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Article

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

by
Daisuke Watase
†,
Shuichi Setoguchi
†,
Nami Nagata-Akaho
,
Shotaro Goto
,
Hirofumi Yamakawa
,
Ayano Yamada
,
Mitsuhisa Koga
,
Yoshiharu Karube
,
Kazuhisa Matsunaga
* and
Jiro Takata
Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Molecules 2022, 27(9), 2727; https://doi.org/10.3390/molecules27092727
Submission received: 4 April 2022 / Revised: 19 April 2022 / Accepted: 21 April 2022 / Published: 23 April 2022
(This article belongs to the Special Issue The Role of Bile Acids in Metabolic Control)
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Abstract

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, α-Tocotrienol (α-T3) has remarkable pharmacological effects, but its intestinal absorption is hampered due to its hydrophobicity. Here, we prepared three ester derivatives of 2R-α-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 α-T3 solution containing TCA, AUC values were determined for α-T3 in plasma obtained from bile duct-ligated rats. Among the three types in the efficiency of the reconversion to the parent drug, α-T3 N,N-dimethylglycinate (α-T3DMG) was the best prodrug; α-T3DMG formed mixed micelles via ion pairs with anionic TCA. The solubility of α-T3DMG in n-octanol/water depended on its ratio to TCA. The AUC after α-T3DMG administration to ligated rats was 2-fold higher than that after α-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 α-T3 via self-micellization with intrinsic bile acid.
Keywords: bile acid; bioavailability; drug delivery system; micelle; prodrug; tocotrienol; vitamin E bile acid; bioavailability; drug delivery system; micelle; prodrug; tocotrienol; vitamin E

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MDPI and ACS Style

Watase, D.; Setoguchi, S.; Nagata-Akaho, N.; Goto, S.; Yamakawa, H.; Yamada, A.; Koga, M.; Karube, Y.; Matsunaga, K.; Takata, J. Cationic N,N-Dimethylglycine Ester Prodrug of 2R-α-Tocotrienol Promotes Intestinal Absorption via Efficient Self-Micellization with Intrinsic Bile Acid Anion. Molecules 2022, 27, 2727. https://doi.org/10.3390/molecules27092727

AMA Style

Watase D, Setoguchi S, Nagata-Akaho N, Goto S, Yamakawa H, Yamada A, Koga M, Karube Y, Matsunaga K, Takata J. Cationic N,N-Dimethylglycine Ester Prodrug of 2R-α-Tocotrienol Promotes Intestinal Absorption via Efficient Self-Micellization with Intrinsic Bile Acid Anion. Molecules. 2022; 27(9):2727. https://doi.org/10.3390/molecules27092727

Chicago/Turabian Style

Watase, Daisuke, Shuichi Setoguchi, Nami Nagata-Akaho, Shotaro Goto, Hirofumi Yamakawa, Ayano Yamada, Mitsuhisa Koga, Yoshiharu Karube, Kazuhisa Matsunaga, and Jiro Takata. 2022. "Cationic N,N-Dimethylglycine Ester Prodrug of 2R-α-Tocotrienol Promotes Intestinal Absorption via Efficient Self-Micellization with Intrinsic Bile Acid Anion" Molecules 27, no. 9: 2727. https://doi.org/10.3390/molecules27092727

APA Style

Watase, D., Setoguchi, S., Nagata-Akaho, N., Goto, S., Yamakawa, H., Yamada, A., Koga, M., Karube, Y., Matsunaga, K., & Takata, J. (2022). Cationic N,N-Dimethylglycine Ester Prodrug of 2R-α-Tocotrienol Promotes Intestinal Absorption via Efficient Self-Micellization with Intrinsic Bile Acid Anion. Molecules, 27(9), 2727. https://doi.org/10.3390/molecules27092727

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