Neurotoxic convulsions induced by theophylline and its metabolites in mice.
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.
Yamamoto
K
K
Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine, University of Tokyo, Japan.
Toyama
E
E
Kawakami
J
J
Sawada
Y
Y
Iga
T
T
D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism; D007262:Infusions, Intravenous; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D009498:Neurotoxins / Q000633:toxicity*; D012640:Seizures / Q000139:chemically induced*; D013806:Theophylline / Q000378:metabolism / Q000633:toxicity*; D014527:Uric Acid / Q000031:analogs & derivatives / Q000097:blood / Q000633:toxicity; D014970:Xanthines / Q000097:blood / Q000633:toxicity
D009498:Neurotoxins; D014970:Xanthines; D014527:Uric Acid; C053085:1-methylxanthine; D013806:Theophylline; C031274:1,3-dimethyluric acid; C029703:3-methylxanthine