Fosphenytoin

Introduction
Fosphenytoin, also known as fosphenytoin sodium, and sold
under the brand name (Cerebyx) among others, is a water-
soluble phenytoin prodrug that is administered intravenously to
deliver phenytoin, potentially more safely than
intravenous phenytoin. It is used in the acute treatment of
convulsive status epilepticus.
Phenytoin, in both its acidic and sodium salt forms, is erratically
bioavailable whether it is injected or taken orally due to its
high melting point, weak acidity, and its being only
sparingly soluble in water. Simply putting patients on other drugs is
not always an option; this was especially true before 1993, when the
number of anticonvulsants available was much more limited. One
solution was to develop a prodrug that did not have these
drawbacks.
Fosphenytoin was approved by the Food and Drug
Administration (FDA) on August 5, 1996, for use in epilepsy.
Fosphenytoin is approved in the United States for the short-
term (five days or fewer) treatment of epilepsy when more widely
used means of phenytoin administration are not possible or are ill-
advised, such as endotracheal intubation, status epilepticus or some
other type of repeated seizures; vomiting, and/or the patient is
unalert or not awake or both.

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Mechanism of action
Fosphenytoin is a prodrug of phenytoin and accordingly, its
anticonvulsant effects are attributable to phenytoin. Phenytoin acts
on sodium channels on the neuronal cell membrane, limiting the
spread of seizure activity and reducing seizure propagation.
By promoting sodium efflux from neurons, phenytoin tends to
stabilize the threshold against hyperexcitability caused by excessive
stimulation or environmental changes capable of reducing
membrane sodium gradient. This includes the reduction of post-
tetanic potentiation at synapses. Loss of post-tetanic potentiation
prevents cortical seizure foci from detonating adjacent cortical areas.

Synthesis and structure

Synthesis of fosphenytoin (1) commences with the nucleophilic

addition of phenytoin (2) to formaldehyde to give compound (3),
which upon chlorination using thionylchloride provides intermediate
(4). Phosphorylation of intermediate (4) using silver dibenzyl
3
phosphate yields the corresponding ester product (5), which on
hydrogenolysis and subsequent treatment with sodium hydroxide
provides fosphenytoin sodium (1)
The chemical structure of fosphenytoin is 3- hydroxymethyl-
5,5-diphenylhydantoin intermediate.
The difference in molecular weights between fosphenytoin and
phenytoin results in 75mg of fosphenytoin sodium being equivalent
on a molar basis to 50mg of phenytoin sodium.
IUPAC name 5,5-Diphenyl-3-[(phosphonooxy)methyl]- 2,4-
imidazolidinedione disodium
Molecular weight 406.24 (phenytoin sodium 275.25)
lonisation pka1 2.04, pKa2 5.89

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Drug design and development:
Fosphenytoin is a phenytoin prodrug, was designed to
overcome many of the shortcomings associated with parenteral
phenytoin sodium. Specifically, fosphenytoin is highly water‒soluble,
it has no known pharmacologic activity before its conversion to
phenytoin. Pharmacokinetic studies documented that the agent is
rapidly and completely converted to PHT after IV and IM dosing.
Phenytoin is only water soluble at a pH of more than 10, and it has
been suspected that poor absorption of the drug. While the new
drug, fosphenytoin, offers an attractive alternative for parenteral
phenytoin in select individuals. it has been developed by
phosphorylating phenytoin which makes the drug water soluble at
physiological pH while it is rapidly transformed to phenytoin after
injection. It is completely converted to phenytoin in adults after
administration and is significantly better tolerated than parenteral
phenytoin.

Fosphenytoin is highly plasma‒protein bound and, when

present in sufficient concentration, will displace phenytoin from
plasma proteins. The clinical utility is that fosphenytoin may be used
to achieve therapeutic phenytoin concentrations more rapidly than
I.V. phenytoin infused at its maximum recommended rate.

Adverse events associated with fosphenytoin generally were

related to the CNS and were similar to those associated with
phenytoin, except for a higher incidence of transient pruritus with
fosphenytoin. Intravenous (I.V) fosphenytoin has significant
advantages over I.V phenytoin: It requires a shorter infusion time
and fewer I.V disruptions, causes less pain and burning at the
infusion site and minimal consequences in case of I.V infiltration,
allows longer maintenance of I.V sites, and has better I.V fluid
compatibility and stability.

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Bioactivation (metabolism):
Fosphenytoin is principally eliminated by metabolism to
phenytoin. As outlined in the figure below, fosphenytoin is cleaved
by phosphatases in the blood and tissues to 3-
(hydroxymethyl)phenytoin, which then spontaneously hydrolyses to
phenytoin, releasing formaldehyde. In vitro studies show
fosphenytoin to be a substrate for both acid and alkaline
phosphatases. The formaldehyde derived from fosphenytoin is
converted to formate and subsequently metabolised. Excretion of
unchanged fosphenytoin in the urine is negligible. (<5% of the
administered dose)
The elimination half-life of fosphenytoin is similar in healthy
subjects and patients with normal renal and hepatic function, and
typically ranges from 7–15 minutes after intravenous administration.
This rapid in vivo half life contrasts with an in vitro half life of 3.2
hours after incubation of fosphenytoin in human whole blood. The
difference between the in vivo and in vitro half lives suggests that
after systemic administration the conversion of fosphenytoin to
phenytoin is predominately mediated by phosphatases in tissues,
such as the liver, kidney and small intestine.