Phenytoin phosphate ester prodrug

SA Varia, VJ Stella. Phenytoin prodrugs VI In vivo evaluation of a phosphate ester prodrug of phenytoin after parenteral administration to rats. J Pharm Sci 73(8) 1087-1090, 1984. 

S. A. Varia, V. J. Stella, Phenytoin Prodrugs VI In vivo Evaluation of a Phosphate Ester Prodrug of Phenytoin after Parenteral Administration to Rats , J. Pharm. Sci. 1984, 73, 1087-1090. 

Figure 8.28 Water-soluble phosphate ester prodrug of phenytoin.

Fosphenytoin, the water-soluble phosphate ester of phenytoin, is a phenytoin prodrug. 

Phenytoin is a diphenyl-substituted hydantoin with the structure shown. It has much lower sedative properties than compounds with alkyl substituents at the 5 position. A more soluble prodrug of phenytoin, fosphenytoin, is available for parenteral use this phosphate ester compound is rapidly converted to phenytoin in the plasma. 

Fig. 9.7. a) Mechanism of activation of (phenytoin-3-yl)methyl phosphate (9.25) to release phenytoin. Phosphoric acid ester hydrolysis is mediated by alkaline phosphatase, b) (Phospho-ryloxy)methyl prodrugs of tertiary amines, whose activation occurs by the same two-step mechanism shown in a [79]. 

Gerber, N., Mays, D. C., Donn, K. H., et al. Safety, tolerance and pharmacokinetics of intravenous doses of phosphate-3-ester of hydroxymethyl-5,5-diphenylhydantoin, a new prodrug of phenytoin. J. Clin. Pharmacol. 28 1023-1032, 1988. 

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