1 Paracetamol metabolism was investigated in eight healthy males, eight healthy females and eight healthy females receiving oral contraceptive steroids (OCS). 2 Paracetamol clearance was 22% greater in males compared to the control female group. This difference was entirely due to increased activity of the glucuronidation pathway in males, there being no sex-related differences in the sulphation or oxidative metabolism of paracetamol. 3 Paracetamol clearance in females using OCS was 49% greater than in the control females. Glucuronidation and oxidative metabolism were both induced in OCS users (by 78% and 36% respectively) but sulphation was not altered. 4 Although sex-related differences in paracetamol metabolism are unlikely to be of clinical importance, induction of paracetamol metabolism by OCS may have clinical and toxicological consequences.

Acetaminophen metabolism and clearance after a single 1 gm oral dose of the drug was investigated in 12 healthy men, six of whom were cigarette smokers, and in six men who were receiving anticonvulsant drugs for epilepsy. The 12 healthy subjects were studied before and after 1 wk of pretreatment with cimetidine (1 gm/day) or sulfinpyrazone (800 mg/day). There was no significant difference in acetaminophen clearance (ClAP) between nonsmokers and smokers; cimetidine pretreatment had no effect on ClAP. Neither cigarette smoking nor cimetidine pretreatment had a significant effect on any of the metabolic pathways of acetaminophen. In contrast, sulfinpyrazone pretreatment increased ClAP by 23% (from 5.70 +/- 0.21 to 7.00 +/- 0.39 ml/min/kg) and ClAP was 46% greater in the epileptic subjects who received anticonvulsant drugs than in the control group (8.32 +/- 0.45 and 5.70 +/- 0.21 ml/ml/kg). In both cases the increase in ClAP was a result of induction of acetaminophen glucuronidation and oxidation; clearance of the glucuronic acid conjugate was 26% and 59% greater and clearance of the glutathione-derived conjugates (reflecting the activity of the oxidative pathway) was 43% and 60% greater in the groups given sulfinpyrazone and anticonvulsants, respectively.

The route of formation of 1-methyluric acid (1MU) from theophylline has been investigated by i.v. administration of 1-methylxanthine (1MX) before and after allopurinol treatment and of 1,3-dimethyluric acid (1,3DMU) to healthy male volunteers. 1,3DMU was recovered unchanged in urine and was not demethylated to 1MU. By contrast after administration of 1MX the major part of the dose was recovered as 1MU. After allopurinol this was reversed with most of the 1MX dose being excreted unchanged and only a minor amount as 1MU. The results show that 1MU derived from theophylline is formed by an initial 3-demethylation to 1MX and then a rapid xanthine oxidase mediated 8-oxidation. No 1MU is formed by 3-demethylation of 1,3DMU.