N-Demethylation of Methyl and Dimethyl Derivatives of Phenytoin and Their Anticonvulsant Activities in Mice

Anticonvulsant activities of 3-methylphenytoin (3-MP) and 1,3-dimethylphenytoin (1,3-DMP) were observed to peak 3 hr after i.p. administration of the drugs dissolved in dimethylsulphoxide (DMSO), while maximal activity was obtained within 15 min with phenytoin. HPLC was employed to monitor the plasma concentrations of all three compounds at various time intervals after injecting 3-MP or 1,3-DMP. In both cases, phenytoin appeared in the plasma, gradually reaching 14-15 μg/ml in 3 hr. The time course of increase in plasma phenytoin levels correlated with that of anticonvulsant activities. It was also found that 1,3-DMP gave rise to a major unidentified metabolite as well as 3-MP and phenytoin. This unidentified metabolite eluted only half a minute in front of 3-MP in the HPLC. Mice injected with high doses of 3-MP (100 mg/kg) in DMSO exhibited severe epileptiform activities. Phenobarbital, diazepam and clonazepam were found to protect against such seizures, but not phenytoin, carbamazepine and valproic acid. This shows that 3-MP is at least a pro-convulsant, taking into account that its effects might have been enhanced by DMSO. Unlike phenytoin, 3-MP lacked the ability to inhibit synaptosomal uptakes of both glutamate and GABA. This difference may be related to the fact that phenytoin, but not 3-MP, possesses potent anticonvulsant activity.