Search

The concentration-time curve of ethosuximide (ESM) in several brain zones of Wistar rats (cortex, midbrain, cerebellum) showed a clear difference from the time course of the drug levels in plasma after administration of 50 mg/kg injected by intraperitoneal route. The brain/plasma ratio in the cortex changes drastically from 2.04 +/- 0.14 (5 m after injection) to 0.14 +/- 0.01 (2 h after injection). Similar behaviour was observed in the brain/plasma ratio of midbrain and cerebellum. The antiepileptic potential of the ESM was closely related to the evolution of the drug time-course in the brain. Reversible opening of the blood-brain barrier modifies the cortex/plasma ratio from 0.14 +/- 0.01 to 0.79 +/- 0.11 (2h after ESM injection). Similar changes were observed in midbrain and cerebellum. The results suggest that the blood-brain barrier plays some part in the time-course of ESM in the brain, and emphasizes the role of brain levels measured by high performance liquid chromatography (HPLC) in clarifying the clinical profile of the drug.

This study was designed to obtain experimental data to correlate duration of spike-and-wave (SW) paroxysms with levels of pentylenetetrazol (PTZ) in several brain regions after intraperitoneal (i.p.) administration of subconvulsive doses of PTZ in Wistar rats. The influence of subconvulsive doses of PTZ on blood-brain barrier (BBB) permeability and tolerance of PTZ to repeated injections were also studied. Intraperitoneal administration of subconvulsive doses of PTZ (25 mg/kg) in single doses resulted in SW activity which accounted for 20% of the continuous electrical brain activity recorded during the first hour after i.p. administration. Brain PTZ levels (cortex, midbrain, cerebellum) were within the range 19.2-34.9 micrograms/g. Repeated doses of PTZ showed a significant decrease in SW activity with no change in PTZ brain levels. As PTZ bioavailability was the same after either a single dose or after repeated doses, the decrease in SW activity may be due to PTZ tolerance. No alterations in the BBB were induced by PTZ subconvulsive doses. The experimental data reported in this study may be useful to quantify modifications of biochemical parameters or to evaluate antiepileptic drugs.