Biopharmaceutical studies on drug/conjugated-metabolite interactions. I. Fate of acetaminophen sulfate, a major conjugated metabolite of acetaminophen, in rats

The plasma elimination kinetics and intestinal absorption kinetics of acetaminophen sulfate (APAPS), a major conjugated metabolite of acetaminophen (APAP), indispensable for the kinetic elucidation of drug/APAPS interactions, were examined in rats. Plasma elimination kinetics of APAPS after i.v. administration could be described by a two-compartment model with linear parameters to the dose. The deconjugation of intravenously administered APAPS, i.e., the formation of APAP, was recognized in neither plasma, urine nor bile. Approx. 80% of intravenously administered APAPS was excreted as the unchanged form in the urine in 4 h while biliary excretion was only a few percent of the dose. Plasma profiles of APAPS after oral administration showed two peaks, but the second one disappeared when the rat was pretreated with kanamycin sulfate. However, APAPS permeation through the small- and the large-intestinal walls determined in situ was not altered after kanamycin treatment. High APAPS-hydrolyzing activities present in the cecal and colonic contents and the feces, but not in the small-intestinal contents, completely disappeared after kanamycin treatment. Thus, part of the orally administered APAPS was absorbed as the unchanged form from both the small and large intestines, and considerable amounts of the remainder were absorbed from the large intestine as APAP after enzymatic hydrolysis by the intestinal microflora during transit through the lower bowel.