Theophylline clearance was studied in normal healthy volunteers before and after chronic oral dosing. Oral theophylline clearance showed a significant decrease (P less than 0.001) from 59.3 +/- 6.48 ml/min (mean +/- s.e. mean, n = 10) to 48.0 +/- 6.4 ml/min. Steady-state intravenous clearance decreased by 26 +/- 2% from 55.1 +/- 7.7 ml/min to 41.0 +/- 5.96 ml/min (mean +/- s.e. mean, n = 6; P less than 0.001) at constant steady-state intravenous test concentrations (mean 15.0 +/- 1.6 micrograms/ml after chronic oral dosing), excluding significant concentration dependence. Extrapolation of acute clearance findings to maintenance requirement may not be valid even in the same individual, with theophylline therapy requiring on-going review beyond acute stabilisation.