Cigarette smoking and theophylline metabolism: effects of phenytoin

The induction of theophylline clearance by phenytoin was investigated in 12 young male subjects (six nonsmokers and six cigarette smokers). Each subject received intravenous theophylline to determine baseline pharmacokinetics. This was followed by an intravenous loading dose of phenytoin sodium and oral maintenance dosing for 2 weeks, after which the intravenous theophylline study was repeated. Phenytoin concentrations were similar in nonsmokers (10.8 +/- 2.0 micrograms/ml) and smokers (11.5 +/- 0.9 micrograms/ml). Control theophylline elimination half-life was 35% less and clearance 88% greater in smokers than in nonsmokers. The proportionate changes in half-life (26.8% +/- 5.6% in smokers and 25.8% +/- 3.5% in nonsmokers) and clearance (48.0% +/- 10.1% in smokers and 39.7% +/- 7.2% in nonsmokers) as the result of phenytoin induction were similar in both groups. These results demonstrate that the induction of theophylline clearance by phenytoin is additive to that caused by cigarette smoking and provide support for the suggestion that theophylline metabolism is influenced by multiple polymorphisms.