Elimination kinetics of theophylline and its major metabolites were investigated in 14 healthy adults in single-dose studies and in a multiple-plateau study. The plasma concentrations of theophylline and the metabolites 3-methylxanthine (3-MX), 1-methyluric acid (1 MU), and 1,3-dimethyluric acid (13-MU) were monitored to about 0.020 mg/l and became convex descending at concentrations below 1 mg/l after single theophylline doses. Renal clearance values of 3-MX, 1-MU, and 13-MU were 12.0 +/- 1.3 l/hr, 22.5 +/-1.5 l/hr, and 22.6 +/- 1.6 l/hr. Metabolite formation of the three metabolites followed Michaelis-Menten kinetics and became capacity limited within the therapeutic range of theophylline. The apparent Michaelis-Menten parameters for each metabolite formation step were obtained by computer fitting. For the formation of 3-MX. 1-MU, and 13-MU, the approximate mean maximal rate of formation of metabolite (Vmax) values were 5 mg/hr, 13 mg/hr, and 34 mg/hr and the apparent concentration of theophylline at which metabolite formation rate is half of Vmax values were 2.7 mg/l, 9.3 mg/l, and 14.2 mg/l. The elimination of each of the metabolites was rate limited by the elimination of theophylline. Concomitant measurement of theophylline urinary excretion rate showed the renal clearance of the drug to be highly dependent on urine flow. The initial renal clearance, elevated due to diuresis, and the distribution phase tended to counterbalance the saturable metabolic formation clearance after a single therapeutic dose. Therefore, plasma theophylline concentration decayed roughly in a log-linear fashion and the convex-descending curve, characterized by capacity-limited elimination kinetics, was observed only at lower concentrations.