Anticonvulsant effect of fosphenytoin in amygdala-kindled rats: Comparison with phenytoin

Abstract 

Phenytoin has been reported to exert variable anticonvulsant effects in the kindling model of complex partial seizures. Phenytoin is only water soluble at a pH of more than 10, and it has been suspected that poor absorption of the drug is responsible for its lack of effect in some experiments. Recently, fosphenytoin, a prodrug of phenytoin, has been developed by phosphorylating phenytoin which makes the drug water soluble at physiological pH while it is rapidly transformed to phenytoin after injection. This study examined the anticonvulsant profile and the absorption after intraperitoneal injection of fosphenytoin, compared to its parental drug phenytoin. The pharmacokinetic parameters of phenytoin and fosphenytoin were compared by determining plasma levels of phenytoin after i.p. injection of 50 mg/kg phenytoin or the equivalent dose of 84 mg/kg of fosphenytoin in non-kindled female Wistar rats. After both injections the maximal plasma concentration of phenytoin was about 30 μg/ml. The relative bioavailability of fosphenytoin was 83%. In contrast to phenytoin, failed injections resulting in non-detectable plasma concentration of phenytoin were almost absent after fosphenytoin. In fully kindled female Wistar rats, fosphenytoin dose-dependently increased the focal seizure (afterdischarge) threshold. Seizure severity and duration at threshold were reduced only after the highest does of fosphenytoin tested (84 mg/kg). Thus, fosphenytoin showed anticonvulsant properties similar to phenytoin in amygdala kindled rats. We conclude that fosphenytoin is an adequate and reliable substitute for the parenteral injection of phenytoin in experimental seizure models of rats.

Keywords:  ACC-9653, Afterdischarge threshold, Bioavailability, Limbic seizure, Kindling