Interaction between valproic acid and carbamazepine: an in vitro study of protein binding.

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 micrograms/ml), while also varying VPA concentrations (0, 50, and 100 micrograms/ml). Using ultrafiltration, we found a significant elevation (p less than 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 micrograms/ml CBZ. The free fraction increased from 23.5% free CBZ controls (2.85% micrograms/ml free) to 29.5% free CBZ (3.56% micrograms/ml free), with 100 micrograms/ml VPA a 25% increase in free 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.