Prediction of Free Levels of Phenytoin and Carbamazepine in Patients Comedicated with Valproic Acid

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Abstract
Serum samples from patients receiving phenytoin (PHT) or carbamazepine (CBZ) and sodium volproate (VPA) polytherapy were filtered at 37 degrees C and the free concentrations were measured by high-performance liquid chromatography. The mean apparent dissociation constants (KD) for the binding of PHT and CBZ to albumin were calculated. The mean KD values were used to predict free levels of PHT or CBZ in serum from patients also taking VPA, based on information about the total serum concentrations of the drugs and albumin. In the presence of VPA the values of the free fraction (alpha) for PHT and CBZ increased and the values for the apparent dissociation constants (KD) decreased compared with the situation of monotherapy. These decreases in the value of KD and increases in the value of alpha were statistically significant. The correlations between values for predicted and analysed free levels of PHT or CBZ were close, with r values of 0.999 and 0.998, respectively. The mean prediction error was small, 0.01 +/- 0.22 mumol/L for PHT and 0.03 +/- 0.42 mumol/L for CBZ. The percentage differences between predicted and observed free levels for PHT and CBZ were < 10%. We conclude that our method of prediction is sufficiently accurate and precise for clinical use.

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