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Research ArticleArticle

Absorption and Metabolism of Flavonoids in the Caco-2 Cell Culture Model and a Perused Rat Intestinal Model

Yan Liu and Ming Hu
Drug Metabolism and Disposition April 2002, 30 (4) 370-377; DOI: https://doi.org/10.1124/dmd.30.4.370
Yan Liu
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Ming Hu
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Abstract

The purpose of present study was to determine the intestinal absorption and metabolism of genistein and its analogs to better understand the mechanisms responsible for their low oral bioavailability. The Caco-2 cell culture model and a perfused rat intestinal model were used for the study. In both models, permeabilities of aglycones (e.g., genistein) were comparable to well absorbed compounds, such as testosterone and propranolol. In the Caco-2 model, permeabilities of aglycones were at least 5 times higher (p < 0.05) than their corresponding glycosides (e.g., genistin), and the vectorial transport of aglycones was similar (p > 0.05). In contrast, vectorial transport of glucosides favored excretion (p < 0.05). Limited hydrolysis of glycosides was observed in the Caco-2 model, which was completely inhibited (p < 0.05) by 20 mM gluconolactone, a broad specificity glycosidase inhibitor. In the perfused rat intestinal model, genistin was rapidly hydrolyzed (about 40% in 15 min) in the upper intestine but was not hydrolyzed at all in the colon. Aglycones were rapidly absorbed (P*eff > 1.5), and absorbed aglycones underwent extensive (40% maximum) phase II metabolism via glucuronidation and sulfation in the upper small intestine. Similar to the hydrolysis, recovery of conjugated genistein was also region-dependent, with jejunum having the highest and colon the lowest (p < 0.05). This difference in conjugate recovery could be due to the difference in the activities of enzymes or efflux transporters, and the results of studies tend to suggest that both of these factors were involved. In conclusion, genistein and its analogs are well absorbed in both intestinal models, and therefore, poor absorption is not the reason for its low bioavailability. On the other hand, extensive phase II metabolism in the intestine significantly contributes to its low bioavailability.

Footnotes

  • This work was supported by National Institutes of Health Grant GM52270 and AT00182. A portion of this report was presented at American Association of Pharmaceutical Scientists 14th Annual Meeting, November 14–18, 1999, in New Orleans, LA.

  • Abbreviations used are::
    MRP2
    multidrug resistant protein 2
    HBSS
    Hanks' balanced salt solution
    HPLC
    high-performance liquid chromatography
    MPA
    mobile phase A
    MPB
    mobile phase B
    ANOVA
    analysis of variance
    pAH
    para-amino hippuric acid
    LPH
    lactase phlorizin hydrolase
    • Received July 12, 2001.
    • Accepted December 18, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (4)
Drug Metabolism and Disposition
Vol. 30, Issue 4
1 Apr 2002
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Research ArticleArticle

Absorption and Metabolism of Flavonoids in the Caco-2 Cell Culture Model and a Perused Rat Intestinal Model

Yan Liu and Ming Hu
Drug Metabolism and Disposition April 1, 2002, 30 (4) 370-377; DOI: https://doi.org/10.1124/dmd.30.4.370

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Research ArticleArticle

Absorption and Metabolism of Flavonoids in the Caco-2 Cell Culture Model and a Perused Rat Intestinal Model

Yan Liu and Ming Hu
Drug Metabolism and Disposition April 1, 2002, 30 (4) 370-377; DOI: https://doi.org/10.1124/dmd.30.4.370
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