Pharmacokinetics and bioavailability of sodium valproate

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Abstract
The pharmacokinetics of the antiepileptic drug, sodium valproate (VPA), was investigated in 6 healthy volunteers after a single intravenous dose of 400 mg, as well as a solution and enteric‐coated tablets. The bioavailability of the enteric‐coated tablets was compared with that of normal tablets in 3 of these subjects. The bioavailability studies demonstrated that the solution was rapidly and almost completely (86% to 100%) absorbed. Peak plasma levels (66 to 196 µg/ml) were reached within 0.5 to 2 hr. Tablets had comparable bioavailabilities which varied in the different persons (68% to 100%). In some subjects VPA was found in plasma only after a lag time of 1 to 4 hr and the peak plasma concentrations of 46 to 88 µg/ml developed after 3 to 7 hr. After the intravenous dose, plasma levels declined biexponentially. The pharmacokinetic parameters were computed according to the two‐compartment open model. The half‐life of the initial phase, t½(α), could be calculated to 1.0 ± 0.86 hr (mean ± SD) and the terminal half‐life, t½(β), varied independently of the route of administration between 8.7 and 21.5 hr (12.2 ± 3.7 hr). The distribution space of the central compartment (V1) was 0.065 ± 0.010 Llkg, and both the apparent volume of distribution at steady‐state (VdSS) and Vdβ had similar values of 0.13 ± 0.04 L/kg and 0.14 ± 0.05 L/kg, respectively. These small volumes indicate that VPA distributes mainly into the extracellular space. The total plasma or blood clearance (Cl) ranged from 4.3 to 10.5 ml/min (7.8 ± 2.4 ml!min) and from 11.9 to 44.3 ml/min (30.1 ± 11.9), respectively. Therapeutic concentrations of VPA (80 µg/ml) revealed relatively strong plasma protein binding between 80% and 94%. The bloodlplasma concentration ratio ranged about 0.28 ± 0.06. Since the calculated hepatic extraction ratio of 0.02 is smaller than the free fraction, it is concluded that clearance of VPA is independent of liver blood flow and of the restrictive type. No measurable amounts of unchanged VPA were excreted during the 2 days of observation. Approximately 10% to 30% of a single dose was eliminated as VPA conjugates which could be hydrolyzed by 2 N HCl and β‐glucuronidase/aryl‐sulfatase.

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