The influences on theophylline metabolism are multifactorial, resulting in significant inter- and intrapatient variability in drug responsiveness. Clinical investigations with adult patients have demonstrated the influence of diet on theophylline metabolism following a single drug dose. We have undertaken this study to examine the effect of nutritional factors on theophylline pharmacokinetics in 14 asthmatic children receiving the drug on a chronic basis. For 12-day periods each patient received three separate diets with different proportions of protein and carbohydrate but with constant fat and caloric intake. Significant differences were detected for theophylline half-life, apparent volume of distribution, and metabolic clearance rate. The high-protein diet markedly shortened the drug-elimination half-life relative to a normal diet, and high carbohydrate significantly increased it (both p less than 0.001). Other kinetic parameters confirmed this pattern. Our findings in children clearly establish that nutritional factors have a significant environmental influence on theophylline metabolism during the drug's steady-state pharmacokinetics.