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Journal of Lipid Research, Vol. 43, 2196-2204, December 2002
Copyright © 2002 by Lipid Research, Inc.

Methods

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

Jiro Takata^1,*, Ryoji Hidaka^*, Akihiko Yamasaki^*, Akihiro Hattori, Takeshi Fukushima, Maiko Tanabe, Kazuhisa Matsunaga^*, Yoshiharu Karube^* and Kazuhiro Imai

^* Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma, Johnan-ku, Fukuoka 814-0180, Japan
Laboratory of Bio-Analytical Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

¹ To whom correspondence should be addressed. e-mail: jtakata{at}fukuoka-u.ac.jp

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

Based on these results, -TDMG was identified as the most promising water-soluble prodrug of -Toc and the two-step prodrug of S--CEHC.

Abbreviations: AUC, area under the concentration-time curve; DBD-PZ, 4-N,N-dimethylaminosulfonyl-7-piperazino-2,1,3-benzoxadiazole; FD-MS, field desorption mass spectrometry; HCO-60, polyoxyethylene hydrogenated castor oil; ¹H-NMR, proton nuclear magnetic resonance spectrometry; -Toc, d--tocopherol; -TDMG, d--tocopheryl N,N-dimethylglycinate hydrochloride; MRT, mean residence time; R--CEHC, 2,7,8-trimethyl-2R-(ß-carboxyethyl)-6-hydroxychroman; S--CEHC, 2,7,8-trimethyl-2S-(ß-carboxyethyl)-6-hydroxychroman; TFA, trifluoroacetic acid

Supplementary key words water-soluble prodrug • drug delivery • d--tocopherol • two-step prodrug

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				N. Akaho, J. Takata, T. Fukushima, K. Matsunaga, A. Hattori, R. Hidaka, K. Fukui, M. Yoshida, T. Fujioka, Y. Karube, et al. Preparation and In Vivo Evaluation of a Water-Soluble Prodrug for 2R-{gamma}-Tocotrienol and as a Two-Step Prodrug for 2,7,8-Trimethyl-2S-({beta}-carboxyethyl)-6-hydroxychroman (S-{gamma}-CEHC) in Rat Drug Metab. Dispos., September 1, 2007; 35(9): 1502 - 1510. [Abstract] [Full Text] [PDF]