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 synthesized 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 studied in isotonic phosphate buffer, rat plasma, human plasma, and rat liver homogenate at 37 degrees C. The hydrolysis of the esters was proved to be catalyzed by liver esterases. The susceptibility of the esters to undergo liver esterase hydrolysis was affected by the structure of the amino functionality and size of the acyl moiety on the promoiety. The N-methylaminoacetyl and N,N-dimethylaminoacetyl esters of d-alpha-tocopherol were more rapidly hydrolyzed than d-alpha-tocopheryl acetate, a commercially available d-alpha-tocopheryl ester. These results suggested that the salts of the N-methylaminoacetyl and N,N-dimethylaminoacetyl esters are promising prodrug candidates of d-alpha-tocopheryl for parenteral use.
Takata
J
J
Faculty of Pharmaceutical Sciences, Fukuoka University, Japan.
Karube
Y
Y
Nagata
Y
Y
Matsushima
Y
Y
D000818:Animals; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D010710:Phosphates / Q000378:metabolism; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry*; D051381:Rats; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet; D014810:Vitamin E / Q000138:chemical synthesis / Q000737:chemistry*
D002264:Carboxylic Acids; D010710:Phosphates; D011355:Prodrugs; D014810:Vitamin E