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Cationic N,N-Dimethylglycine Ester Prodrug of 2R-α-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, α-Tocotrienol (α-T3) has remarkable pharmacological effects, but its intestinal absorption is hampered d...

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Autores principales: Watase, Daisuke, Setoguchi, Shuichi, Nagata-Akaho, Nami, Goto, Shotaro, Yamakawa, Hirofumi, Yamada, Ayano, Koga, Mitsuhisa, Karube, Yoshiharu, Matsunaga, Kazuhisa, Takata, Jiro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9102404/
https://www.ncbi.nlm.nih.gov/pubmed/35566078
http://dx.doi.org/10.3390/molecules27092727
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author Watase, Daisuke
Setoguchi, Shuichi
Nagata-Akaho, Nami
Goto, Shotaro
Yamakawa, Hirofumi
Yamada, Ayano
Koga, Mitsuhisa
Karube, Yoshiharu
Matsunaga, Kazuhisa
Takata, Jiro
author_facet Watase, Daisuke
Setoguchi, Shuichi
Nagata-Akaho, Nami
Goto, Shotaro
Yamakawa, Hirofumi
Yamada, Ayano
Koga, Mitsuhisa
Karube, Yoshiharu
Matsunaga, Kazuhisa
Takata, Jiro
author_sort Watase, Daisuke
collection PubMed
description 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.
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spelling pubmed-91024042022-05-14 Cationic N,N-Dimethylglycine Ester Prodrug of 2R-α-Tocotrienol Promotes Intestinal Absorption via Efficient Self-Micellization with Intrinsic Bile Acid Anion Watase, Daisuke Setoguchi, Shuichi Nagata-Akaho, Nami Goto, Shotaro Yamakawa, Hirofumi Yamada, Ayano Koga, Mitsuhisa Karube, Yoshiharu Matsunaga, Kazuhisa Takata, Jiro Molecules Article 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. MDPI 2022-04-23 /pmc/articles/PMC9102404/ /pubmed/35566078 http://dx.doi.org/10.3390/molecules27092727 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Watase, Daisuke
Setoguchi, Shuichi
Nagata-Akaho, Nami
Goto, Shotaro
Yamakawa, Hirofumi
Yamada, Ayano
Koga, Mitsuhisa
Karube, Yoshiharu
Matsunaga, Kazuhisa
Takata, Jiro
Cationic N,N-Dimethylglycine Ester Prodrug of 2R-α-Tocotrienol Promotes Intestinal Absorption via Efficient Self-Micellization with Intrinsic Bile Acid Anion
title Cationic N,N-Dimethylglycine Ester Prodrug of 2R-α-Tocotrienol Promotes Intestinal Absorption via Efficient Self-Micellization with Intrinsic Bile Acid Anion
title_full Cationic N,N-Dimethylglycine Ester Prodrug of 2R-α-Tocotrienol Promotes Intestinal Absorption via Efficient Self-Micellization with Intrinsic Bile Acid Anion
title_fullStr Cationic N,N-Dimethylglycine Ester Prodrug of 2R-α-Tocotrienol Promotes Intestinal Absorption via Efficient Self-Micellization with Intrinsic Bile Acid Anion
title_full_unstemmed Cationic N,N-Dimethylglycine Ester Prodrug of 2R-α-Tocotrienol Promotes Intestinal Absorption via Efficient Self-Micellization with Intrinsic Bile Acid Anion
title_short Cationic N,N-Dimethylglycine Ester Prodrug of 2R-α-Tocotrienol Promotes Intestinal Absorption via Efficient Self-Micellization with Intrinsic Bile Acid Anion
title_sort cationic n,n-dimethylglycine ester prodrug of 2r-α-tocotrienol promotes intestinal absorption via efficient self-micellization with intrinsic bile acid anion
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9102404/
https://www.ncbi.nlm.nih.gov/pubmed/35566078
http://dx.doi.org/10.3390/molecules27092727
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