Effect of sodium valproate on midazolam distribution

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Abstract
The displacement of midazolam, a new water-soluble, short-acting benzodiazepine, from its plasma binding sites by sodium valproate, has been studied in man. An increase of its free fraction (ranging from 2.71 to 5.35%) in plasma from epileptic patients receiving sodium valproate was observed. A similar situation was created in rabbits by pretreatment with sodium valproate (600 mg kg−1 day−1) and posterior hypnosis with midazolam. Due to the interaction, sodium valproate-pretreated rabbits showed an increase in midazolam brain levels (130.91 μg g−1 in cortex vs 84.55 μg g−1 in control animals). Therefore, it seems likely that displacement of midazolam by sodium valproate in epileptic patients could lead to an increase of the midazolam response.