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

Research output: Contribution to journalArticle

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

Fingerprint

Tocopherols
Prodrugs
Derivatives
Liver
Water
Castor Oil
Rats
Liver Microsomes
Esterases
Surface-Active Agents
Availability
Hydrolysis
Pharmacology
Metabolites
Plasmas

Keywords

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

ASJC Scopus subject areas

  • Endocrinology

Cite this

Novel d-γ-tocopherol derivative as a prodrug for d-γ-tocopherol and a two-step prodrug for S-γ-CEHC. / Takata, Jiro; Hidaka, Ryoji; Yamasaki, Akihiko; Hattori, Akihiro; Fukushima, Takeshi; Tanabe, Maiko; Matsunaga, Kazuhisa; Karube, Yoshiharu; Imai, Kazuhiro.

In: Journal of Lipid Research, Vol. 43, No. 12, 01.12.2002, p. 2196-2204.

Research output: Contribution to journalArticle

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, vol. 43, no. 12, pp. 2196-2204. https://doi.org/10.1194/jlr.D200027-JLR200
Takata, Jiro ; Hidaka, Ryoji ; Yamasaki, Akihiko ; Hattori, Akihiro ; Fukushima, Takeshi ; Tanabe, Maiko ; Matsunaga, Kazuhisa ; Karube, Yoshiharu ; Imai, Kazuhiro. / Novel d-γ-tocopherol derivative as a prodrug for d-γ-tocopherol and a two-step prodrug for S-γ-CEHC. In: Journal of Lipid Research. 2002 ; Vol. 43, No. 12. pp. 2196-2204.
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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.",
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AU - Yamasaki, Akihiko

AU - Hattori, Akihiro

AU - Fukushima, Takeshi

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AU - Matsunaga, Kazuhisa

AU - Karube, Yoshiharu

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AB - 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.

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