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[C-14]fosphenytoin, (3-phosphoryloxy-methyl phen ytoin disodium), a phosphate ester prodrug of phenytoin sodium, to hum an serum proteins, serum albumin and alpha(1)-acid glycoprotein was de termined by ultrafiltration. The mean +/- SD % of fosphenytoin bound t o 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 conce ntration was increased from 6 to 200 mu g/ml. Fosphenytoin was weakly bound to alpha(1)-acid glycoprotein (13.3%). Simultaneous incubation w ith high concentrations of carbamazepine (10 mu g/ml) and diazepam (5 mu g/ml) or therapeutic concentrations of phenytoin (10 mu g/ml) had n o effect on the binding of fosphenytoin to human serum proteins. High concentrations of phenobarbital (160 mu g/ml), phenytoin (50 mu g/ml), or valproic acid (500 mu g/ml), however, caused slight, but significa nt, increases in the free fraction of fosphenytoin in serum protein. P henylbutazone and sulfisoxazole resulted in a 48% increase in fospheny toin free fraction while warfarin had a slight (8%), but significant, increase in free fraction of fosphenytoin. It was concluded that the c oncentration of albumin was the most important determinant for the pla sma free fraction of fosphenytoin in man. Potential increase in fosphe nytoin clearance may be observed in hypoalbuminemia.