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Preparation and In Vivo Evaluation of a Water-Soluble Prodrug for 2R--Tocotrienol and as a Two-Step Prodrug for 2,7,8-Trimethyl-2S-(ß-carboxyethyl)-6-hydroxychroman (S--CEHC) in Rat

Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan (N.A., J.T., K.M., R.H., K.F., M.Y., To.F., Y.K.); and Department of Bio-Analytical Chemistry, Graduate School of Pharmaceutical Sciences, the University of Tokyo, Tokyo, Japan (Ta.F., A.H., K.I.)

2R--Tocotrienol (-T3) is currently receiving attention because it has beneficial effects not observed with -tocopherol. To achieve the effective delivery of -T3, we synthesized three kinds of ester derivatives of -T3 and evaluated their use as hydrophilic prodrugs for -T3 in vitro and in vivo. 2R--Tocotrienyl N,N-dimethylamino-acetate hydrochloride (compound 3) was a solid compound, with high solubility and stability in water, and was converted to -T3 by esterases in rat and human liver. Intravenous administration of 3 in rats led to a rapid increase in the plasma, liver, heart, and kidney levels of -T3. The bioavailability (plasma level) after intravenous administration was 82.5 ± 13.4% and 100 ± 11.3% for 3 and -T3 in surfactant, respectively, and the availability in liver was 213 ± 47.6% and 100 ± 4.8% for 3 and -T3 in surfactant, respectively. Furthermore, the systemic availability of 2,7,8-trimethyl-2S-(ß-carboxyethyl)-6-hydroxychroman (S--CEHC), a metabolite of -T3, was 78.6% for compound 3, 47.1% for -T3 in surfactant, and 100% for racemic -CEHC. Based on these results, we identified compound 3 as the most promising water-soluble prodrug of -T3 and two-step prodrug of S--CEHC.