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Research ArticleArticle

20(S)-Ginsenoside Rh2 Noncompetitively Inhibits P-Glycoprotein In Vitro and In Vivo: A Case for Herb-Drug Interactions

Jingwei Zhang, Fang Zhou, Xiaolan Wu, Yi Gu, Hua Ai, Yuanting Zheng, Yannan Li, Xiaoxuan Zhang, Gang Hao, Jianguo Sun, Ying Peng and Guangji Wang
Drug Metabolism and Disposition December 2010, 38 (12) 2179-2187; DOI: https://doi.org/10.1124/dmd.110.034793
Jingwei Zhang
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Fang Zhou
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Xiaolan Wu
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Yi Gu
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Hua Ai
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Yuanting Zheng
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Yannan Li
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Xiaoxuan Zhang
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Gang Hao
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Jianguo Sun
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Ying Peng
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Guangji Wang
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Abstract

P-glycoprotein (P-gp) is an ATP-dependent efflux transporter highly expressed in gastrointestinal tract and multidrug resistance tumor cells. Inhibition or induction of P-gp can cause drug-drug interactions and thus influence the effects of P-gp substrate drugs. Previous studies indicated that 20(S)-ginsenoside Rh2 [20(S)-Rh2] could synergistically enhance the anticancer effects of conventional chemotherapeutic agents at a nontoxic dose. The aim of present study was to investigate in vitro and in vivo whether 20(S)-Rh2 was a P-gp inhibitor and analyze the possible inhibitory mechanisms and potential herb-drug interactions. Results showed that in vitro, 20(S)-Rh2 significantly enhanced rhodamine 123 retention in cells and decreased the efflux ratio of digoxin, fexofenadine, and etoposide, which were comparable to the effects of the established P-gp inhibitor verapamil. However, the transport of 20(S)-Rh2 suggested that 20(S)-Rh2 was not a P-gp substrate. Furthermore, the inhibitory effect persisted for at least 3 h after removal of 20(S)-Rh2. Unlike P-gp substrates, 20(S)-Rh2 inhibited both basal and verapamil-stimulated P-gp ATPase activities. It also significantly decreased UIC2 binding fluorescence, a marker for conformational change of P-gp. In situ and in vivo experiments showed that 20(S)-Rh2 increased the area under the plasma concentration-time curve and maximum plasma concentration of digoxin, fexofenadine, and etoposide significantly without affecting terminal elimination half-time. Long-term treatment with 20(S)-Rh2 failed to affect intestinal P-gp expression in vitro and in vivo. In conclusion, 20(S)-Rh2 is a potent noncompetitive P-gp inhibitor, which indicates a potential herb-drug interaction when 20(S)-Rh2 is coadministered with P-gp substrate drugs. It could increase the absorption of P-gp substrate drugs without long-term induction of P-gp expression in rats.

Footnotes

  • This work was supported by the China National Nature Science Foundation [Grants 30973583, 30801411]; China “Creation of New Drugs” Key Technology Projects [Grants 2009ZX09304-001, 2009ZX09502-004]; and the Jiangsu Province Nature Science Foundation [Grant BK2008038].

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.110.034793.

  • ABBREVIATIONS:

    20(S)-Rh2
    20(S)-ginsenoside Rh2
    P-gp
    P-glycoprotein
    HPLC
    high-performance liquid chromatography
    HBSS
    Hank's balanced salt solution
    LC
    liquid chromatography
    MS/MS
    tandem mass spectrometry
    MES
    4-morpholineethanesulfonic acid
    MDR
    multidrug resistance
    CMC
    carboxymethylcellulose
    AUC
    the area under the concentration-time curve
    AP
    apical
    BL
    basolateral
    DDI
    drug-drug interaction
    XR9576
    N-[2-[[4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]phenyl]carbamoyl]-4,5-dimethoxyphenyl]quinoline-3-carboxamide
    GF120918
    N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide.

  • Received May 29, 2010.
  • Accepted September 13, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (12)
Drug Metabolism and Disposition
Vol. 38, Issue 12
1 Dec 2010
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Research ArticleArticle

20(S)-Ginsenoside Rh2 Noncompetitively Inhibits P-Glycoprotein In Vitro and In Vivo: A Case for Herb-Drug Interactions

Jingwei Zhang, Fang Zhou, Xiaolan Wu, Yi Gu, Hua Ai, Yuanting Zheng, Yannan Li, Xiaoxuan Zhang, Gang Hao, Jianguo Sun, Ying Peng and Guangji Wang
Drug Metabolism and Disposition December 1, 2010, 38 (12) 2179-2187; DOI: https://doi.org/10.1124/dmd.110.034793

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Research ArticleArticle

20(S)-Ginsenoside Rh2 Noncompetitively Inhibits P-Glycoprotein In Vitro and In Vivo: A Case for Herb-Drug Interactions

Jingwei Zhang, Fang Zhou, Xiaolan Wu, Yi Gu, Hua Ai, Yuanting Zheng, Yannan Li, Xiaoxuan Zhang, Gang Hao, Jianguo Sun, Ying Peng and Guangji Wang
Drug Metabolism and Disposition December 1, 2010, 38 (12) 2179-2187; DOI: https://doi.org/10.1124/dmd.110.034793
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