Prodrugs as drug delivery systems. 107. Synthesis and chemical and enzymatic hydrolysis kinetics of various mono- and diester prodrugs of N-acetylcysteine

Abstract

Abstract The systemic bioavailability of N -acetylcysteine (NAC) following oral administration is very low due to extensive first-pass metabolism by deacetylation, primarily in the gut. In an attempt to depress this metabolism and hence increase the systemic bioavailability various esters of NAC were synthesized and assessed as prodrug forms for the parent drug. The esters studied included alkyl esters, glycolamide esters and an acyloxymethyl ester formed at the carboxylic acid part of NAC as well as the S -benzoyl ester and various carboxylic acid esters thereof. An S -benzoyl carbamate ester was also studied. The pH-rate profiles for the hydrolysis of the derivatives were obtained at 37°C and interpreted in terms of hydrogen ion-, hydroxide ion- and water-catalyzed reactions. The hydrolysis of the oxy- and thioesters was enzymatically catalyzed by human and rat plasma as well as by rat liver and intestinal homogenate. The chemical and enzymic hydrolysis characteristics of the esters suggest that esterification of NAC at the carboxylic acid function or at the thiol group, or both, may be a potentially useful means to obtain prodrug forms of the drug for protecting it against intestinal deacetylation.