BIOPHARMACEUTICAL STUDIES ON DRUG CONJUGATED-METABOLITE INTERACTIONS .2. EFFECT OF ACETAMINOPHEN SULFATE ON PHARMACOKINETICS OF ACETAMINOPHEN IN RATS/

The effect of conjugated-metabolite, acetaminophen sulfate (APAPS), on the pharmacokinetics of its parent drug, acetaimnophen (APAP), was ex amined in rats. Following the i.v. bolus administration of APAP with A PAPS, the plasma elimination of APAP was delayed and the distribution volume of APAP was increased at the APAPS coadministration with 60 mg APAP equivalent per kg (eq/kg). The percentages of dose excreted in th e urine and bile in 4 h as APAP and its conjugated metabolites, APAPS and acetaminophen glucuronide, were significantly decreased. On the ot her hand, following the i.v. bolus administration of APAP under the st eady-state concentration of APAPS, the distribution volume and total b ody clearance of APAP were significantly increased. Competitive displa cement in serum protein binding of APAP by APAPS was ascertained in vi tro and in vivo. A part of the conflict between the bolus and infusion experiment may be explained by the changes in the distribution volume of APAP contributed to the APAPS concentration-dependent serum protei n binding of APAP. It was speculated that the pharmacokinetics of APAP was partly interacted with APAPS by the displacement of serum protein binding. (C) 1997 Elsevier Science B.V.