A new method for the investigation of inter-individual differences in drug metabolism

Inter-individual differences in rates of hepatic oxidation are due to a multiplicity of factors and are probably under polygenic control. The genetic influence in drug oxidation for a particular individual is reflected in their hepatic enzyme activity. We are studying a metabolic pathway which allows us to compare the enzymes involved in aliphatic and aromatic oxidation in man. Acetanilide and phenacetin are both metabolised to paracetamol in man, approximately 80 per cent of each compound being converted to paracetamol, which is found in plasma as the free and conjugated material, and which is excreted in the urine as the sulphate and glucuronide conjugate (Brodie and Axelrod, 1948, 1949). We have studied the C-oxidation of acetanilide-d5 and phenacetin in man following an equimolar dose of both compounds. Phenacetin is metabolised to paracetamol by oxidative de-alkylation and aromatic hydroxylation of acetanilide-d5 will produce paracetamol-d4. The hydroxylated metabolites are excreted as the glucuronide and sulphate (Figure 13.1). Using selected ion monitoring techniques, we can monitor the pharmacokinetics of the two forms of paracetamol and can thus compare the relative amounts of paracetamol produced by different individuals at the same time periods after dosing (Baty and Robinson, 1977). We have studied the biological isotope effects present in this system and in the de-alkylation of phenacetin labelled with five deuterium atoms in the ethyl group.