Binding of fosphenytoin, phosphate ester pro drug of phenytoin, to human serum proteins and competitive binding with carbamazepine, diazepam, phenobarbital, phenylbutazone, phenytoin, valproic acid or warfarin.

The protein binding of [14C]fosphenytoin, (3-phosphoryloxy-methyl phenytoin disodium), a phosphate ester prodrug of phenytoin sodium, to human serum proteins, serum albumin and alpha 1-acid glycoprotein was determined by ultrafiltration. The mean +/- SD% of fosphenytoin bound to human serum proteins was 95.7 +/- 0.48%. Binding to albumin (36.5 mg/ml) decreased linearly from 89.2 to 67.3% when the fosphenytoin concentration was increased from 6 to 200 micrograms/ml. Fosphenytoin was weakly bound to alpha 1-acid glycoprotein (13.3%). Simultaneous incubation with high concentrations of carbamazepine (10 micrograms/ml) and diazepam (5 micrograms/ml) or therapeutic concentrations of phenytoin (10 micrograms/ml) had no effect on the binding of fosphenytoin to human serum proteins. High concentrations of phenobarbital (160 micrograms/ml), phenytoin (50 micrograms/ml), or valproic acid (500 micrograms/ml), however, caused slight, but significant, increases in the free fraction of fosphenytoin in serum protein. Phenylbutazone and sulfisoxazole resulted in a 48% increase in fosphenytoin free fraction while warfarin had a slight (8%), but significant, increase in free fraction of fosphenytoin. It was concluded that the concentration of albumin was the most important determinant for the plasma free fraction of fosphenytoin in man. Potential increase in fosphenytoin clearance may be observed in hypoalbuminemia.