A comparative pharmacokinetic study of theophylline between the first and repeated oral administration and the assessment of clinical utility of theophylline test-dose concept were performed in 6 (study I) and 4 (study II) healthy male volunteers with different dosing schedules. In study I, although the average of theophylline systemic clearance (Clsys) was significantly (p less than 0.05) lower in the repeated dosing than in the first dosing, large intersubject variations were observed. Plasma free fatty acids which inhibit drug metabolizing enzyme activity were not influenced by theophylline chronic administration. In study II, the volunteers received oral multiple doses of a theophylline powder preparation to maintain 5 to 15 micrograms/ml plasma concentration on the basis of the pharmacokinetic parameters calculated from the single oral test-dose. A good prediction of the plasma concentration was observed only in one case and the maximum levels in the rest exceeded 20 micrograms/ml, a toxic concentration. Throughout the Studies, a stable Clsys was obtained in smokers, but the Clsys in non-smokers decreased by one third to a half during multiple dosing. These findings suggest that theophylline showed time-dependent pharmacokinetics and that test-dose concept for theophylline may not be applicable in all cases because of a large intersubject variation in the Clsys change between single and multiple dosing.