Intra-dose variation in plasma protein binding of sodium valproate in epileptic patients

1 The fluctuations in protein binding of sodium valproate during one dosing interval were studied in five patients stabilized on valproate and taking concurrent anticonvulsant therapy. 2 The patients took their usual morning dose of valproate (400-800 mg) and serial blood samples were collected by venepuncture at 0, 1, 2, 3, 4, and 6 h post-dose. 3 Free valproate was separated from protein bound drug by plasma ultrafiltration and the ultrafiltrate and total plasma valproate concentrations were measured by a gas chromatographic method. 4 The maximum and minimum concentrations in the ultrafiltrates occurred at the same times as in the plasma. However, the percentage fluctuation was always greater in the ultrafiltrates (range 192-412%) compared with the plasma (range 153-374%) due to the concentration-dependent nature of valproate protein binding. 5 If free valproate levels are to be monitored, knowledge of sampling time and dosage history is important for interpretation of the results.