Novel d-γ-tocopherol derivative as a prodrug for d-γ-tocopherol and a two-step prodrug for S-γ-CEHC

Jiro Takata, Ryoji Hidaka, Akihiko Yamasaki, Akihiro Hattori, Takeshi Fukushima, Maiko Tanabe, Kazuhisa Matsunaga, Yoshiharu Karube, Kazuhiro Imai

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20 Citations (Scopus)

Abstract

d-γ-Tocopherol (γ-Toc) and its major metabolite, 2, 7, 8-trimethyl-2S-(β-carboxyethyl)-6-hydroxychroman (S-γ-CEHC), are currently receiving attention concerning their unique pharmacological activities. In order to achieve the efficient delivery of γ-Toc and S-γ-CEHC in vivo, we synthesized d-γ-tocopheryl N,N-dimethylglycinate hydrochloride (γ-TDMG) as a water-soluble prodrug of γ-Toc and a two-step prodrug of S-γ-CEHC. γ-TDMG is a solid (mp 161-163°C) and is quite soluble in water over 50 mM. The hydrolysis of γ-TDMG was effectively catalyzed by esterases in rat and human liver microsomes. The disposition of γ-TDMG after iv administration in rats was compared with that of γ-Toc solubilized with the surfactant, polyoxyethylene hydro-genated castor oil. The plasma and liver levels of γ-Toc rapidly increased after the iv administration of the γ-TDMG. The liver availability of γ-Toc after the administration of γ-TDMG was two times higher than that of the γ-Toc administration. The relative systemic availability of S-γ-CEHC after the γ-TDMG administration was an equivalent value (102%), and the mean residence time of S-γ-CEHC was eight times longer than the racemic γ-CEHC administration. Based on these results, γ-TDMG was identified as the most promising water-soluble prodrug of γ-Toc and the two-step prodrug of S-γ-CEHC.

Original languageEnglish
Pages (from-to)2196-2204
Number of pages9
JournalJournal of Lipid Research
Volume43
Issue number12
DOIs
Publication statusPublished - 2002 Dec 1
Externally publishedYes

Keywords

  • D-γ-tocopherol
  • Drug delivery
  • Two step prodrug
  • Water-soluble prodrug

ASJC Scopus subject areas

  • Endocrinology

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    Takata, J., Hidaka, R., Yamasaki, A., Hattori, A., Fukushima, T., Tanabe, M., Matsunaga, K., Karube, Y., & Imai, K. (2002). Novel d-γ-tocopherol derivative as a prodrug for d-γ-tocopherol and a two-step prodrug for S-γ-CEHC. Journal of Lipid Research, 43(12), 2196-2204. https://doi.org/10.1194/jlr.D200027-JLR200