Prodrugs of 2',3'-didehydro-3'-deoxythymidine

Six ester prodrugs of 2',3'-didehydro-3'-deoxythymidine (D4T) were synthesized, and their physicochemical properties were evaluated. Marked differences were observed. All of the prodrugs were chemically stable within the pH range 2-7. Hydrolysis of these esters was observed in all cases for four rat enzyme systems (plasma, liver, duodenum, and kidney), with D4T being regenerated. D4T or the prodrug was administered orally to rats, and the plasma concentrations of D4T and a corresponding prodrug were measured. The half-life of D4T after intravenous administration was 35.9 min. The half-life calculated from the terminal phase and the maximum concentration in plasma following oral administration of D4T were 35.9 min and 48.4 microM, respectively. After oral prodrug administration (with water or olive oil as a solvent), though none of the prodrugs was detected in plasma except for 5'-hemisuccinyl D4T and 5'-hemiglutaryl D4T with olive oil as a solvent, retention time of plasma D4T concentration was extended and the elevated D4T concentration in plasma decreased.