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

doi:10.1194/jlr.D200027-JLR200

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A more recent version of this article appeared on December 1, 2002

Papers In Press, published online ahead of print September 16, 2002
J. Lipid Res., doi:10.1194/jlr.D200027-JLR200

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Submitted on July 26, 2002
Revised on September 6, 2002
Accepted on September 10, 2002

Novel d- $gamma$ -Tocopherol derivative as a prodrug for d- $gamma$ -tocopherol and a two-step prodrug for S- $gamma$ -CEHC

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

Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180

Corresponding Author: jtakata{at}fukuoka-u.ac.jp

d- $gamma$ -Tocopherol ( $gamma$ -Toc) and its major metabolite, 2, 7, 8-trimethyl-2S-( $gamma$ -carboxyethyl)-6-hydroxychroman (S- $gamma$ -CEHC), are currently receiving attention concerning their unique pharmacological activities. In order to achieve the efficient delivery of $gamma$ -Toc and S- $gamma$ -CEHC in vivo, we synthesized d- $gamma$ -tocopheryl N,N-dimethylglycinate hydrochloride ( $gamma$ -TDMG) as a water-soluble prodrug of $gamma$ -Toc and a two-step prodrug of S- $gamma$ -CEHC. $gamma$ -TDMG is a solid (mp 161-163°C) and is quite soluble in water over 50 mM. The hydrolysis of $gamma$ -TDMG was effectively catalyzed by esterases in rat and human liver microsomes. The disposition of $gamma$ -TDMG after intravenous (i.v.) administration in rats was compared with that of $gamma$ -Toc solubilized with the surfactant, HCO-60. The plasma and liver levels of $gamma$ -Toc rapidly increased after the i.v. administration of the $gamma$ -TDMG. The liver availability of $gamma$ -Toc after the administration of $gamma$ -TDMG was 2-times higher than that of the $gamma$ -Toc administration. The relative systemic availability of S- $gamma$ -CEHC after the $gamma$ -TDMG administration was an equivalent value (102%), and the mean residence time of S- $gamma$ -CEHC was 8 times longer than the racemic $gamma$ -CEHC administration. Based on these results, $gamma$ -TDMG was identified as the most promising water-soluble prodrug of $gamma$ -Toc and the two-step prodrug of S- $gamma$ -CEHC.

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This article has been cited by other articles:

N. Akaho, J. Takata, T. Fukushima, K. Matsunaga, A. Hattori, R. Hidaka, K. Fukui, M. Yoshida, T. Fujioka, Y. Karube, et al.
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Novel d--Tocopherol derivative as a prodrug for d--tocopherol and a two-step prodrug for S--CEHC

Novel d- $gamma$ -Tocopherol derivative as a prodrug for d- $gamma$ -tocopherol and a two-step prodrug for S- $gamma$ -CEHC