Abstract
2R-γ-Tocotrienol (γ-T3) is currently receiving attention because it has beneficial effects not observed with α-tocopherol. To achieve the effective delivery of γ-T3, we synthesized three kinds of ester derivatives of γ-T3 and evaluated their use as hydrophilic prodrugs for γ-T3 in vitro and in vivo. 2R-γ-Tocotrienyl N,N-dimethylamino-acetate hydrochloride (compound 3) was a solid compound, with high solubility and stability in water, and was converted to γ-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 γ-T3. The bioavailability (plasma level) after intravenous administration was 82.5 ± 13.4% and 100 ± 11.3% for 3 and γ-T3 in surfactant, respectively, and the availability in liver was 213 ± 47.6% and 100 ± 4.8% for 3 and γ-T3 in surfactant, respectively. Furthermore, the systemic availability of 2,7,8-trimethyl-2S-(β-carboxyethyl)-6-hydroxychroman (S-γ-CEHC), a metabolite of γ-T3, was 78.6% for compound 3, 47.1% for γ-T3 in surfactant, and 100% for racemic γ-CEHC. Based on these results, we identified compound 3 as the most promising water-soluble prodrug of γ-T3 and two-step prodrug of S-γ-CEHC.
Footnotes
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↵1 Current affiliation: Division of Bio-Analytical Chemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
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↵2 Current affiliation: Research Institute of Pharmaceutical Sciences, Musashino University, Tokyo, Japan.
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doi:10.1124/dmd.106.014365.
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ABBREVIATIONS: γ-T3, R-γ-tocotrienol; S-γ-CEHC, 2,7,8-trimethyl-2S-(β-carboxyethyl)-6-hydroxychroman; R-γ-CEHC, 2,7,8-trimethyl-2R-(β-carboxyethyl)-6-hydroxychroman; MS, mass spectroscopy; N-t-boc, N-t-butyloxycarbonyl; γ-T3-H, γ-T3 solubilized with water containing 10% (w/v) polyoxyethylene hydrogenated castor oil and 15% (v/v) propylene glycol; AUC, area under the concentration-time curve; MRT, mean residence time; Cmax, maximum concentration; Tmax, time at the maximum concentration.
- Received December 21, 2006.
- Accepted May 23, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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