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

Abstract

Abstract-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 /ag/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.Phenytoin (5,5-diphenylhydantoin) is a widely used drug in the treatment of most forms of epilepsy. In laboratory animals, its anticonvulsant activity is characterized by the effectiveness against maximal electroshock seizure (MES) but not pentylenetetrazole induced seizure. The ED50 is approx. 8 mg/kg in mice (1, 2). In our hands, the ED50 is 11 mg/kg (P.T.-H. Wong and S.-F. Tan, un published). Vida et al. (3) reported that two methyl derivatives of phenytoin, 3-methyl phenytoin (3-MP) and 1,3-dimethylpheny toin (1,3-DMP), are effective against MES in mice with ED50 values of about 5 and 50 mg/kg, respectively. Peak activities for 3-MP, 1,3-DMP and phenytoin were obtained at 2-3 hr post-administration, probably because the drugs were administered by the oral route as suspensions in 10% aqueous acacia. It is well known that mephenytoin (3-methyl-5 ethyl 5-phenylhydantoin), a phenytoin ana logue with clinical efficacy, is N-demethylated to an active metabolite 5-ethyl-5-phenyl hydantoin (4). This means that there is a distinct possibility of phenytoin being formed from its methyl derivatives, particularly when there is a considerable time lapse of 2-3 hr between drug administration and the meas urement of anticonvulsant activities. By using a suitable vehicle and route of admin istration to ensure rapid absorption and penetration into the brain, we reevaluated the actions of these phenytoin analogues. Materials and MethodsChemical synthesis: 3-MP was prepared by adding with continuous stirring 2 ml of NaOH (10%) followed by 1 ml of dimethyl sulphate to 10 ml of phenytoin sodium (0.2 g/ml). After standing for 30 min at room temp., the mixture was cooled in an ice ...

Anticonvulsant activity of the cyclooxygenase-2 (COX-2) inhibitor etoricoxib in pentylenetetrazole-kindled rats is associated with memory impairment

“…It is also known to decrease the seizure threshold and act as a proconvulsant [29]. In our study, we found an improvement in learning and memory in the passive avoidance apparatus and the Morris water maze apparatus after 30% DMSO coupled with a decrease in seizure latency when compared with DMSO pretreatment.…”

The effect of intraperitoneally administered dimethyl sulfoxide on absence-like epileptic activity of freely moving WAG/Rij rats

“…However, it was demonstrated that DMSO may enhance the proconvulsant activity of the dissolved drugs because DMSO may lower seizure threshold (Wong et al, 1988). Similarly, the antiepileptic effect of i.p.…”

Anticonvulsant Activity of Phenylmethylenehydantoins: A Structure−Activity Relationship Study

“…Therefore, in general, the structure−activity relationship studies of anticonvulsants revealed the need for the retention of at least one hydrophobic site and H-bond donors/acceptors together with certain relative orientation between these features to exhibit anticonvulsant activity. 5a-g The hydantoin nucleus and the phenyl ring in phenylmethylenehydantoin (PMH) provided the basic structural requirement for activity. Previous studies from our laboratory have demonstrated a weak maximal electroshock seizure (MES) response for the unsubstituted PMH . Thus, the main objective of the present study is to investigate the influence of substitutions in the phenyl ring of PMH on its anticonvulsant activity.…”