A comparison of central brain (cerebrospinal and extracellular fluids) and peripheral blood kinetics of phenytoin after intravenous phenytoin and fosphenytoin

Phenytoin (PHT) is a first-line drug in the treatment of status epilepticus. However, the parenteral PHT formulation is associated with administration difficulties and therefore fosphenytoin (FosPHT), a PHT pro-drug, has been developed. As the peripheral (blood) and central (cerebrospinal fluid [CSF] and brain extracellular fluid [ECF]) kinetic inter-relationship of PHT after i.v. FosPHT administration is unknown we sought to ascertain the relationship and to compare it to that of i.v. PHT. A freely behaving rat model, which allows for the concurrent and temporal sampling of blood (jugular vein), CSF (cisterna magna) and brain ECF (frontal cortex and hippocampus), was used. PHT and FosPHT were administered by i.v. infusion and blood, CSF and microdialysate samples collected at timed intervals up to 6 hours. The pharmacokinetic parameters in plasma of PHT after PHT and FosPHT (30 and 60 mg/kg) administration were indistinguishable. The PHT plasma free fraction (free/total concentration ratio) was 0.25-0.31 and 0.26-0.31 for PHT and FosPHT, respectively. Mean PHT Tmax values for CSF were 9-13 minutes. The equivalent values in the frontal cortex and hippocampal ECF were 29-34 minutes. Cmax values increased dose-dependently and were independent of whether PHT or FosPHT was administered. Furthermore the kinetic profiles of PHT for the frontal cortex and hippocampus were indistinguishable suggesting that PHT distribution in the brain is not brain region specific. Thus, overall, the central and peripheral kinetics of PHT are indistinguishable after PHT and FosPHT.