出版社：American Society for Biochemistry and Molecular Biology
摘要：d -γ-Tocopherol (γ-Toc) and its major metabolite, 2, 7, 8-trimethyl-2 S -(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 hydrogenated 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.
