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-tocophe rol were in a previous in vitro study identified as prodrug candidates for a parenteral form of d-alpha-tocopherol. The disposition of d-alp ha-tocopheryl N,N-dimethylaminoacetate hydrochloride (TDMA), the most potential candidate for the prodrug, after a single intravenous admini stration was investigated and compared with that of the d-alpha-tocoph eryl 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 (lipopolysaccha ride (LPS))-induced liver lipid peroxidation,vas also investigated in mice, The plasma and liver levels of alpha-tocopherol (Toe) were incre ased rapidly after i.v. administration of the prodrug, The distributio n of Toc and TDMA in the plasma and the liver at 1 h was as follows; 2 .1 +/- 0.2 (plasma, Toe), 2.0 +/- 0.2 (plasma, TDMA), 32.8 +/- 2.9 (li ver, Toe), and 35.3 +/- 6.5% of dose (liver, TDMA). The rapid and live r-selective uptake and liver-esterase specific regeneration characteri stics of the prodrug enhance the delivery of Toc to liver, The liver a vailability 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 s ingle i.v. postadministration of TDMA (over 10 mg/kg equivalent for To e), These results indicated that the water-soluble and liver-esterase hydrolyzable derivative of Toc was a potential candidate for a parente ral prodrug which can thus achieve the systemic liver-specific deliver y of Toe. 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.