BIOPHARMACEUTICAL STUDIES ON DRUG CONJUGATED-METABOLITE INTERACTIONS .1. 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 acetam inophen (APAP), indispensable for the kinetic elucidation of drug/APAP S interactions, were examined in rats. Plasma elimination kinetics of APAPS after i.v. administration could be described by a two-compartmen t model with linear parameters to the dose. The deconjugation of intra venously administered APAPS, i.e., the formation of APAP, was recogniz ed in neither plasma, urine nor bile. Approx. 80% of intravenously adm inistered 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 pr ofiles of APAPS after oral administration showed two peaks, but the se cond one disappeared when the rat was pretreated with kanamycin sulfat e. However, APAPS permeation through the small- and the large-intestin al walls determined in situ was not altered after kanamycin treatment. High APAPS-hydrolyzing activities present in the cecal and colonic co ntents and the feces, but not in the small-intestinal contents, comple tely disappeared after kanamycin treatment. Thus, part of the orally a dministered APAPS was absorbed as the unchanged form from both the sma ll and large intestines, and considerable amounts of the remainder wer e absorbed from the large intestine as APAP after enzymatic hydrolysis by the intestinal microflora during transit through the lower bowel.