Yamamoto K, Toyama E, Kawakami J, Sawada Y, Iga T
Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine, University of Tokyo, Japan.
Biol Pharm Bull. 1996 Jun;19(6):869-72. doi: 10.1248/bpb.19.869.
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.
为评估茶碱及其主要代谢产物1-甲基黄嘌呤（1-MX）、3-甲基黄嘌呤（3-MX）、1,3-二甲基尿酸（1,3-DMUA）和1-甲基尿酸（1-MUA）诱导神经毒性的风险，我们比较了它们在给小鼠脑内给药后对中枢神经系统（CNS）的惊厥效力。所有研究的化合物均以剂量依赖性方式诱发阵挛性惊厥，茶碱、1-MX、3-MX、1,3-DMUA和1-MUA惊厥的半数有效剂量（ED50）值分别为490、546、1107、360和620 nmol/kg。这些化合物还通过恒速输注静脉注射给小鼠，直至惊厥发作。静脉输注茶碱、1-MX和3-MX可诱发阵挛性惊厥，而在输注1,3-DMUA或1-MUA 60分钟期间未观察到惊厥。这一发现可能是由于与茶碱、1-MX和3-MX相比，1-MUA和1,3-DMUA的血脑屏障通透性较差。然而，从其内在的惊厥效力来看，也可能有必要考虑1,3-DMUA诱导神经毒性的可能性。
