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Novel Cationic Prodrug of Ubiquinol-10 Enhances Intestinal Absorption via Efficient Formation of Nanosized Mixed-Micelles with Bile Acid Anions

The aim of this study was to develop a prodrug of ubiquinol-10 (UqH-10), the active form of ubiquinone-10 (Uq-10), for oral delivery. Bioavailability of UqH-10 is hampered by its high susceptibility to oxidation and water-insolubility. We prepared three novel N,N-dimethylglycine ester derivatives of...

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Autores principales: Setoguchi, Shuichi, Hidaka, Ryoji, Nagata-Akaho, Nami, Watase, Daisuke, Koga, Mitsuhisa, Matsunaga, Kazuhisa, Karube, Yoshiharu, Takata, Jiro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7037610/
https://www.ncbi.nlm.nih.gov/pubmed/32012733
http://dx.doi.org/10.3390/molecules25030546
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author Setoguchi, Shuichi
Hidaka, Ryoji
Nagata-Akaho, Nami
Watase, Daisuke
Koga, Mitsuhisa
Matsunaga, Kazuhisa
Karube, Yoshiharu
Takata, Jiro
author_facet Setoguchi, Shuichi
Hidaka, Ryoji
Nagata-Akaho, Nami
Watase, Daisuke
Koga, Mitsuhisa
Matsunaga, Kazuhisa
Karube, Yoshiharu
Takata, Jiro
author_sort Setoguchi, Shuichi
collection PubMed
description The aim of this study was to develop a prodrug of ubiquinol-10 (UqH-10), the active form of ubiquinone-10 (Uq-10), for oral delivery. Bioavailability of UqH-10 is hampered by its high susceptibility to oxidation and water-insolubility. We prepared three novel N,N-dimethylglycine ester derivatives of UqH-10, including a 1-monoester (UqH-1-DMG), 4-monoester (UqH-4-DMG), and 1,4-bis-ester (UqH-DMG), and assessed their physicochemical properties in vitro and in vivo. UqH-DMG spontaneously formed an aqueous micelle solution comprising 20 nm particles at 36.5 °C. Cationic UqH-DMG formed nano-sized (5 nm) mixed-micelles with taurocholic acid. Reconversion of the derivatives to UqH-10 was accelerated in human liver microsomes. The oral bioavailability of UqH-10 after administration of UqH-derivatives or Uq-10 was determined in fasted and postprandial rats secreting normal and high levels of bile, respectively. In fasted rats, plasma UqH-10 after UqH-derivatives administration reached C(max) at 2–3 h and after Uq-10 administration, it remained low. The AUC(0-24h) of UqH-10 after UqH-derivatives administration was 2–3-fold higher than that after Uq-10 administration. In postprandial rats, the T(max) of UqH-10 after UqH-derivatives administration was an hour earlier than after Uq-10 administration. In conclusion, cationic UqH-derivatives are convenient prodrugs that enhance UqH-10 bioavailability by forming nanosized mixed-micelles with intestinal bile acids.
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spelling pubmed-70376102020-03-11 Novel Cationic Prodrug of Ubiquinol-10 Enhances Intestinal Absorption via Efficient Formation of Nanosized Mixed-Micelles with Bile Acid Anions Setoguchi, Shuichi Hidaka, Ryoji Nagata-Akaho, Nami Watase, Daisuke Koga, Mitsuhisa Matsunaga, Kazuhisa Karube, Yoshiharu Takata, Jiro Molecules Article The aim of this study was to develop a prodrug of ubiquinol-10 (UqH-10), the active form of ubiquinone-10 (Uq-10), for oral delivery. Bioavailability of UqH-10 is hampered by its high susceptibility to oxidation and water-insolubility. We prepared three novel N,N-dimethylglycine ester derivatives of UqH-10, including a 1-monoester (UqH-1-DMG), 4-monoester (UqH-4-DMG), and 1,4-bis-ester (UqH-DMG), and assessed their physicochemical properties in vitro and in vivo. UqH-DMG spontaneously formed an aqueous micelle solution comprising 20 nm particles at 36.5 °C. Cationic UqH-DMG formed nano-sized (5 nm) mixed-micelles with taurocholic acid. Reconversion of the derivatives to UqH-10 was accelerated in human liver microsomes. The oral bioavailability of UqH-10 after administration of UqH-derivatives or Uq-10 was determined in fasted and postprandial rats secreting normal and high levels of bile, respectively. In fasted rats, plasma UqH-10 after UqH-derivatives administration reached C(max) at 2–3 h and after Uq-10 administration, it remained low. The AUC(0-24h) of UqH-10 after UqH-derivatives administration was 2–3-fold higher than that after Uq-10 administration. In postprandial rats, the T(max) of UqH-10 after UqH-derivatives administration was an hour earlier than after Uq-10 administration. In conclusion, cationic UqH-derivatives are convenient prodrugs that enhance UqH-10 bioavailability by forming nanosized mixed-micelles with intestinal bile acids. MDPI 2020-01-27 /pmc/articles/PMC7037610/ /pubmed/32012733 http://dx.doi.org/10.3390/molecules25030546 Text en © 2020 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Setoguchi, Shuichi
Hidaka, Ryoji
Nagata-Akaho, Nami
Watase, Daisuke
Koga, Mitsuhisa
Matsunaga, Kazuhisa
Karube, Yoshiharu
Takata, Jiro
Novel Cationic Prodrug of Ubiquinol-10 Enhances Intestinal Absorption via Efficient Formation of Nanosized Mixed-Micelles with Bile Acid Anions
title Novel Cationic Prodrug of Ubiquinol-10 Enhances Intestinal Absorption via Efficient Formation of Nanosized Mixed-Micelles with Bile Acid Anions
title_full Novel Cationic Prodrug of Ubiquinol-10 Enhances Intestinal Absorption via Efficient Formation of Nanosized Mixed-Micelles with Bile Acid Anions
title_fullStr Novel Cationic Prodrug of Ubiquinol-10 Enhances Intestinal Absorption via Efficient Formation of Nanosized Mixed-Micelles with Bile Acid Anions
title_full_unstemmed Novel Cationic Prodrug of Ubiquinol-10 Enhances Intestinal Absorption via Efficient Formation of Nanosized Mixed-Micelles with Bile Acid Anions
title_short Novel Cationic Prodrug of Ubiquinol-10 Enhances Intestinal Absorption via Efficient Formation of Nanosized Mixed-Micelles with Bile Acid Anions
title_sort novel cationic prodrug of ubiquinol-10 enhances intestinal absorption via efficient formation of nanosized mixed-micelles with bile acid anions
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7037610/
https://www.ncbi.nlm.nih.gov/pubmed/32012733
http://dx.doi.org/10.3390/molecules25030546
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