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

Institute of Liver Studies, King's College Hospital and King's College School of Medicine and Dentistiy, Denmark Hill, London SE5 9RS

Paul Thuluvath

and Gastrointestinal Unit, Charing Cross Hospital, Fulham Palace Road, London W6 8RF, UK

Roger Williams

Institute of Liver Studies, King's College Hospital and King's College School of Medicine and Dentistiy, Denmark Hill, London SE5 9RS

Iain M. Murray-Lyon

and Gastrointestinal Unit, Charing Cross Hospital, Fulham Palace Road, London W6 8RF, UK

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 with out 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 conju gates (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 pharmaco- genetic deficiencies in cytochrome P450 isoenzymes per sisting despite chronic alcohol consumption (40—60 g per day) or resulted from inhibition of paracetamol acti vation by concomitant ingestion of aminophylline.

Key Words: paracetamol (acetaminophen) • paracetamol hepatotoxicity • paracetamol absorption • paracetamol sul phation • paracetamol monooxygenation

Human & Experimental Toxicology, Vol. 14, No. 1, 8-12 (1995)
DOI: 10.1177/096032719501400102


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