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
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|