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Research ArticleArticle

Intestinal Absorption of γ-Tocotrienol Is Mediated by Niemann-Pick C1-Like 1: In Situ Rat Intestinal Perfusion Studies

Bilal Abuasal, Paul W. Sylvester and Amal Kaddoumi
Drug Metabolism and Disposition June 2010, 38 (6) 939-945; DOI: https://doi.org/10.1124/dmd.109.031567
Bilal Abuasal
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Paul W. Sylvester
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Amal Kaddoumi
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Abstract

γ-Tocotrienol (γ-T3) is a member of the vitamin E family that displays potent anticancer activity and other therapeutic benefits. The objective of this study was to evaluate γ-T3 intestinal uptake and metabolism using the in situ rat intestinal perfusion model. Isolated segments of rat jejunum and ileum were perfused with γ-T3 solution, and measurements were made as a function of concentration (5–150 μM). Intestinal permeability (Peff) and metabolism were studied by measuring total compound disappearance and major metabolite, 2,7,8-trimethyl-2-(β-carboxy-ethyl)-6-hydroxychroman, appearance in the intestinal lumen. γ-T3 and metabolite levels were also determined in mesenteric blood. The Peff of γ-T3 was similar in both intestinal segments and significantly decreased at concentrations ≥25 μM in jejunum and ileum (p < 0.05), whereas metabolite formation was minimal and mesenteric blood concentrations of γ-T3 and metabolite remained very low. These results indicate that γ-T3 intestinal uptake is a saturable carrier-mediated process and metabolism is minimal. Results from subsequent in situ inhibition studies with ezetimibe, a potent and selective inhibitor of Niemann-Pick C1-like 1 (NPC1L1) transporter, suggested γ-T3 intestinal uptake is mediated by NPC1L1. Comparable findings were obtained when Madin-Darby canine kidney II cells that express endogenous NPC1L1 were incubated with increasing concentrations of γ-T3 or γ-T3 with increasing concentrations of ezetimibe. The present data show for the first time that γ-T3 intestinal absorption is partly mediated by NPC1L1.

Footnotes

  • This work was supported by a grant from First Tech International Co., Ltd., Hong Kong.

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

    doi:10.1124/dmd.109.031567.

  • ABBREVIATIONS:

    γ-T3
    γ-tocotrienol
    γ-CEHC
    2,7,8-trimethyl-2-(β-carboxy-ethyl)-6-hydroxychroman
    NPC1L1
    Niemann-Pick C1-like 1
    PEG4000
    polyethylene glycol 4000
    HPLC
    high-performance liquid chromatography
    LC/MS/MS
    liquid chromatography/tandem mass spectrometry
    MRM
    multiple-reaction monitoring
    Peff
    effective permeability
    Fmet
    fraction metabolized
    MDCK
    Madin-Darby canine kidney
    SR-B1
    scavenger receptor class B type 1.

  • Received December 4, 2009.
  • Accepted March 5, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (6)
Drug Metabolism and Disposition
Vol. 38, Issue 6
1 Jun 2010
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Research ArticleArticle

Intestinal Absorption of γ-Tocotrienol Is Mediated by Niemann-Pick C1-Like 1: In Situ Rat Intestinal Perfusion Studies

Bilal Abuasal, Paul W. Sylvester and Amal Kaddoumi
Drug Metabolism and Disposition June 1, 2010, 38 (6) 939-945; DOI: https://doi.org/10.1124/dmd.109.031567

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Research ArticleArticle

Intestinal Absorption of γ-Tocotrienol Is Mediated by Niemann-Pick C1-Like 1: In Situ Rat Intestinal Perfusion Studies

Bilal Abuasal, Paul W. Sylvester and Amal Kaddoumi
Drug Metabolism and Disposition June 1, 2010, 38 (6) 939-945; DOI: https://doi.org/10.1124/dmd.109.031567
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