Determinants of acetaminophen metabolism: Effect of inducers and inhibitors of drug metabolism on acetaminophen's metabolic pathways

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Abstract
Acetaminophen metabolism and clearance after a single 1 g oral dose of the drug was studied in 12 healthy men, 6 of whom were cigarette smokers and in 6 men who were receiving anticonvulsant drugs for epilepsy. The 12 healthy subjects were studied before and after 1 wk of pretreatment with cimetidine (1 g/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. Sulfinpyrazone pretreatment increased ClAP by 23% (from 5.70 .+-. 0.21 to 7.00 .+-. 0.39 ml/min per 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/min per 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.