Background: Valproate (VPA) is a commonly used AED; however is mechanisms of action are uncertain. We explored the pharmacokinetic-pharmacodynamic relationship of VPA levels and seizure activity, and investigated the efficacy of continuous versus highly fluctuating administration of VPA in Genetic Absence Epilepsy Rats from Strasbourg (GAERS).
Methods: Adult GAERS (n=12) received boluses of 50, 100 and 200mg/kg iv. A separate group received 25mg/kg (n=8). EEG was recorded 1h before till 3h after VPA administration and blood samples taken. A third group (n=17) received three days of continuous saline iv (1ml/h) followed by two serial treatments: 3 days of 42mg/kg/h VPA separated by 2 days of wash-out: 1) continuous infusion 2) intermittent hourly bolus injections. Seizure activity was quantified on Day 3.
Results: Bolus injections of 50, 100, 200mg/kg VPA all decreased time in seizure (77%, 82%, 84% respectively, p<0.01), but not 25mg/kg. Seizures progressively suppressed, with a peak effect at 45-75min and lasting until 180min. In contrast, plasma VPA peaked in 2min dropping to “subtherapeutic” levels by 45min. Chronic continuous and fluctuating VPA infusions suppressed seizures (77% vs. 57% respectively vs. saline, p<0.05). In the fluctuating group, there was no correlation between plasma levels and seizure suppression. Brain VPA levels closely reflected those of CSF and plasma.
Conclusion: Temporal discordance between VPA levels and seizure efficacy suggests that VPA is acting via a secondary effect rather than direct receptor interaction. Peak VPA concentrations do not result in greater anti-seizure efficacy, with the maintenance of steady mid-range concentrations being as potent.