PRODRUGS OF VITAMIN-E .1. PREPARATION AND ENZYMATIC-HYDROLYSIS OF AMINOALKANECARBOXYLIC ACID-ESTERS OF D-ALPHA-TOCOPHEROL

Nine aminoalkanecarboxylic acid esters of d-alpha-tocopherol were synt hesized and evaluated as potential water-soluble prodrugs suitable for parenteral administration. The hydrochloric acid salts of the esters were soluble in water. The kinetics of hydrolysis of the esters was st udied in isotonic phosphate buffer, rat plasma, human plasma, and rat liver homogenate at 37 degrees C. The hydrolysis of the esters was pro ved to be catalyzed by liver esterases. The susceptibility of the este rs to undergo liver esterase hydrolysis was affected by the structure of the amino functionality and size of the acyl moiety on the promoiet y. The N-methylaminoacetyl and N,N-dimethylaminoacetyl esters of d-alp ha-tocopherol were more rapidly hydrolyzed than d-alpha-tocopheryl ace tate, a commercially available d-alpha-tocopheryl ester. These results suggested that the salts of the N-methylaminoacetyl and N,N-dimethyla minoacetyl esters are promising prodrug candidates of d-alpha-tocopher yl for parenteral use.