Cationic N,N-Dimethylglycine Ester Prodrug of 2R-alpha-Tocotrienol Promotes Intestinal Absorption via Efficient Self-Micellization with Intrinsic Bile Acid Anion

The intestinal absorption of hydrophobic compounds is severely influenced by their transportation rate through the unstirred water layer in the intestinal lumen. A member of the vitamin E family, alpha-Tocotrienol (alpha-T3) has remarkable pharmacological effects, but its intestinal absorption is hampered due to its hydrophobicity. Here, we prepared three ester derivatives of 2R-alpha-T3, and we selected a suitable prodrug compound using rat plasma and liver microsomes. The micellization profile of the selected compound in the presence of taurocholic acid (TCA) was evaluated. After gastrostomy administration of the prodrug candidate or alpha-T3 solution containing TCA, AUC values were determined for alpha-T3 in plasma obtained from bile duct-ligated rats. Among the three types in the efficiency of the reconversion to the parent drug, alpha-T3 N,N-dimethylglycinate (alpha-T3DMG) was the best prodrug; alpha-T3DMG formed mixed micelles via ion pairs with anionic TCA. The solubility of alpha-T3DMG in n-octanol/water depended on its ratio to TCA. The AUC after alpha-T3DMG administration to ligated rats was 2-fold higher than that after alpha-T3 administration, suggesting a smooth interaction with intrinsic bile acids. In conclusion, utilization of the prodrug synthesized using N,N-dimethylglycine ester may be a beneficial approach to promote intestinal absorption of alpha-T3 via self-micellization with intrinsic bile acid.