Biopharmaceutical studies on drug/conjugated-metabolite interactions. II. 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 examined in rats. Following the i.v. bolus administration of APAP with APAPS, 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 the urine and bile in 4 h as APAP and its conjugated metabolites, APAPS and acetaminophen glucuronide, were significantly decreased. On the other hand, following the i.v. bolus administration of APAP under the steady-state concentration of APAPS, the distribution volume and total body clearance of APAP were significantly increased. Competitive displacement in serum protein binding of APAP by APAPS was ascertained in vitro 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 protein binding of APAP. It was speculated that the pharmacokinetics of APAP was partly interacted with APAPS by the displacement of serum protein binding.