Abstracts

RATIONALE: Fosphenytoin (FosPHT) has been designed to overcome some undesirable characteristics of phenytoin (PHT) so that its use in the treatment of seizures and status epilepticus is more practical. However, the kinetic inter-relationship of PHT in blood cerebrospinal fluid (CSF) and brain extracellular fluid (ECF) after iv FosPHT is unknown. This study was designed to determine this inter-relationship and to compare with that obtained after iv PHT.
METHODS: Male Sprague Dawley rats (300-350 g) were anaesthetised with halothane and a catheter placed in the internal jugular vein for the iv infusion of PHT or FosPHT and for blood sampling and a cannula in the cisterna magna for CSF sampling. Microdialysis probes were implanted stereotactically into the hippocampus and frontal cortex for monitoring of the ECF. Two days post-surgery rats were administered iv PHT or FosPHT (30 mg/kg or 60 mg/kg). Blood, CSF and ECF were collected concurrently from the freely moving rats at various intervals for 6 hours. Samples were analysed for PHT content using high performance liquid chromatography.
RESULTS: Plasma PHT Cmax values increased dose-dependently after PHT and FosPHT iv administration. However, AUC and t1/2 values increased disproportionately to dose. After PHT administration the PHT free fraction varied between 0.25 and 0.31, whilst after FosPHT administration it varied between 0.26 and 0.31. Overall the pharmacokinetic parameters for PHT in the blood compartment after PHT and FosPHT administration were indistinguishable. PHT was rapidly detectable in the CSF compartment. Mean Tmax values varied between 9 and 13 mins and were neither dose nor formulation dependent. However, although CSF AUC and t1/2 values increased disproportionately to dose after PHT administration, as observed for plasma, values increased dose-dependently after FosPHT administration. PHT was detectable in ECF at time of first dialysate sample (10 mins) after PHT and FosPHT administration. However, Tmax values (29-34 mins) were significantly greater than that of CSF. Although ECF AUC and t1/2 values were comparable to those in the hippocampus and there was no difference between PHT and FosPHT administration, t1/2 values were two fold greater than those seen in blood and CSF.
CONCLUSIONS: The kinetics of PHT after iv PHT and FosPHT in blood, CSF and ECF of the hippocampus and frontal cortex are indistinguishable. However, PHT blood concentrations may not necessarily reflect concentrations in the ECF and the site of drug action.
[Supported by: The work was supported in part by Parke-Davis and by the National Society for Epilepsy.]