Neurotoxic Convulsions Induced by Theophylline and Its Metabolites in Mice

Abstract

To evaluate the risk of neurotoxicity induced by theophylline and its main metabolites, 1-methylxanthine (1-MX), 3-methylxanthine (3-MX), 1, 3-dimethyluric acid (1, 3-DMUA) and 1-methyluric acid (1-MUA), we compared their convulsive potency to central nervous system (CNS) after intracerebral administration to mice. All compounds studied induced clonic convulsion in a dose-dependent manner, and the ED₅₀ values for convulsion were 490, 546, 1107, 360 and 620 nmol/kg for theophylline, 1-MX, 3-MX, 1, 3-DMUA and 1-MUA, respectively. These compounds were also administered intravenously to mice by constant rate infusion until the onset of convulsion. Clonic convulsion was induced by i.v. infusion of theophylline, 1-MX and 3-MX, while convulsion was not observed during 1, 3-DMUA or 1-MUA infusion for 60 min. This finding may be due to the poor blood-brain barrier permeability of both 1-MUA and 1, 3-DMUA as compared with theophylline, 1-MX and 3-MX. However, it may be also necessary to consider the possibility of 1, 3-DMUA-induced-neurotoxicity judging from its intrinsic convulsive potency.