Acetaminophen Prodrugs II: Effect of Structure and Enzyme Source on Enzymatic and Nonenzymatic Hydrolysis of Carbonate Esters

Abstract

Hydrolysis rates are reported for acetaminophen prodrugs with the structure CH3CONH-ϕ-OCOOR at pH 7.4 in phosphate buffer alone or containing 1% human plasma or serum from several animal species. The hydrolysis rates in buffer decreased as the electrophilic character of the R group decreased. Dilute plasma or serum accelerated the hydrolysis; and the number of carbon atoms, the degree of chain branching, aromaticity, and chlorine substitution in the R group variously affected the degree of acceleration. In general, the sera of small rodents (mouse, guinea pig, and rat) were more potent catalysts of the hydrolyses of all types of acetaminophen carbonates than that of other animals (cat, dog, sheep, and rabbit) or human plasma. Hydrolysis rates are reported for acetaminophen prodrugs with the structure CH3CONH-ϕ-OCOOR at pH 7.4 in phosphate buffer alone or containing 1% human plasma or serum from several animal species. The hydrolysis rates in buffer decreased as the electrophilic character of the R group decreased. Dilute plasma or serum accelerated the hydrolysis; and the number of carbon atoms, the degree of chain branching, aromaticity, and chlorine substitution in the R group variously affected the degree of acceleration. In general, the sera of small rodents (mouse, guinea pig, and rat) were more potent catalysts of the hydrolyses of all types of acetaminophen carbonates than that of other animals (cat, dog, sheep, and rabbit) or human plasma.