Received for publication December 26, 2006.
Revised April 5, 2007.
Accepted for publication May 23, 2007.

Preparation and In Vivo Evaluation of a Water-soluble Prodrug for 2R--Tocotrienol and as a Two-step Prodrug for S--CEHC in Rat

Abstract

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 hydrophylic prodrugs for -T3 in vitro and in vivo. 2R--Tocotrienyl N,N-dimethylaminoacetate hydrochloride (compound 3) was a solid compound, with high solubility and stability in water, and 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) following 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-(-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.

Key words: antioxidants, bioavailability, drug delivery, prodrugs, vitamin E