Blood Concentration Profiles of Acetaminophen following Oral Administration of Fatty Acid Esters of Acetaminophen with Pancreatic Lipase to Dogs

Abstract

Fatty acid esters of acetaminophen were administered orally to dogs, and blood concentrations of acetaminophen were determined at various time intervals. Blood concentrations of acetaminophen following oral administration of a short chain ester, p‐acetamidophenyl acetate, were not significantly different from those found using acetaminophen. Blood concentrations of acetaminophen following oral administration of intermediate hydrocarbon chain‐length compounds were less than those of the control at 1 and 3hr postdosing. There appears to be a direct relationship between the in vitro hydrolysis rates and the blood concentration in vivo. Concomitant oral administration of acetaminophen derivatives, pancreatic lipase, and calcium salts resulted in an increase in the blood levels of acetaminophen as compared to administration of the esters alone. Calcium carbonate was included as a source of calcium ion to activate the lipase involved in the hydrolysis of the fatty acid esters. A combination of p‐acetamidophenyl acetate, p‐acetamidophenyl dodecanoate, pancreatic lipase, and calcium carbonate was shown to achieve a prolonged release of acetaminophen. p‐Acetamidophenyl acetate was thought to provide the initial release of acetaminophen; p‐acetamidophenyl dodecanoate, being hydrolyzed more slowly, provided the prolonged release, which maintained therapeutic blood concentrations for 13hr following a single dose of the combination in dogs.