Absolute Bioavailability of Phenytoin After 3-Phosphoryloxymethyl Phenytoin Disodium (ACC-9653)Administration to Humans

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Abstract
3-Phosphoryloxymethyl phenytoin disodium (ACC-9653) is a water-soluble investigational phenytoin (PHT) prodrug for parenteral administration. The objective 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 (t1/2) of ACC-9653 to PHT was 9.3 .+-. 2.7 min. ACC-9653 was not detected in urine and >99% of ACC-9653 was converted to PHT. The PHT area under the curve (AUC) was not statisticaly 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 .mu.g/ml ACC-9653, was significantly higher than at 180 min, when the concentration of ACC-9653 was 0.1 .mu.g/ml. ACC-9653 was shown to be a bioequivalent PHT prodrug exhibiting less irritation at the injection site than the current marked PHT.