Reduced in vitro displacement of valproic acid from protein binding by salicylate in uremic sera compared with normal sera. Role of uremic compounds.

Limited studies indicate increased free fraction of valproic acid in uremia. One study also described displacement of valproic acid from protein binding by salicylate in children with epilepsy. The authors studied in vitro interaction of valproic acid and salicylate in uremic sera and compared their results with same interactions in normal sera. As expected, the concentrations of free valproic acid were always significantly higher in uremic sera compared with normal sera. When uremic sera were supplemented with both valproic acid and salicylate, a much lower displacement of valproic acid by salicylate was observed, compared with the effects observed in normal sera. Treatment of uremic sera with charcoal removed those uremic compounds, and the concentration of free valproic acid in charcoal-treated uremic sera were comparable to the concentrations observed in normal sera. When uremic compounds were extracted from charcoal with methanol, lyophilized, and added to normal serum, an increase in free valproic acid concentration in normal serum was observed, indicating that uremic compounds, rather than altering albumin structure, are responsible for elevated free valproic acid concentration in uremia. However, uremic extract failed to produce any further displacement of valproic acid in normal serum in the presence of salicylate. The authors concluded that uremic compounds are responsible for elevated free valproic acid concentrations, but the displacement of valproic acid by salicylate in uremic sera are less remarkable compared with such effect in normal sera.