Theophylline metabolism in relation to antipyrine, debrisoquine, and sparteine metabolism

Theophylline plasma clearance (Cl_p) and clearance to its metabolites (Cl_m) as well as antipyrine saliva clearance (Cl_sat) and its Cl_m 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]). Cl_m of theophylline (1,3-dimethyluric acid, l-methyluric acid, and 3-methylxanthine) correlated (r ≥ 0.92) to each other and to total theophylline Cl_p (r ≥ 0.97). Smokers had higher Cl_m 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 Cl_p or Cl_m Antipyrine clearances by EMs and PMs (Cl_sat and Cl_m of 4-OH-antipyrine, 3-OH-methylantipyrine, or norantipyrine) also did not differ. Antipyrine Cl_sat and Cl_m correlated to theophylline Cl_p (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.