The pharmacokinetics of theophylline were studied in 6 healthy volunteers at rest, during light and moderate exercise and during exercise in a hot environment. Exercise was performed between 2 and 4 h after oral ingestion of theophylline in solution at a dose of 200 mg/m2 body surface. Significant prolongations of the half-life (t1/2) of the drug and reductions in its body clearance were observed during exercise to 30% of VO2, max both at 22 and 40 degrees C, as well as during exercise to 50% of VO2, max at 22 degrees C. t1/2 was (mean +/- SEM) 8.5 +/- 0.8, 8.0 +/- 1.0 and 7.2 +/- 1.0 h at the three exercise sessions, respectively, compared with 6.4 +/- 0.9 h at rest. Plasma clearances at the three exercise sessions were 0.70 +/- 0.09, 0.62 +/- 0.1 and 0.75 +/- 0.09 ml/min/kg, respectively, compared with 0.99 +/- 0.13 ml/min/kg at rest. The apparent volumes of drug distribution (Vd) decreased significantly at the 50% and the 30% exercise in the heat, suggestive of some dehydration. The areas under the concentration-time curves (AUC0-infinity) and the elimination rate constants (Kel) also changed significantly under the different experimental conditions. It is suggested that appropriate dose adjustments may have to be made in moderately active patients who are treated with theophylline.