Influence of phenytoin on theophylline clearance.

The influence of phenytoin on theophylline elimination was studied in six healthy, nonsmoking subjects who were not taking any other drugs. Subjects were given an intravenous infusion of theophylline (aminophylline), 5 mg/kg, and several blood specimens were drawn over the following 24 hr for theophylline concentration determination. Subjects then began a 2-wk course on oral phenytoin, 300 mg/day, and on day 15 were again challenged with theophylline. For each subject theophylline clearance (ClT) was greater when taking phenytoin (range 31% to 65%). Mean ClT of the six subjects was 45% greater when taking phenytoin than when not taking phenytoin. In one subject, 24-hr urine collections were obtained in the untreated and treated state for analysis of theophylline metabolites. These results showed a general increase in excretion for each of the three major theophylline metabolites in the phenytoin pretreated state compared to the control state. Results indicate that phenytoin increases theophylline elimination. Patients taking phenytoin may require larger theophylline doses than recommended to achieve therapeutic blood theophylline concentrations.