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 Cmax at 2–3 h and after Uq-10 administration, it remained low. The AUC0-24h of UqH-10 after UqH-derivatives administration was 2–3-fold higher than that after Uq-10 administration. In postprandial rats, the Tmax 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.

中文翻译：

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Ubiquinol-10 的新型阳离子前药通过有效形成具有胆汁酸阴离子的纳米级混合胶束增强肠道吸收

本研究的目的是开发一种用于口服给药的 ubiquinol-10 (UqH-10) 前药，即 ubiquinone-10 (Uq-10) 的活性形式。UqH-10 的生物利用度因其对氧化的高度敏感性和水不溶性而受到阻碍。我们制备了 UqH-10 的三种新型 N,N-二甲基甘氨酸酯衍生物，包括 1-单酯 (UqH-1-DMG)、4-单酯 (UqH-4-DMG) 和 1,4-双酯 (UqH -DMG)，并在体外和体内评估了它们的理化特性。UqH-DMG 在 36.5 °C 下自发形成包含 20 nm 颗粒的胶束水溶液。阳离子 UqH-DMG 与牛磺胆酸形成纳米级 (5 nm) 混合胶束。在人肝微粒体中，衍生物重新转化为 UqH-10 的速度加快。在分别分泌正常和高水平胆汁的禁食和餐后大鼠中测定在施用 UqH 衍生物或 Uq-10 后 UqH-10 的口服生物利用度。在禁食大鼠中，UqH 衍生物给药后的血浆 UqH-10 在 2-3 小时达到 Cmax，而在 Uq-10 给药后，它仍然很低。UqH-衍生物给药后UqH-10的AUC0-24h比Uq-10给药后高2-3倍。在餐后大鼠中，UqH-衍生物给药后UqH-10的Tmax比Uq-10给药后早1小时。总之，阳离子 UqH 衍生物是方便的前药，通过与肠道胆汁酸形成纳米级混合胶束来提高 UqH-10 的生物利用度。UqH 衍生物给药后血浆 UqH-10 在 2-3 小时达到 Cmax，而在 Uq-10 给药后，它仍然很低。UqH-衍生物给药后UqH-10的AUC0-24h比Uq-10给药后高2-3倍。在餐后大鼠中，UqH-衍生物给药后UqH-10的Tmax比Uq-10给药后早1小时。总之，阳离子 UqH 衍生物是方便的前药，通过与肠道胆汁酸形成纳米级混合胶束来提高 UqH-10 的生物利用度。UqH 衍生物给药后血浆 UqH-10 在 2-3 小时达到 Cmax，而在 Uq-10 给药后，它仍然很低。UqH-衍生物给药后UqH-10的AUC0-24h比Uq-10给药后高2-3倍。在餐后大鼠中，UqH-衍生物给药后UqH-10的Tmax比Uq-10给药后早1小时。总之，阳离子 UqH 衍生物是方便的前药，通过与肠道胆汁酸形成纳米级混合胶束来提高 UqH-10 的生物利用度。