d-γ-Tocopherol (γ-Toc) and its major metabolite, 2, 7, 8-trimethyl-2S-(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 hydro-genated 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.
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