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 sal ) 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 metaboUzers [EMs]). Cl m of theophylline (1,3‐dimethyluric acid, 1‐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 sal and Cl m of 4‐OH‐antipyrine, 3‐OH‐methylantipyrine, or norantipyrine) also did not differ. Antipyrine Cl sal 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. Clinical Pharmacology and Therapeutics (1984) 35 , 815–821; doi: 10.1038/clpt.1984.118