Absolute bioavailability of phenytoin after 3-phosphoryloxymethyl phenytoin disodium (ACC-9653) administration to humans.

3-Phosphoryloxymethyl phenytoin disodium (ACC-9653) is a water-soluble investigational phenytoin (PHT) prodrug for parenteral administration. The objectives of this investigation were to determine the absolute bioavailability and free fraction of PHT after intravenous (i.v.) administration of ACC-9653. Twelve healthy male volunteers received PHT sodium (250 mg/5 ml; 229.95 mg free acid) and ACC-9653 (375 mg/5 ml; 232.87 mg free acid) i.v. in 30 min in a randomized, double-blind cross-over fashion. The conversion half-life (t 1/2) of ACC-9653 to PHT was 9.3 +/- 2.7 min. ACC-9653 was not detected in urine and greater than 99% of ACC-9653 was converted to PHT. The PHT area under the curve (AUC) was not statistically different between treatments; the bioavailability of PHT after ACC-9653 was 99 +/- 11%. The fraction of unbound converted PHT at the end of the prodrug infusion, in the presence of 44 micrograms/ml ACC-9653, was significantly higher than at 180 min, when the concentration of ACC-9653 was 0.1 microgram/ml. ACC-9653 was shown to be a bioequivalent PHT prodrug exhibiting less irritation at the injection site than the current marketed PHT.