gamma-Tocotrienol (gamma-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 gamma-T3 intestinal uptake and metabolism using the in situ rat intestinal perfusion model. Isolated segments of rat jejunum and ileum were perfused with gamma-T3 solution, and measurements were made as a function of concentration (5-150 microM). Intestinal permeability (P(eff)) and metabolism were studied by measuring total compound disappearance and major metabolite, 2,7,8-trimethyl-2-(beta-carboxy-ethyl)-6-hydroxychroman, appearance in the intestinal lumen. gamma-T3 and metabolite levels were also determined in mesenteric blood. The P(eff) of gamma-T3 was similar in both intestinal segments and significantly decreased at concentrations > or =25 microM in jejunum and ileum (p < 0.05), whereas metabolite formation was minimal and mesenteric blood concentrations of gamma-T3 and metabolite remained very low. These results indicate that gamma-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 gamma-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 gamma-T3 or gamma-T3 with increasing concentrations of ezetimibe. The present data show for the first time that gamma-T3 intestinal absorption is partly mediated by NPC1L1.
