BIOPHARMACEUTICAL STUDIES ON DRUG CONJUGATED-METABOLITE INTERACTIONS .3. EFFECT OF ACETAMINOPHEN SULFATE AND ITS POSITIONAL ISOMERS ON THE PHARMACOKINETICS OF ACETAMINOPHEN IN RATS/

The effect of three positional isomers, o-, m- and p-acetylaminophenyl sulfate (AOAPS, AMAPS and APAPS (acetaminophen sulfate), respectively ), on the pharmacokinetics of acetaminophen (APAP) was investigated in rats. All of the intravenously administered positional isomers were r apidly eliminated from plasma, and approximately 80% of the dose was e xcreted in an unchanged form in the urine within 4 h, while biliary ex cretions represented a small percent of the doses. Following the intra venous bolus injection of APAP, plasma elimination of APAP was acceler ated and the distribution volume of APAP was increased under a steady state concentration (about 10 mu g APAP eq/ml) of AOAPS or APAPS, but not AMAPS, as compared with saline infusion. Total body clearances of APAP sere increased from 18.3 ml/min/kg for the control to 23.9 and 26 .9 ml/min/kg for AOAPS and APAPS coadministration, respectively. AOAPS and APAPS competitively displaced the serum protein binding of APAP, while AMAPS had little effect. The distribution volume of unbound APAP was anomalously increased by APAPS, while it was not affected by AOAP S or AMAPS. Tissue-to-plasma concentration ratios of APAP were signifi cantly increased by APAPS in the liver, kidney and brain, while they w ere only slightly increased by AOAPS. It was suggested that APAPS has not only the displacing activity of serum protein binding but also oth er specific effectiveness on the distribution of APAP.