A model for chronic treatment of rats with sodium valproate has been developed balancing efficacy, toxicity and dose control. The dose (300 mg/kg) and frequency (every 8 h) selected were somewhat toxic as measured by weight gain and failed to provide continuous protection against Indoklon induced seizures but yielded plasma valproate levels near the range of therapeutic human levels. Chronic treatment of rats at this dose and frequency yielded a significant negative correlation between weight gain and length of treatment as well as a significant negative correlation between plasma valproate concentration and length of treatment. It was concluded that due to the short half-life of valproate in rats it is impossible to maintain continuously protective, nontoxic levels of valproate with a reasonable frequency (every 8 h) of controlled dose administration.
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