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

The temporal pharmacokinetic (blood) and neuropharmacokinetic (cerebro spinal fluid, CSF) interrelationship of phenytoin was studied after ac ute and during chronic (up to 5 days) intraperitoneal administration o f phenytoin (30, 50 or 100 mg/kg) using a new freely behaving rat mode l. After administration, phenytoin rapidly appeared in both serum (T-m ax mean range 0.15-0.38 h) and CSF (T-max mean range 0.9-1.4 h), sugge sting ready penetration of the blood-brain barrier. However, transport across the blood-brain barrier may be rate limiting since whilst phen ytoin concentrations rose dose dependently in serum, CSF concentration s did not. Further, the divergence between the blood and CSF compartme nts increased with chronic dosing. C-max, AUC and t(1/2) values for se rum increased non-linearly, suggestive of accumulation kinetics. Based on these data, high initial phenytoin blood concentrations are essent ial if phenytoin entry into the brain is to be facilitated, and this m ay be important in studies of phenytoin in animal models of status epi lepticus.