A CASE FOR PRODRUGS - FOSPHENYTOIN

The objective of this paper is to review the development of fosphenyto in (3-hydroxymethyl-5,5-diphenylhydantoin, phosphate ester, disodium s alt), a parenterally useful prodrug form of phenytoin, a sparingly wat er-soluble (20-25 mu g/ml) weakly acidic (pK(a) 8.3) drug. Sodium phen ytoin for parenteral administration is formulated as a very alkaline s olution (pH 12) containing 10% ethanol and 40% propylene glycol. Intra venous administration of this formulation must be given undiluted, or minimally diluted, over an extended period for acute safety reasons (l ocal irritation is still a problem) and intramuscular administration l eads to erratic systemic delivery due to probable crystallization of p henytoin at the injection site due to pH adjustment and co-solvent dil ution. Fosphenytoin is water-soluble, intrinsically safe and readily b ioreverts to phenytoin through the action of phosphatases once adminis tered. Pharmacokinetics and pharmacodynamics in animals and humans hav e shown that it quantitatively releases phenytoin on parenteral admini stration and provides far greater safety than sodium phenytoin. Intram uscular administration of fosphenytoin gives plasma phenytoin levels c omparable to intravenous administration allowing for possible phenytoi n delivery to patients for which intravenous administration is not pos sible. Fosphenytoin is a good example of a novel prodrug that can over come the parenteral delivery problems associated with a sparingly wate r-soluble drug.