Strategies in the design of solution-stable, water-soluble prodrugs III: influence of the pro-moiety on the bioconversion of 21-esters of corticosteroids.

Succinate esters and many other carboxylic acid esters utilized as water-soluble prodrugs have limited utility due to their aqueous solution instability. In an earlier study, a strategy for the design of solution-stable 21-carboxylic acid esters of corticosteroids was developed from a consideration of various physical organic factors which influence ester hydrolysis. Several 21-esters of methylprednisolone were synthesized, and their stability in aqueous solution was monitored to demonstrate the feasibility of the approach. In this study, the bioconversion of representative examples of 21-esters of methylprednisolone exhibiting shelf lives of greater than or equal to 2 years at 25 degrees C was monitored to evaluate their utility as prodrugs in comparison to a commercially marketed sodium succinate ester. Ester hydrolysis studies conducted in human and rhesus monkey serum suggest that derivatives having an anionic solubilizing moiety (sulfonate or carboxylate) are not hydrolyzed in serum, while compounds having a cationic (tertiary amino) solubilizing moiety are hydrolyzed rapidly by serum esterases. In vivo pharmacokinetic studies in rhesus monkeys were also conducted to compare the bioconversion rates and overall bioavailability of several solution-stable prodrugs with the 21-succinate ester. Derivatives having solution stability exceeding 2 years at 25 degrees C with a faster bioconversion rate and an overall bioavailability equal to or higher than that of the succinate ester have been identified. Relative bioavailability appears to be highly sensitive to the charge of the solubilizing pro-moiety and pro-moiety chain length.