ANTIEPILEPTIC DRUG PHARMACOKINETICS AND NEUROPHARMACOKINETICS IN INDIVIDUAL RATS BY REPETITIVE WITHDRAWAL OF BLOOD AND CEREBROSPINAL-FLUID - PHENYTOIN

The temporal pharmacokinetic (blood) and neuropharmacokinetic (cerebrospinal fluid, CSF) interrelationship of phenytoin was studied after acute and during chronic (up to 5 days) intraperitoneal administration of phenytoin (30, 50 or 100 mg/kg) using a new freely behaving rat model. After administration, phenytoin rapidly appeared in both serum (T-max mean range 0.15-0.38 h) and CSF (T-max mean range 0.9-1.4 h), suggesting ready penetration of the blood-brain barrier. However, transport across the blood-brain barrier may be rate limiting since whilst phenytoin concentrations rose dose dependently in serum, CSF concentrations did not. Further, the divergence between the blood and CSF compartments increased with chronic dosing. C-max, AUC and t(1/2) values for serum increased non-linearly, suggestive of accumulation kinetics. Based on these data, high initial phenytoin blood concentrations are essential if phenytoin entry into the brain is to be facilitated, and this may be important in studies of phenytoin in animal models of status epilepticus.