Theophylline plasma clearance (Clp) and clearance to its metabolites ( Clm ), as well as antipyrine saliva clearance ( Clsal ) and its Clm were compared in a crossover study in 25 healthy subjects. They were selected with regard to smoking status (nine smokers, 16 nonsmokers) and oxidation phenotype of debrisoquine and sparteine (six poor metabolizers [PMs] and 19 extensive metabolizers [EMs]). Clm of theophylline (1,3-dimethyluric acid, 1-methyluric acid, and 3-methylxanthine) correlated (r greater than or equal to 0.92) to each other and to total theophylline Clp (r greater than or equal to 0.97). Smokers had higher Clm to all metabolites, particularly by the N-demethylation pathways. After correction for the effect of smoking, there was no difference between EMs and PMs with regard to theophylline Clp or Clm . Antipyrine clearances by EMs and PMs ( Clsal and Clm of 4-OH-antipyrine, 3-OH- methylantipyrine , or norantipyrine) also did not differ. Antipyrine Clsal and Clm correlated to theophylline Clp (r between 0.50 and 0.69). It is concluded that theophylline metabolism (N-demethylations and C-oxidation) is not under the same genetic control as sparteine and debrisoquine oxidations, and that there may be a partial overlap in factors that regulate the metabolism of theophylline and antipyrine.