Pharmacodynamics of phenytoin-induced ataxia in rats

The relationship between phenytoin-induced ataxia and its concentration was characterized in rats who received i.v. infusions of the drug at either 0.52, 0.85 or 1.70 mg/min/rat until the onset of ataxia. Phenytoin dose to ataxia did not change with infusion rate but the total and unbound serum concentrations at onset of ataxia increased with increasing infusion (input) rate. Concentrations in cerebrospinal fluid, CSF, and in brain, at this end-point, were not affected by the infusion rate. Direct i.v. infusion of phenytoin major metabolite, p-HPPH, failed to produce ataxia. Thus phenytoin in CSF and brain, unlike serum phenytoin, equilibrates rapidly with site(s) of phenytoin neurotoxicity and represents appropriate sampling sites for identifying factors affecting phenytoin neurotoxicity.