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

Abstract

1. The degree of liver damage observed 48 h after administration of ¹⁴C ring-labelled 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.

2. With increasing doses of paracetamol, urinary excretion of the glucuronide and sulphate conjugates reached a plateau, whereas the output of cysteine and mercapturic acid conjugates increased markedly.

3. The degree of covalent binding at 48 h was proportional to the rate of urinary elimination of these two latter conjugates in the first 24 h after dosing.