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Research ArticleArticle

Predicting Phenolic Acid Absorption in Caco-2 Cells: A Theoretical Permeability Model and Mechanistic Study

Tracy L. Farrell, Laure Poquet, Tristan P. Dew, Stuart Barber and Gary Williamson
Drug Metabolism and Disposition February 2012, 40 (2) 397-406; DOI: https://doi.org/10.1124/dmd.111.041665
Tracy L. Farrell
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Laure Poquet
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Tristan P. Dew
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Stuart Barber
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Gary Williamson
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Abstract

There is a considerable need to rationalize the membrane permeability and mechanism of transport for potential nutraceuticals. The aim of this investigation was to develop a theoretical permeability equation, based on a reported descriptive absorption model, enabling calculation of the transcellular component of absorption across Caco-2 monolayers. Published data for Caco-2 permeability of 30 drugs transported by the transcellular route were correlated with the descriptors 1-octanol/water distribution coefficient (log D, pH 7.4) and size, based on molecular mass. Nonlinear regression analysis was used to derive a set of model parameters a′, β′, and b′ with an integrated molecular mass function. The new theoretical transcellular permeability (TTP) model obtained a good fit of the published data (R2 = 0.93) and predicted reasonably well (R2 = 0.86) the experimental apparent permeability coefficient (Papp) for nine non-training set compounds reportedly transported by the transcellular route. For the first time, the TTP model was used to predict the absorption characteristics of six phenolic acids, and this original investigation was supported by in vitro Caco-2 cell mechanistic studies, which suggested that deviation of the Papp value from the predicted transcellular permeability (Papptrans) may be attributed to involvement of active uptake, efflux transporters, or paracellular flux.

Footnotes

  • This research was supported by Nestlé Research Center, Lausanne, Switzerland.

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

    doi:http://dx.doi.org/10.1124/dmd.111.041665.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    HCA
    hydroxycinnamic acid
    5-O-CQA
    5-O-caffeoylquinic acid
    3,5-diCQA
    3,5-di-O-caffeoylquinic acid
    5-O-FQA
    5-O-feruloylquinic acid
    TTP
    theoretical transcellular permeability
    HBSS
    Hanks' balanced salt solution
    DMSO
    dimethyl sulfoxide
    TEER
    transepithelial electrical resistance
    A→B
    apical-to-basal
    B→A
    basal-to-apical
    HPLC
    high-performance liquid chromatography
    DAD
    diode array detector
    ABC
    ATP-binding cassette
    BCRP
    breast cancer resistance protein
    P-gp
    P glycoprotein
    MRP
    multidrug resistance-associated protein
    MK571
    (E)-3-[[[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-[[3-dimethylamino)-3-oxopropyl]thio]methyl]thio]-propanoic acid.

  • Received July 7, 2011.
  • Accepted November 17, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (2)
Drug Metabolism and Disposition
Vol. 40, Issue 2
1 Feb 2012
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Research ArticleArticle

PREDICTING ABSORPTION OF PHENOLIC ACIDS

Tracy L. Farrell, Laure Poquet, Tristan P. Dew, Stuart Barber and Gary Williamson
Drug Metabolism and Disposition February 1, 2012, 40 (2) 397-406; DOI: https://doi.org/10.1124/dmd.111.041665

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Research ArticleArticle

PREDICTING ABSORPTION OF PHENOLIC ACIDS

Tracy L. Farrell, Laure Poquet, Tristan P. Dew, Stuart Barber and Gary Williamson
Drug Metabolism and Disposition February 1, 2012, 40 (2) 397-406; DOI: https://doi.org/10.1124/dmd.111.041665
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