Metabolism of paracetamol and phenacetin in relation to debrisoquine oxidation phenotype

The metabolism of paracetamol and phenacetin has been studied in subjects previously phenotyped as either extensive or poor metabolisers of debrisoquine (EM and PM, respectively), in order to examine the relationship between phenacetin and paracetamol activation and debrisoquine oxidation status. In separate experiments, paracetamol and phenacetin were administered orally to groups of 5 EM and 5 PM subjects, and the excretion of metabolites measured for 24 h. There were no differences between EM and PM subjects in the excretion of metabolites. After phenacetin, 0.82 of the dose was recovered in urine, mostly as paracetamol glucuronide (51%) and sulphate (30%), with smaller amounts of free paracetamol (4%) and the mercapturate (5%) and cysteine conjugates (5%), 2-hydroxyphenetidine (5%) and N-hydroxyphenacetin (0.5%). Following paracetamol, 0.87 of the dose was recovered, with similar proportions of paracetamol-derived metabolites. It is concluded that the debrisoquine oxidation phenotype is unrelated to either the metabolic activation of phenacetin and paracetamol, or to their overall metabolic clearance.