Metabolic basis for high paracetamol dosage without hepatic injury: a case study

1. Studies of paracetamol metabolism were performed in a 58-year-old female with rheumatoid arthritis who had consumed 15-20 g paracetamol daily for 5 years without developing liver damage and data were compared with results in seven normal volunteers. 2. After a test dose of 2 g paracetamol, the formation of paracetamol sulphate and glucuronide conjugates detected in plasma from the patient was delayed by around 2 h relative to values in normal volunteers and the proportion of sulphate conjugates excreted in urine was 1.5 to 2 times those in normal volunteers (52% vs 26-35% of dose, respectively). The fractional metabolite clearance of paracetamol to glutathione-derived conjugates (0.28 ml min-1 kg-1) in our patient was > 30% lower than in normal females. 3. A combination of slow paracetamol absorption, enhanced detoxication of paracetamol (by sulphation) and reduced metabolism to potentially cytotoxic metabolites may have reduced the risk of liver damage in this patient. The latter may have reflected pharmacogenetic deficiencies in cytochrome P450 isoenzymes persisting despite chronic alcohol consumption (40-60 g per day) or resulted from inhibition of paracetamol activation by concomitant ingestion of aminophylline.