Protein binding of valproic acid in the presence of elevated free fatty acids in patient and normal human serum.

Two recent reports indicate that free fatty acids (FFA) can decrease the binding of valproic acid (VPA) to plasma proteins. Since FFA can increase in several physiological and clinical situations, it becomes necessary to define the relationship between elevated FFA and VPA free fraction. This study was conducted in two phases. In the first phase, serum was obtained from nine patients who were receiving Intralipid. A base-line sample was taken when therapy was absent. A second sample was taken during or immediately after Intralipid therapy. Protein binding VPA (equilibrium dialysis) and FFA levels were determined on each sample. FFA increased in eight patients; the median increase was 80.1%. VPA free fractions increased in six of the eight patients showing an increase in FFA; the median increase in free fraction was 18.7%. Rank correlation between FFA differences and free fraction differences indicated a significant positive linear correlation (r = 0.800). In the second phase, oleic acid was added to normal serum in five different concentrations (500-5,000 microEq/liter) with VPA at 100 microgram/ml. Free fraction of VPA increased continuously from a blank value of 9.6% (+/- 1.4) to 44.1% (+/- 2.5) with increasing concentrations of oleic acid.