Pharmacokinetics

All preparations of valproate are completely absorbed after oral administration. The rate of absorption varies slightly with the different preparations, but these differences are probably not clinically significant. Co-administration with food can delay absorption. Valproate is approximately 90 per cent protein-bound. Only the unbound drug crosses the blood-brain barrier and is pharmacologically active in the central nervous system. As the total serum valproate concentration increases, the unbound portion of valproate is disproportionately increased, presumably due to saturation of the protein-binding sites. Therefore, at higher serum concentrations, small increases in dose may result in significant changes in efficacy and side-effects. Valproate is metabolized by the liver to a glucuronide conjugate or one of several metabolites, some having antiepileptic activity. The half-life of valproate ranges from 6 to 17 h. Enzyme-inducing antiepileptic drugs, such as carbamazepine and phenytoin, shorten the half-life of valproate (see later).(3)

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