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.
Highlights
Abstract d-␥-Tocopherol (␥-Toc) and its major metabolite, 2, 7, 8-trimethyl-2S-(-carboxyethyl)-6-hydroxychroman (S-␥CEHC), are currently receiving attention concerning their unique pharmacological activities
Several independent investigations have demonstrated that the plasma concentration of ␥-Toc, not of ␣-Toc, was correlated to the incidence of coronary heart disease [3,4,5]. ␥-Toc is superior to ␣-Toc in its ability to trap reactive nitrogen species, mutagenic electrophiles generated during inflammation [6,7,8,9]
It has been shown that ␥-Toc and S-␥-CEHC inhibited the generation of prostaglandin E2 (PGE2), an important mediator synthesized via the cyclooxygenase-2 (COX-2)-catalyzed oxidation of arachidonic acid during inflammation [13]
Summary
Melting points were determined using a Yazawa micromelting point BY-1 apparatus and are uncorrected. The 1H-NMR spectra were recorded at 500 MHz in solutions of CDCl3 using a JEOL JNM-A500 spectrometer. N,N-dimethylglycine hydrochloride was purchased from Tokyo Kasei Kogyo Co., Ltd. HCO-60 was purchased from Nikko Chemical (Tokyo, Japan). The EMix 80 was fractionated by flash chromatography and normal phase HPLC, and ␥-Toc was isolated without delay by solvent evaporation under vacuum stored under argon at Ϫ30ЊC. The purity of the isolated ␥-Toc was determined by normal phase HPLC analysis comparing with ␣-Toc, -Toc, ␥-Toc, and ␦-Toc standards, and verified by mass spectra, 1H-NMR, and microanalysis. The isolated ester was directly collected in isopropyl ether containing 3% HCl dioxane solution, and the precipitate was collected and recrystallized from acetone to give the hydrochloride salt of d-␥-tocopheryl N,N-dimethylglycinate (␥-TDMG). Found: C, 70.89; H, 10.54; N, 2.60
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