Paracetamol metabolism in man
The absorption, metabolism and elimination of paracetamol was investigated in healthy subjects after therapeutic doses and also in patients with paracetamol overdosage, some of whom developed liver damage. Paracetamol disposition was also studied in relation to treatment with N-acetylcysteine (NAG),cysteamine and methionine, which were used to prevent paracetamol hepatotoxicity. Sensitive, specific and reproducible analytical methods were developed for the estimation of paracetamol and its sulphate, glucuronide, mercaoturic acid and cysteine conjugates in plasma and urine. These methods, which employed high-performance liquid chromatography, were significant improvements on existing procedures, especially in terms of simplicity and total assay times. N Following a therapeutic dose, absorption and metabolism of paracetamol was rapid and essentially complete. Paracetamol metabolism showed wide but reproducible individual variation. NAC had little appreciable effect on paracetamol elimination after a therapeutic dose but may have delayed absorption. The renal clearance of paracetamol was very low, indicating extensive renal tubular reabsorption whereas that of the sulphate and glucuronide conjugates was high, suggesting active tubular secretion. The mercapturic acid and cysteine conjugates were probably also actively secreted since they were not measureable (< C 1 fig/ml) in plasma. Renal clearance of paracetamol and its conjugates wan not appreciably altered at high plasma concentrations following overdosage. Following overdosage, paracetamol elimination was rapid but prolonged relative to therapeutic dosage, particularly in patients who developed severe liver damage. The proportions of overall drug recovery excreted as the sulphate and glucuronide conjugates were lower and higher respectively, indicating saturation of sulphate conjugation. Also, the proportion excreted as the mercapturic acid and cysteine conjugates was increased in patients who developed severe liver damage. Early treatment of paracetamol overdosage with NAG was associated with reduced hepatotoxicity, enhanced formation of paracetamol sulphate, increased excretion of the mercapturic acid and cysteine conjugates and decreased plasma paracetamol half-life. Cysteamine treatment also resulted in reduced toxicity and enhanced formation of paracetamol sulphate but decreased excretion of the mercapturic acid and cysteine conjugates. Methionine had little appreciable effect on the metabolism of paracetamol and was the least effective treatment. NAG probably protects the liver by "unsaturating" sulphate conjugation and assisting removal of the toxic intermediate metabolite of paracetamol by direct conjugation and/or repleting hepatic glutathione. Cysteamine apparently inhibits the microsomal oxidation of paracetamol to its toxic intermediate metabolite.