Interaction Between Valproic Acid and Carbamazepine

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Abstract
Valproic acid (VPA) is highly bound to plasma protein (92–96%) and is likely to compete with carbamazepine (CBZ), another drug that is bound extensively (75%). CBZ protein binding was evaluated in vitro by ultrafiltration at concentrations within the therapeutic range (6, 8, and 12 μg/ml), while also varying VPA concentrations (0, 50, and 100 μg/ml). Using ultrafiltration, we found a significant elevation (p < 0.01) in free and percent-free CBZ for every CBZ concentration tested as the total VPA concentration increased. Maximal effect was evident at 12 μg/ml CBZ. The free fraction increased from 23.5% free CBZ controls (2.85 μg/ml free) to 29.5% free CBZ (3.56 μg/ml free), with 100 μg/ml VPA a 25% increase in free CBZ. The binding of VPA at 50 or 100 μg was unaltered by the addition of CBZ. This in vitro study demonstrates that VPA competes with CBZ for plasma protein binding sites, resulting in a significant increase in free CBZ that may be clinically important.