Phenytoin Prodrugs IV: Hydrolysis of Various 3-(Hydroxymethyl)phenytoin Esters

Phenytoin Prodrug 3-Phosphoryloxymethyl Phenytoin (ACC-9653): Pharmacokinetics in Patients following Intravenous and Intramuscular Administration

“…The first in vitro and in vivo evaluation of the phenytoin prodrug 1 in animals appeared in a series of articles in the early 198Os.4J2-14 This particular chemical modification of the parent compound, phenytoin, surfaced among several other potential alternatives because of its favorable physicochemical properties, including excellent aqueous solubility and stability, and its rapid enzymatic hydrolysis to phenytoin in animal models. Readers are directed to this series of reports for an in-depth analysis of these properties for 1.4J2- 14 Our study represents one of the few published reports on the phenytoin prodrug 1 in humans. 1"17,22 Favorable pharmamkinetic findings of iv and im administration of 1 in normal volunteers and in patients as described above support the conclusions of other studies15.16 which indicate that the phenytoin prodrug offers many potential advantages over the currently available formulation of parenteral phenytoin sodium relative to safety and tolerability.…”

Water-Soluble Progesterone Analogues Are Effective, Injectable Treatments in Animal Models of Traumatic Brain Injury

“…Proline conjugate 8 was also highly unstable, with a half-life of only 52 min. At neutral pH, α-amino acid esters have been reported to undergo general base catalyzed hydrolysis, assisted by complexing to buffer components, 27 and this behavior proved to be operative for these analogous oxime esters as well. This aqueous instability could have skewed solubility results at neutral pH, as the common byproduct of hydrolysis was the highly insoluble 3 in each case.…”

Phenytoin Prodrugs VI: In Vivo Evaluation of a Phosphate Ester Prodrug of Phenytoin after Parenteral Administration to Rats

“…Based on those studies, 11-IV were thought to be possible parenteral forms of phenytoin because of their superior solubility properties compared with phenytoin (9). In a dog study, these prodrugs quantitatively released phenytoin after intravenous injection (1 l), although 111 was observed to cause significant acute toxicity in the dog and 11 had only marginal chemical stability (10). It was concluded that IV would be the best candidate among prodrugs 11-IV…”