Relaxing and contracting effects of theophylline's metabolites on the rabbit upper gastrointestinal tract

The present study, aimed to clarify whether the gastrointestinal adverse effects following administration of the bronchodilator theophylline are owing to the action of the drug itself or its metabolites, investigates the pharmacodymanic effects of theophylline's metabolites on the spontaneous contractility in the rabbit upper gastrointestinal tract. Comparative examination reveals that while two of the metabolites, namely 1-methylxanthine (1-MX) and 3-methylxanthine (3-MX), cause a similar, but less pronounced than the parent drug, concentration-dependent relaxation on the isolated oesophagus, lower oesophageal sphincter (LOS), fundus, antrum and pylorus, the remaining two metabolites, 1,3-dimethyluric acid (1,3-DMU) and 1-methyluric acid (1-MU), produce either a weak stimulating effect, or an even weaker relaxation. The relaxation which is muscle-mediated, non-adrenergic non-cholinergic (NANC) and nitric oxide (NO)-independent is probably mediated via inhibition of the metabolites on phosphodiesterases (PDEs), while a presynaptic cholinergic pathway is involved in the weak stimulating effect. The effects of all substances are additive. As a consequence, the net result of the cumulative action of all metabolites in the oesophagus, LOS, antrum and pylorus is, at 10(-3) m, comparable with that of theophylline, but in the fundus it is lower than that of the parent drug, because in the latter tissue the stimulating effect of 1,3-DMU and 1-MU counteracts the relaxing effect of the other two metabolites. However, combination of the parent drug with its metabolites leads to a considerable relaxation in all the gastrointestinal regions extending from the oesophagus to pylorus. Conclusively, upper gastrointestinal adverse effects following theophylline's administration are also because of theophylline's metabolites.