Novel d-gamma-tocopherol derivative as a prodrug for d-gamma-tocopherol and a two-step prodrug for S-gamma-CEHC.
d-gamma-Tocopherol (gamma-Toc) and its major metabolite, 2, 7, 8-trimethyl-2S-(beta-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 degrees 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 iv administration in rats was compared with that of gamma-Toc solubilized with the surfactant, polyoxyethylene hydrogenated castor oil. The plasma and liver levels of gamma-Toc rapidly increased after the iv administration of the gamma-TDMG. The liver availability of gamma-Toc after the administration of gamma-TDMG was two 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 eight 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.
Takata
Jiro
J
Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma, Johnan-ku, Fukuoka 814-0180, Japan. jtakata@fukuoka-u.ac.jp
Hidaka
Ryoji
R
Yamasaki
Akihiko
A
Hattori
Akihiro
A
Fukushima
Takeshi
T
Tanabe
Maiko
M
Matsunaga
Kazuhisa
K
Karube
Yoshiharu
Y
Imai
Kazuhiro
K
D000818:Animals; D002839:Chromans / Q000378:metabolism*; D007275:Injections, Intravenous; D011422:Propionates / Q000378:metabolism*; D051381:Rats; D024504:gamma-Tocopherol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics
D002839:Chromans; D011422:Propionates; C107690:2,7,8-trimethyl-2-(beta-carboxyethyl)-6-hydroxychroman; D024504:gamma-Tocopherol