Paracetamol Metabolism in the Rat: Relationship to Covalent Binding and Hepatic Damage

Abstract

The degree of liver damage observed 48 h after administration of 14C ring-labeled paracetamol (3-23 mmol/kg) to rats was proportional to the amount of a highly reactive metabolite retained in the liver, bound covalently to hepatocellular proteins. With increasing doses of paracetamol, urinary excretion of the glucuronide and sulfate conjugates reached a plateau; the output of cysteine and mercapturic acid conjugates increased markedly. The degree of covalent binding at 48 h was proportional to the rate of urinary elimination of these 2 latter conjugates in the first 24 h after dosing.