MICRODIALYSIS STUDY OF THE NEUROPHARMACOKINETICS OF PHENYTOIN IN RAT HIPPOCAMPUS AND FRONTAL-CORTEX

Acute administration of phenytoin (PHT) is used in the treatment of st atus epilepticus, yet little is known about the neuropharmacokinetics of PHT in brain extracellular fluid (ECF), the pharmacodynamically rel evant compartment. To characterize the neuropharmacokinetics of brain ECF PHT we implanted microdialysis probes in rat hippocampus and front al cortex and placed a catheter in the internal jugular vein. PI-IT (5 0 or 100 mg/kg intraperitoneally, i.p.) was then administered, and mic rodialysate and serum samples were collected. PHT was rapidly absorbed , with a time to maximum concentration (T-max) of similar to 20 min fo r serum concentrations. PHT rapidly entered the brain ECF compartment, with T-max values similar to those of serum. In brain ECF, pi-IT conc entrations then plateaued for 40-60 min despite decreasing serum conce ntrations. The area under the brain ECF concentration-time curve (AUG) was higher in hippocampus than frontal cortex. The possible mechanism s for these observations include entry of PHT into specific brain area s both across capillaries and through the cerebrospinal fluid (CSF), e xtensive binding of PHT in brain white matter, and differing blood flo w in different brain regions.