Chemical and Enzymatic Degradation of Ganciclovir Prodrugs: Enhanced Stability of the Diadamantoate Prodrug Under Acid Conditions

Publisher Website
Google Scholar
Abstract
We report the chemical and enzymatic hydrolysis of two hydrophobic prodrugs of ganciclovir (3 = dipropionate ester; 4 = diadamantoate ester). Both prodrugs undergo hydrolysis showing a pH dependence of kobs = kH+ aH+ + ko + kHO-aHO− and a pH of maximum stability near pH 5. Only 4 exhibited a shelf life (t90) greater than 2 years. Compound 4 reacts significantly slower than ganciclovir in acidic media, even though the adamantyl esters provide additional reaction sites (which would be expected to increase the rate of degradation) that are distally removed from the guanine ring system, offering negligible steric or electronic substituent effects. Both 3 and 4 hydrolyzed in tissue homogenate, where kobs followed liver > intestine ≫ skin. Based on these findings of chemical stability, lipophilicity, and acceptable rate of enzymatic cleavage by skin es-terases, 4 meets several of the criteria required for the topical sustained delivery of ganciclovir.

This publication has 14 references indexed in Scilit: