Conjugation kinetics of acetaminophen by the perfused rat liver preparation

Sulfate conjugation of acetaminophen was studied in the perfused rat liver preparation. Varying input concentrations of unlabeled acetaminophen (0.22 to 6.0 μg/ml or 1.5 to 40 μM) were added in a stepwise fashion once-through the liver preparation at a flow rate of 10 ml/min. For the concentration range tested, acetaminophen sulfate conjugate remained the only detectable metabolite in perfusate plasma. Other metabolites such as the glucuronide and the glutathione conjugates, however, were detected only in bile and, together with the sulfate conjugate and unconjugated acetaminophen, constituted 5 per cent of the total administered dose. Hepatic elimination of acetaminophen in the formation of sulfate conjugate was apparently maximal at input concentrations ⩽ 1.0 μg/ml (6.7 μM) and could be viewed as mediated via a uni-enzyme system. Sulfate conjugation also decreased with preloading of the liver, especially with high concentrations of acetaminophen. A plot of the ratio of the steady-state output concentrations of drug to metabolite versus the reciprocal of drug extraction ratio, which might prove useful in the prediction of metabolite concentrations in the liver, was introduced.