Increased Free Phenytoin Concentrations in Predialysis Serum Compared to Postdialysis Serum in Patients with Uremia Treated with Hemodialysis: Role of Uremic Compounds

Abstract

Patients with uremia are reported to have elevated concentrations of free phenytoin as a result of decreases in protein binding. This appears to be related to the presence of uremic compounds. To determine the dialyzability of these compounds, the in vitro protein binding levels of phenytoin in pre- and postdialysis serum (supplemented with phenytoin) of 12 patients with uremia were compared. For these patients, the concentrations of free phenytoin were significantly greater in predialysis serum (lower protein binding) compared to postdialysis serum, although the concentrations of total phenytoin did not vary. Low levels of protein binding of phenytoin in predialysis serum also were observed in two hemodialysis patients receiving phenytoin. Several serum pools, prepared from both normal volunteers and the predialysis sera of uremic patients, were dialyzed (in vitro equilibrium dialysis). Then both undialyzed and dialyzed sera were supplemented with phenytoin and analyzed to determine free and total phenytoin concentrations. The free phenytoin concentrations were increased in equilibrium-dialyzed normal serum pools compared to undialyzed original pools because of decreases in albumin concentrations after equilibrium dialysis. In contrast, free phenytoin concentrations were decreased in the equilibrium-dialyzed uremic serum pools, thereby indicating an attenuation of the albumin dilution effect on free phenytoin concentration, probably by the preexisting uremic compounds. These compounds can be removed completely by treating sera with activated charcoal at pH 3. The results obtained from charcoal treatment experiments, in combination with other results, indicate that these uremic compounds can be removed partially by in vivo hemodialysis and by in vitro equilibrium dialysis.