Specificity of esterases and structure of prodrug esters: reactivity of various acylated acetaminophen compounds and acetylaminobenzoated compounds

Abstract

The relative rates of enzymatically catalyzed hydrolysis of various esters of p-acetylaminobenzoic acid (APAB) and variously acylated acetaminophen (APAP) derivatives were measured. Neutral, anionic, and cationic esters were examined. The enzyme sources adopted were rat intestinal homogenate, rat liver homogenate, rat plasma, and a partly purified commercial enzyme. In both APAB and APAP esters, neutral esters were the most sensitive of the enzyme sources examined, and the sensitivity was due to the carbon chain length. The APAB esters were enzymatically more stable than the APAP esters. The relative rates of hydrolysis of these esters varied depending on the enzyme source. The ability of structure recognition was good in rat intestinal homogenate, but weak in rat plasma. These results suggest that ester prodrugs can be designed to cleave preferentially at selected sites along the pathway between absorption and disposition in the body.