Phenytoin prodrugs V: In vivo evaluation of some water-soluble phenytoin prodrugs in dogs.

Phenytoin bioavailability was evaluated in beagle dogs after oral and intravenous administrations of sodium phenytoin and two amino acyl esters and a disodium phosphate ester of 3-(hydroxymethyl)phenytoin (three prodrugs of phenytoin). Phenytoin displayed nonlinear pharmacokinetics in the dogs, complicating the determination of the absolute bioavailability of phenytoin from sodium phenytoin and the prodrugs. All three prodrugs essentially released phenytoin after intravenous administration in a quantitative manner, and all gave plasma levels of phenytoin after oral administration greater than those found after administration of sodium phenytoin. Based on the behavior in dogs and the earlier determination of the physicochemical properties of the prodrugs, it was concluded that one of the amino acyl esters, 3-(hydroxymethyl)-5,5-diphenylhydantoin N,N-dimethylglycine ester methanesulfonate, would be the most useful prodrug for oral administration, while 3-(hydroxymethyl)-5,5-diphenylhydantoin disodium phosphate ester would be the most useful for parenteral administration.