Pharmacokinetic study of the fate of acetaminophen and its conjugates in rats

Abstract

Pharmacokinetic studies of the fate of acetaminophen and its major metabolites, acetaminophen sulfate (AS) and acetaminophen glucuronide (AG), were made in rats. The rates of conjugate formation were calculated by deconvolution. The Michaelis-Menten equation gave maximum velocity and Michaelis constant (K_m)values of 4.92 μ-mol/min/kg and 109 μM for AS formation, and 2.76 μmol/min/kg and 915 μM for AG formation. However, AG formation showed approximately first-order behavior in the present dose range because of its large K_m value. The disposition of acetaminophen could be described by a two-compartment model with simultaneous first-order and Michaelis-Menten type elimination kinetics for AS formation. Curve fitting of the data based on this model was successfully done for doses of up to 1058 μmol/kg, suggesting that sulfation proceeds without depletion of sulfate in the blood at least up to this dose. The disposition of AS could be described by a two-compartment model and was apparently dose-independent over an 8-fold dose range. Although a slight dose dependence in the elimination of AG was suggested over a 16-fold dose range, for the purpose of the present study, it was assumed that the disposition of AG is approximately linear. The excretion of AS in the bile was negligibly small, whereas a considerable amount of AG was excreted into the bile. The results following intraduodenal injection of AS or AG indicated that AS or AG was hydrolyzed by the microflora and the liberated acetaminophen was reabsorbed, confirming enterohepatic circulation of the conjugates. This was consistent with the urinary metabolite excretion patterns observed after acetaminophen injection in normal and bile fistula rats. Based on the kinetic parameters obtained, the plasma concentrations of AS and AG after acetaminophen injection were simulated, and a fairly good agreement was obtained between calculated and observed values at the dose of 264.6 μmol/kg. Although the urinary metabolite excretion pattern differs from that of humans, the kinetic parameters obtained for rats were similar to those for humans in some respects, suggesting that the rat might be useful as a model animal to predict human data.