Dose-dependent elimination kinetics of theophylline.

There are an increasing number of clinical and experimental studies appearing in the literature suggesting that the elimination kinetics of theophylline may be dose-dependent in man. Evidence of nonlinearity includes observations that steady-state serum theophylline concentrations may increase disproportionately with increases in dose and that the elimination half-life of theophylline after multiple doses is longer than after single doses. Theophylline is apparently eliminated by parallel Michaelis-Menten and first-order kinetics. Although no specific studies of theophylline metabolism have been carried out to determine the causes of nonlinearity, it would appear that 1-demethylation of theophylline is a potentially saturable metabolic pathway. Dietary methylxanthines or their metabolites may influence the rate of elimination of theophylline and contribute to the causes of nonlinearity. Until the elimination kinetics of theophylline have been studied in more detail as a function of dose, it would seem prudent to increase doses of theophylline cautiously to minimise the risks of adverse side effects which might be associated with unexpected accumulation of theophylline.