Paracetamol overdose in man: relationship between pattern of urinary metabolites and severity of liver damage

Abstract

The urinary excretion of paracetamol and its conjugates was studied, using a two dimensional thin layer chromatography system, in three volunteers after therapeutic (6-5-26-6 mmoles) doses of the drug, and in 30 patients admitted early after overdoses taken in suicidal attempts. In both volunteers and patients 85-100 per cent of the drug was excreted into the urine--almost entirely as conjugates--in the first 24 hours, which was before biochemical signs of liver damage had appeared. Higher quantities of paracetamol conjugates were recovered from patients who developed moderate of severe liver damage than those less severely affected, although correlations in individuals between quantity excreted and clinical outcome was poor. The pattern of individual paracetamol conjugates changed markedly the higher the ingested dose of the drug. Thus, the excretion of paracetamol sulphate reached a plateau as the administered dose was increased from 20-26-5 mmoles in the volunteers, whilst in patients who developed liver damage after overdose there was also a plateau in the excretion of the glucuronide conjugate. In the latter group, there was a greatly increased production of the cysteine and mercapturic acid conjugates of the drug. These are formed via a highly chemically reactive metabolite of the drug, which binds to glutathione, and if hepatic stores of the latter become depleted, binding will occur instead to hepatocyte macromolecules with ensuing liver damage.