The influence of mexiletine (200 mg every 8 hours) on theophylline metabolism was studied in young male (n = 7) and female (n = 8) nonsmokers. A single-dose study of theophylline kinetics was performed at baseline and after 5 days of mexiletine treatment. With mexiletine the plasma clearance of theophylline decreased from 33.5 +/- 2.6 (mean +/- SEM) to 17.9 +/- 1.0 ml/kg per hour in the female group (p less than 0.001) and from 32.3 +/- 2.6 to 19.3 +/- 1.3 ml/kg per hour in the male group (p less than 0.001). The elimination half-life was prolonged by 74% and 103% in the male and female groups, respectively. Mexiletine decreased the formation of all theophylline metabolites in both groups. Within each group, the demethylation pathways were affected more than the hydroxylation pathway. These data indicate that mexiletine is a potent inhibitor of theophylline metabolism. This effect is not influenced by gender. Concurrent administration of these drugs may require a dose reduction of theophylline by as much as 50% to minimize the risk of toxicity.