Water-soluble prodrug of vitamin E for parenteral use and its effect on endotoxin-induced liver toxicity.

The acid salts of aminoalkanecarboxylic acid esters of d-alpha-tocopherol were in a previous in vitro study identified as prodrug candidates for a parenteral form of d-alpha-tocopherol. The disposition of d-alpha-tocopheryl N,N-dimethylaminoacetate hydrochloride (TDMA), the most potential candidate for the prodrug, after a single intravenous administration was investigated and compared with that of the d-alpha-tocopheryl acetate (TA) and dl-alpha-tocopherol, solubilized with HCO-60, in order to establish the utility as a prodrug for i.v. administration. The preventive effect of the prodrug against endotoxin (lipopolysaccharide (LPS))-induced liver lipid peroxidation was also investigated in mice. The plasma and liver levels of alpha-tocopherol (Toc) were increased rapidly after i.v. administration of the prodrug. The distribution of Toc and TDMA in the plasma and the liver at 1 h was as follows; 2.1 +/- 0.2 (plasma, Toc), 2.0 +/- 0.2 (plasma, TDMA), 32.8 +/- 2.9 (liver, Toc), and 35.3 +/- 6.5% of dose (liver, TDMA). The rapid and liver-selective uptake and liver-esterase specific regeneration characteristics of the prodrug enhance the delivery of Toc to liver. The liver availability of Toc after i.v. administration of TDMA, TA and Toc were 116, 50 and 100%, respectively. The elevation of liver lipid peroxide induced with LPS was significantly suppressed to a normal range by a single i.v. postadministration of TDMA (over 10 mg/kg equivalent for Toc). These results indicated that the water-soluble and liver-esterase hydrolyzable derivative of Toc was a potential candidate for a parenteral prodrug which can thus achieve the systemic liver-specific delivery of Toc. Such effective and selective delivery of Toc into the liver can therefore lead to enhanced pharmacological efficacy against liver oxidative injury associated with free radicals.