Relationship between concentration and anticonvulsant effect of phenytoin against electroshock-induced seizures in rats: comparison of sampling sites for concentration determinations.

Abstract

The purpose of this investigation was to determine the optimum sampling site for phenytoin concentration measurements in the context of pharmacodynamic studies of the anticonvulsant effect of phenytoin. Determination of drug concentrations in the serum, serum water, brain, and cerebrospinal fluid (CSF) of rats as a function of time after iv injection of a 6-mg/kg dose revealed a significant disequilibrium between brain and serum water for 15 min and between CSF and serum water for 5 min after injection. The concentrations of phenytoin in serum water 1 min after injection of 3 mg/kg (0.371 +/- 0.054 microgram/mL) and 45 min after injection of 8 mg/kg (0.399 +/- 0.049 microgram/mL) were not significantly different, but drug concentrations in the CSF and brain were appreciably higher after the latter dose. There was no protection against electroshock-induced seizures 1 min after the 3-mg/kg dose, but there was complete protection 45 min after the 8-mg/kg dose. At 15 min after drug injection, phenytoin concentrations in CSF and serum water were essentially identical over a wide concentration range. Fifty female Lewis rats weighing approximately 225 g, that consistently exhibited maximal electroshock-induced seizures in three preliminary trials on separate days, received 1, 2, 4, 6, or 8 mg/kg of phenytoin by iv injection. Electroshock was applied 15 min later, the percentage of animals protected from seizure by each dose was determined, and drug concentrations in serum, serum water, brain, and CSF were measured by gas chromatography. The relationship between anticonvulsant activity and drug concentration could be described by a Hill-type equation.(ABSTRACT TRUNCATED AT 250 WORDS)