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

Abstract

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.

The gastrointestinal effects that may follow the administration of theophylline reflect the pharmacodynamic profiles of both the parent drug and its metabolites

“…The dominant mechanism underlying the smooth muscle relaxing properties of theophylline is thought to be its inhibitory action on the PDEs, the enzymes which degrade the cyclic nucleotides [23,38,39]. Previous data deriving from studies exploring the mechanism of theophylline's relaxing effects in gastrointestinal tissues [20][21][22][23]26,27], in addition to the well documented role of PDE types III, IV and V in regulating the LOS and fundus tone [20,[40][41][42][43], provide reasons to hypothesize that the here observed relaxing effect of theophylline on the rabbit gastrointestinal tract is mediated mainly through inhibition of PDEs. Thus, the drug's concentrations required to relax the tissues should be adequate to act on the enzymes.…”

“…Pharmacology and rabbit [21,22], but also the guinea pig antrum [23], the rabbit fundus, antrum and pylorus [21], the rabbit distal [24] and ascending [25] colon, as well as the colon [26] and taenia coli [27] in the guinea pig. Conversely, a contractile effect of theophylline was also described on the stimulated guinea pig ileum [28][29][30], and more recently in the rabbit small intestine [25].…”

“…Information about the effects of theophylline's metabolites, 1-methylxanthine (1-MX), 3-methylxanthine (3-MX), 1,3-dimethyluric acid (1,3-DMU) and 1-methyluric acid (1-MU), derives from the authors' previous studies, where it was shown that the effects of the metabolites on the regions of the rabbit upper gastrointestinal tract are either weaker or opposite to those of theophylline [21], while all four metabolites were found to mimic the contractile effect of theophylline on the small intestinal regions, their efficacy and potency being comparable and in some cases higher than that of the parent drug [25]. Moreover, there is experimental evidence suggesting that the pharmacodynamic effects of the metabolites are additive [21]. In order to examine the contribution of theophylline's metabolites to the final pharmacodynamic effects following its administration, this study investigates the effect of theophylline along the various regions of the rabbit gastrointestinal tract in comparison with the pharmacodynamic effect produced after the combination of 3-MX, 1,3-DMU and 1-MU, the three major metabolites of theophylline.…”

“…Besides the relaxing effect of theophylline on the respiratory tissues in several animal species [9–14], man included [15–17], which underlies the clinical bronchodilator properties of the drug, a relaxing effect has been also demonstrated on gastrointestinal smooth muscle tissues. In particular, in vitro and in vivo studies have shown that theophylline relaxes the lower oesophageal sphincter (LOS) in man [18], opossum [19,20] and rabbit [21,22], but also the guinea pig antrum [23], the rabbit fundus, antrum and pylorus [21], the rabbit distal [24] and ascending [25] colon, as well as the colon [26] and taenia coli [27] in the guinea pig. Conversely, a contractile effect of theophylline was also described on the stimulated guinea pig ileum [28–30], and more recently in the rabbit small intestine [25].…”

“…Conversely, a contractile effect of theophylline was also described on the stimulated guinea pig ileum [28–30], and more recently in the rabbit small intestine [25]. Information about the effects of theophylline’s metabolites, 1‐methylxanthine (1‐MX), 3‐methylxanthine (3‐MX), 1,3‐dimethyluric acid (1,3‐DMU) and 1‐methyluric acid (1‐MU), derives from the authors’ previous studies, where it was shown that the effects of the metabolites on the regions of the rabbit upper gastrointestinal tract are either weaker or opposite to those of theophylline [21], while all four metabolites were found to mimic the contractile effect of theophylline on the small intestinal regions, their efficacy and potency being comparable and in some cases higher than that of the parent drug [25]. Moreover, there is experimental evidence suggesting that the pharmacodynamic effects of the metabolites are additive [21].…”