The effects of hepatic and renal damage on paracetamol metabolism and excretion following overdosage. A pharmacokinetic study.

1. The kinetics of paracetamol metabolism and excretion were studied in 41 patients following overdosage. Acute hepatic necrosis developed in 23 patients and in 3 of these acute renal failure also occurred. Two patients died in hepatic failure.2. Paracetamol metabolism was impaired in the patients with liver damage. The plasma half-life of the unchanged drug was significantly prolonged, and the ratio of the plasma concentrations of unchanged to conjugated paracetamol was significantly higher than in the patients without liver damage.3. Paracetamol and its conjugates were rapidly excreted in the urine. However, excretion was slower in patients with liver damage and a higher proportion was excreted unchanged.4. The renal clearance of unchanged (but not conjugated) paracetamol was related to the urine flow rate. However, forced diuresis is of no practical value and is contraindicated on clinical grounds. There was no correlation between urine pH and clearance of unchanged or conjugated drug.5. In patients with hepatic necrosis there was a marked decrease in the overall elimination rate constant which could be accounted for by decreased metabolite formation. Except in patients with acute renal failure, the urinary excretion rate constants were similar to those observed in patients without liver damage.