Enhancement of Oral Bioavailability of 20(<i>S</i>)-Ginsenoside Rh2 through Improved Understanding of Its Absorption and Efflux Mechanisms

Yang, Zhen; Gao, Song; Wang, Jingrong; Yin, Tongming; Teng, Yang; Wu, Baojian; You, Ming; Jiang, Zhi‐Hong; Hu, Ming

doi:10.1124/dmd.111.040006

Cited by 77 publications

(59 citation statements)

References 31 publications

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“…The protocol for determining C-K's intracellular amounts in the cells was the same as that described previously (Yang et al, 2011). The protein concentration of the cell lysate was measured using the BCA protein assay kit.…”

Section: Methodsmentioning

confidence: 99%

“…The transcellular transport study was performed as described previously, and the permeabilities from the apical to basolateral side (P a-b ) and the basolateral to apical side (P b-a ) were calculated based on the method we described previously (Yang et al, 2011). In brief, 2.5 ml of C-K solution was loaded onto one side of the cell monolayer, and 2.5 ml of blank HBSS was loaded onto the other side.…”

Section: Methodsmentioning

confidence: 99%

“…However, there is evidence that C-K could reverse multidrug resistance in tumor cells (Hasegawa et al, 1994). In addition, our previous study on Rh2s, a ginsenoside analog with glucose attached to the C3 position and the same molecular weight and log P value as C-K, indicates that Rh2 underwent strong P-glycoprotein (P-gp)-mediated efflux both in vitro and in vivo (Yang et al, 2011). P-gp is one of the most prevalent efflux transporters (Aller et al, 2009;Chen et al, 2011) and plays an important role in limiting the intestinal absorption of many compounds that are its substrates (Kusuhara and Sugiyama, 2002;del Amo et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

“…P-gp is one of the most prevalent efflux transporters (Aller et al, 2009;Chen et al, 2011) and plays an important role in limiting the intestinal absorption of many compounds that are its substrates (Kusuhara and Sugiyama, 2002;del Amo et al, 2009). Inhibition of P-gp leads to the improvement of oral bioavailability of several anticancer drugs (Meerum Terwogt et al, 1998;Kemper et al, 2004;van Waterschoot et al, 2009), including ginsenoside Rh2 (Yang et al, 2011). A better understanding of P-gp involvement in the transport of ginsenosides and a more quantitative measurement with regard to if and how P-gp affects their bioavailabilities and potential drug-drug interactions are important for the development of ginsenosides as chemopreventive agents, because these studies are recommended by the Food and Drug Administration in recently published Drug-Drug Interaction Guidance (February, 2012, www.fda.gov).…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of P-Glycoprotein Leads to Improved Oral Bioavailability of Compound K, an Anticancer Metabolite of Red Ginseng Extract Produced by Gut Microflora

Yang

Wang²,

Niu³

et al. 2012

Drug Metab Dispos

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ABSTRACT:Ginsenosides are hydrolyzed extensively by gut microflora after oral administration, and their metabolites are pharmacologically active against lung cancer cells. In this study, we measured the metabolism of various ginsenosides by gut microflora and determined the mechanisms responsible for the observed pharmacokinetic behaviors of its active metabolite, Compound K (C-K). The results showed that biotransformation into C-K is the major metabolic pathway of ginsenosides after the oral administration of the red ginseng extract containing both protopanaxadiol and protopanaxatriol ginsenosides. Pharmacokinetic studies in normal mice showed that C-K exhibited low oral bioavailability. To define the mechanisms responsible for this low bioavailability, two P-glycoprotein (P-gp) inhibitors, verapamil and cyclosporine A, were used, and their presence substantially decreased C-K's efflux ratio in Caco-2 cells (from 26.6 to <3) and significantly increased intracellular concentrations (by as much as 40-fold). Similar results were obtained when transcellular transport of C-K was determined using multidrug resistance 1 (MDR1)-overexpressing Madin-Darby canine kidney II cells. In MDR1a/b(؊/؊) FVB mice, its plasma C max and AUC 0-24h were increased substantially by 4.0-and 11.7-fold, respectively. These increases appear to be due to slower elimination and faster absorption of C-K in MDR1a/b(؊/؊) mice. In conclusion, C-K is the major active metabolite of ginsenosides after microflora hydrolysis of primary ginsenosides in the red ginseng extract, and inhibition/deficiency of P-gp can lead to large enhancement of its absorption and bioavailability.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Inhibition of P-Glycoprotein Leads to Improved Oral Bioavailability of Compound K, an Anticancer Metabolite of Red Ginseng Extract Produced by Gut Microflora

