Elevated free fosphenytoin concentrations in uremic sera: uremic toxins hippuric acid and indoxyl sulfate do not account for the impaired protein binding of fosphenytoin.

Fosphenytoin is a new phosphate ester prodrug of phenytoin. Impaired protein binding of phenytoin in uremia has been extensively documented, which prompted us to investigate the protein binding of fosphenytoin in uremic sera. Also studied was the role of uremic toxins hippuric acid and indoxyl sulfate as potential inhibitor of the protein binding of fosphenytoin because these compounds impair protein binding of phenytoin in uremia. Five serum pools were prepared from normal volunteers and five pools from patients with uremia. None of them received phenytoin. The normal serum pools were diluted with saline to mimic the albumin concentration of uremic pool. Both the diluted normal pool and the uremic pool were supplemented with fosphenytoin; after incubation at room temperature for 30 minutes, total and free fosphenytoin concentrations as phenytoin equivalents were measured using fluorescence polarization immunoassay (Abbott Laboratories; Abbott Park, IL, U.S.A.). The authors observed significantly elevated free fosphenytoin concentration in uremic sera compared with that of normal sera in all cases. Because both normal and uremic sera had the same concentrations of albumin, the elevated free fosphenytoin concentration in uremic sera was not caused by hypoalbuminemia. Both indoxyl sulfate and hippuric acid cause significant displacement of phenytoin from protein binding. In contrast, none caused any displacement of fosphenytoin from protein binding.