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

@article{citeulike:625181, abstract = {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.}, address = {Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma, Johnan-ku, Fukuoka 814-0180, Japan. jtakata@fukuoka-u.ac.jp}, author = {Takata, J. and Hidaka, R. and Yamasaki, A. and Hattori, A. and Fukushima, T. and Tanabe, M. and Matsunaga, K. and Karube, Y. and Imai, K.}, citeulike-article-id = {625181}, citeulike-linkout-0 = {http://view.ncbi.nlm.nih.gov/pubmed/12454283}, citeulike-linkout-1 = {http://www.hubmed.org/display.cgi?uids=12454283}, issn = {0022-2275}, journal = {J Lipid Res}, keywords = {gamma-cehc, tocopherol}, month = {December}, number = {12}, pages = {2196--2204}, posted-at = {2006-05-12 14:53:00}, priority = {0}, title = {Novel d-gamma-tocopherol derivative as a prodrug for d-gamma-tocopherol and a two-step prodrug for S-gamma-CEHC.}, url = {http://view.ncbi.nlm.nih.gov/pubmed/12454283}, volume = {43}, year = {2002} }

TY - JOUR ID - citeulike:625181 L3 - citeulike-article-id:625181 N2 - 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. IS - 12 JF - J Lipid Res SN - 0022-2275 AD - Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma, Johnan-ku, Fukuoka 814-0180, Japan. jtakata@fukuoka-u.ac.jp EP - 2204 TI - Novel d-gamma-tocopherol derivative as a prodrug for d-gamma-tocopherol and a two-step prodrug for S-gamma-CEHC. VL - 43 SP - 2196 KW - gamma-cehc KW - tocopherol AU - Takata, J AU - Hidaka, R AU - Yamasaki, A AU - Hattori, A AU - Fukushima, T AU - Tanabe, M AU - Matsunaga, K AU - Karube, Y AU - Imai, K PY - 2002/12// UR - http://view.ncbi.nlm.nih.gov/pubmed/12454283 ER -