability in gut metabolism of compound K rather than the intestinal absorption of compound K may contribute to the large inter-individual variations in plasma compound K concentrations. Therefore, differences in the gut metabolism of compound K could also explain the variability of the compound K pharmacokinetics between species.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and Intestinal Metabolism of Compound K in Rats and Mice

et al. 2020

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We aimed to investigate the plasma concentration, tissue distribution, and elimination of compound K following the intravenous administration of compound K (2 mg/kg) in rats and mice. The plasma concentrations of compound K in mice were much higher (about five-fold) than those in rats. In both rats and mice, compound K was mainly distributed in the liver and underwent biliary excretion. There was 28.4% fecal recovery of compound K in mice and 13.8% in rats, whereas its renal recovery was less than 0.1% in both rats and mice. Relative quantification of compound K and its metabolite protopanaxadiol (PPD) in rat bile and intestinal feces indicated that the metabolism from compound K into PPD occurred in the intestine but not in the plasma. Therefore, PPD detected in the plasma samples could have been absorbed from the intestine after metabolism in control rats, while PPD could not be detected in the plasma samples from bile duct cannulated rats. In conclusion, mice and rats shared common features such as exclusive liver distribution, major excretion pathway via biliary route, and intestinal metabolism to PPD. However, there were significant differences between rats and mice in the plasma concentrations of compound K and the fecal recovery of compound K and PPD.

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“…It was estimated that an in vivo interaction potential via the inhibition of UGT would likely occur if the ratio of inhibitor C max /K i were greater than 1 and would be possible if it were between 1.0 and 0.1 (Bjornsson et al, 2003;Bachmann and Lewis, 2005). Based on ginsenoside Rc's maximum concentrations (0.09 mM) in human blood after repeated administration of red ginseng extract (.60% dried ginseng, once daily for 2 weeks; content: 23.0 mg of ginsenoside Rb1, 11.4 mg of ginsenoside Rb2, 13.0 mg of ginsenoside Rc, 6.6 mg of ginsenoside Rd, 6.2 mg of ginsenoside Re, 2.8 mg of ginsenoside Rg1, 8.0 mg of ginsenoside Rh1, and 14.1 mg of ginsenoside Rg3) (Choi et al, 2019), the values of C max /K i after a repeated administration of red ginseng extract in human were more than 0.032 from the data of HLMs (K i 5 2.83 mM), indicating that ginsenoside Rc has no drug interaction potential in humans (Liu et al, 2016). The area under the plasma drug concentrationtime curve of the coadministered drug may not change based on the in vitro-in vivo extrapolation prediction equation of Fang et al (2013) when red ginseng extract is coadministered with drugs that are mainly eliminated via UGT1A9 in humans.…”

Section: Discussionmentioning

confidence: 99%

Ginsenoside Rc Is a New Selective UGT1A9 Inhibitor in Human Liver Microsomes and Recombinant Human UGT Isoforms

et al. 2019

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Ginseng is known to have inhibitory effects on UGT1A9 activity. However, little is known about the inhibitory effects of ginsenosides, the major active compounds in ginseng, on UGT1A9 activity. In vitro investigation of UGT1A9 inhibition by ginsenosides was carried out using human liver microsomes (HLMs). Among 10 ginsenosides, ginsenoside Rc was the strongest inhibitor of UGT1A9-mediated mycophenolic acid glucuronidase activity. Further inhibition kinetic studies using HLMs suggested that ginsenoside Rc competitively and noncompetitively inhibited UGT1A9-mediated propofol and mycophenolic acid glucuronidation activities, with K i values of 2.83 and 3.31 mM, respectively. Next, to investigate whether the inhibitory effect of ginsenoside Rc is specific to the UGT1A9 isoform, we studied the inhibitory potency of ginsenoside Rc on nine human uridine diphospho-glucuronosyltransferase (UGT) activities using recombinant human UGT isoforms. Ginsenoside Rc exhibited a 12.9-fold selectivity (which was similar to niflumic acid at 12.5-fold) for UGT1A9 inhibition. Ginsenoside Rc at 50 mM also inhibited none of the other UGT isoform-specific activities above 12.0%, except for UGT1A9 (>91.5%) in HLMs, indicating that ginsenoside Rc might be used as a selective UGT1A9 inhibitor in reaction phenotyping studies of new chemical entities. Considering lower plasma concentrations (0.01 mM) of ginsenoside Rc in healthy subjects and no induction potential on UGT isoforms, ginsenoside Rc does not cause pharmacokinetic drug interactions with other coadministered drugs metabolized by UGT1A9. SIGNIFICANCE STATEMENT Ginsenoside Rc selectively inhibited UGT1A9-mediated propofol and mycophenolic acid glucuronidation activities in human liver microsomes and recombinant uridine diphospho-glucuronosyltransferase (UGT) isoforms. It exhibited a 12.9-fold selectivity for UGT1A9 inhibition. Therefore, ginsenoside Rc might be used as a selective UGT1A9 inhibitor in reaction phenotyping studies of new chemical entities, such as niflumic acid.

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Tolerability and pharmacokinetics of ginsenosides Rb1, Rb2, Rc, Rd, and compound K after single or multiple administration of red ginseng extract in human beings

Cited by 44 publications

References 30 publications

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

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

Pharmacokinetics and Intestinal Metabolism of Compound K in Rats and Mice

Ginsenoside Rc Is a New Selective UGT1A9 Inhibitor in Human Liver Microsomes and Recombinant Human UGT Isoforms

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