Yang

Wang²,

Niu³

et al. 2012

Drug Metab Dispos

Self Cite

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“…a potent noncompetitive inhibitor of P-gp [13][14][15] , indicating that there may be a potential pharmacokinetic interaction between Rh2 and the P-gp substrate of PIs. Ritonavir (RTV), one of the most commonly used HIV PIs, has been demonstrated to be a substrate and inhibitor of P-gp both in vitro and in vivo [9,10,16,17] .…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic interactions between 20(S)-ginsenoside Rh2 and the HIV protease inhibitor ritonavir in vitro and in vivo

et al. 2013

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Aim: 20(S)-Ginsenoside Rh2 (Rh2) has shown potent inhibition on P-glycoprotein (P-gp), while most HIV protease inhibitors are both substrates and inhibitors of P-gp and CYP3A4. The aim of this study was to investigate the potential pharmacokinetic interactions between Rh2 and the HIV protease inhibitor ritonavir. Methods: The effects of Rh2 on the cellular accumulation and transepithelial transport of ritonavir were studied in Caco-2 and MDCK-MDR1 cells. Male rats were administered Rh2 (25 or 60 mg/kg, po) or Rh2 (5 mg/kg, iv), followed by ritonavir (25 mg/kg, po). The P-gp inhibitors verapamil (20 mg/kg, po) or GF120918 (5 mg/kg, po) were used as positive controls. The concentrations of ritonavir in plasma, bile, urine, feces and tissue homogenates were analyzed using LC-MS. Results: Rh2 (10 μmol/L) significantly increased the accumulation and inhibited the efflux of ritonavir in Caco-2 and MDCK-MDR1 cells, as verapamil did. But Rh2 did not significantly alter ritonavir accumulation or transport in MDCK-WT cells. Intravenous Rh2 significantly increased the plasma exposure of ritonavir while reducing its excretion in the bile, and oral verapamil or GF120918 also increased plasma exposure of ritonavir but without changing its excretion in the bile. Interestingly, oral Rh2 at both doses did not significantly change the plasma profile of ritonavir. Moreover, oral Rh2 (25 mg/kg) significantly elevated the ritonavir concentration in the hepatic portal vein, and markedly increased its urinary excretion and tissue distribution, which might counteract the elevated absorption of ritonavir. Conclusion: Rh2 inhibits the efflux of ritonavir through P-gp in vitro. The effects of Rh2 on ritonavir exposure in vivo depend on the administration route of Rh2: intravenous, but not oral, administration of Rh2 significantly increased the plasma exposure of ritonavir.

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Identification and quantitative investigation of the effects of intestinal microflora on the metabolism and pharmacokinetics of notoginsenoside Fc assayed by liquid chromatography with electrospray ionization tandem mass spectrometry

Lü

et al. 2019

J of Separation Science

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Notoginsenoside Fc, which is a protopanaxdiol‐type saponin isolated from the leaves of Panax notoginseng, exhibits an exceptional antiplatelet aggregatory effect. To study the modulating effect of gastrointestinal contents on the metabolic profile and pharmacokinetics, pseudo germ‐free rats were used to study the influence of the bacterial community structure on the metabolic profile. Glycosidase activities were measured using the spectrophotometric method. Biotransformations of notoginsenoside Fc in normal and pseudo germ‐free rat intestinal microflora were systematically investigated using ultra high performance liquid chromatography with tandem quadrupole/time‐of‐flight mass spectrometry. Moreover, a liquid chromatography with tandem mass spectrometry method was established for simultaneous determination of the notoginsenoside Fc prototype and its degradation products. Through an in vivo pharmacokinetic study, the pharmacokinetic characteristics were compared between normal rats and pseudo germ‐free rats. During the in vitro biotransformation, seven deglycosylated products were detected and identified after incubation in the intestinal bacteria of normal rats. In pseudo germ‐free rats, glycosidase activities were significantly decreased, and no obvious degradation occurred. In an in vivo study, the systemic exposure was significantly increased 40%, as evidenced by the area under the blood concentration–time curve from time zero to infinity value and half‐life value, which were prolonged more in the pseudo germ‐free group than in normal rats. The results demonstrate that patients who use intestinal bacteria‐metabolized herbs, such as panax notoginseng, should understand the profile of intestinal bacteria to ensure therapeutic efficacy.

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Enhancement of Oral Bioavailability of 20(S)-Ginsenoside Rh2 through Improved Understanding of Its Absorption and Efflux Mechanisms

Cited by 77 publications

References 31 publications

Inhibition of P-Glycoprotein Leads to Improved Oral Bioavailability of Compound K, an Anticancer Metabolite of Red Ginseng Extract Produced by Gut Microflora

Inhibition of P-Glycoprotein Leads to Improved Oral Bioavailability of Compound K, an Anticancer Metabolite of Red Ginseng Extract Produced by Gut Microflora

Pharmacokinetic interactions between 20(S)-ginsenoside Rh2 and the HIV protease inhibitor ritonavir in vitro and in vivo

Identification and quantitative investigation of the effects of intestinal microflora on the metabolism and pharmacokinetics of notoginsenoside Fc assayed by liquid chromatography with electrospray ionization tandem mass spectrometry

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