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 (P_eff) 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 P_eff 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.