Absorption, Distribution and Excretion
Intravenous infusion of 15–20 mg PE/kg of fosphenytoin sodium at a rate of 100–150 mg PE/min results in plasma free phenytoin concentrations similar to those achieved with an equivalent dose of phenytoin sodium administered intravenously at a rate of 50 mg/min. Following a single intravenous injection of fosphenytoin sodium, the mean maximum total phenytoin concentration increases linearly, while the mean maximum free phenytoin concentration increases with both dose and infusion rate. After intravenous injection, fosphenytoin sodium is rapidly converted to phenytoin with a half-life of 15 minutes; if administered intramuscularly, it takes up to 3 hours to reach peak plasma phenytoin concentrations. Phenytoin produced after fosphenytoin sodium administration is primarily excreted in the urine as 5-(p-hydroxyphenyl)-5-phenylhydantoin and its glucuronide. Almost no unmetabolized phenytoin sodium (only 1%–5% of the administered dose) is found, and fosphenytoin sodium is virtually undetectable in urine.
The volume of distribution of fosphenytoin sodium increases with increasing dose and rate of administration, ranging from 4.3 to 10.8 liters.
Bioavailability via intravenous or intramuscular route is almost 100%.
Fosphenytoin sodium is most likely distributed in the heart, kidneys, small intestine, liver, lungs, and spleen, where it is hydrolyzed to phenytoin sodium by phosphatases. It is primarily distributed in the central (plasma) compartment.
The volume of distribution ranges from 4.3 to 10.8 liters and increases with increasing dose and rate of administration of fosphenytoin sodium.
Protein binding is very high (95%–99%). The degree of binding of fosphenytoin sodium is saturable; therefore, the percentage of binding decreases with increasing total plasma fosphenytoin sodium concentration.
For more complete data on the absorption, distribution, and excretion of fosphenytoin sodium (10 types), please visit the HSDB records page.

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Metabolism/Metabolites
Fosphenytoin sodium may be metabolized by phosphatases to phenytoin sodium, phosphate, and formaldehyde; formaldehyde is then converted to formic acid. The resulting phenytoin sodium is primarily metabolized by hepatic CYP2C9, with a small amount metabolized by CYP2C19.
Fosphenytoin sodium is rapidly hydrolyzed to phenytoin sodium. …The conversion of fosphenytoin sodium also produces two other metabolites: phosphate and formaldehyde. Formaldehyde is then converted to formic acid, which is metabolized via a folic acid-dependent mechanism. …Phosphoplasty may play an important role in the conversion of fosphenytoin to phenytoin.
This study aimed to identify the structure of a novel immunoreactive metabolite derived from fosphenytoin, which previous studies hypothesized to be present in the serum of patients with impaired renal function who had taken this prodrug. The metabolite was isolated from the serum of uremic patients using solid-phase extraction and high-performance liquid chromatography (HPLC). Structural analysis was performed using HPLC-tandem mass spectrometry, nuclear magnetic resonance (NMR), deuterium exchange, and chemical derivatization. Immunoreactivity was assessed using fluorescence polarization immunoassay. The metabolite, in negative ion mode, has a parent ion at m/z 457 and fragments to produce a phenytoin ion at m/z 251, along with other phenytoin fragment ions. Mass spectrometric fragmentation associated with glucuronic acid was also present. The chromatographic peaks corresponding to this metabolite showed sufficient immunoreactivity to cause a false increase in the phenytoin immunoassay report value. The observed immunoreactivity was also proportional to the relative concentration of the metabolite in the collected fraction. NMR analysis revealed the presence of a phenyl group with the same chemical shift as phenytoin, as well as a methylene bridge, consistent with the methylene bridge present on fosphenytoin phosphate. Comparative analysis of serum samples from patients with impaired renal function treated with phenytoin and fosphenytoin using multiple reaction monitoring quantification showed that this metabolite was associated with fosphenytoin administration. A unique immunoreactive hydroxymethylglucuronide metabolite was isolated from the serum of uremic patients treated with fosphenytoin sodium. Fosphenytoin sodium is a phenytoin derivative anticonvulsant. Fosphenytoin sodium is a water-soluble phosphate ester of phenytoin, a prodrug that has almost no anticonvulsant activity before being hydrolyzed to phenytoin in the body. The pharmacological effects of fosphenytoin are the same as those of phenytoin.
Hepatic metabolism.
Excretion route: Phenytoin produced after Cerebyx administration is extensively metabolized in the liver and mainly excreted in the urine as 5-(p-hydroxyphenyl)-5-phenylphenytoin and its glucuronide; only a small amount of unmetabolized phenytoin sodium is recovered in the urine (1%-5% of the Cerebyx dose).
Half-life: The half-life of fosphenytoin sodium is approximately 15 minutes.
Biological half-life
The conversion half-life of fosphenytoin sodium is approximately 15 minutes. The average total half-life of the generated phenytoin sodium ranges widely (12 to 28.9 hours), with a longer half-life at higher doses.
In subjects with cirrhosis (n = 4), renal disease requiring maintenance hemodialysis (n = 4), and healthy controls (n = 4), a single dose of fosphenytoin sodium (250 mg, administered over 30 minutes) was given. The half-lives of fosphenytoin sodium in the three groups were 4.5 minutes, 9.2 minutes, and 9.5 minutes, respectively.
The half-life of fosphenytoin sodium to phenytoin sodium was 8 to 15 minutes. This value was independent of the dose, infusion rate, or plasma concentration of fosphenytoin sodium or phenytoin sodium. The elimination half-life of fosphenytoin sodium after intravenous or intramuscular injection was also independent of the dose.

Toxicity Summary
Phenotodextrin sodium is a prodrug of phenytoin sodium; therefore, its anticonvulsant effect is attributed to phenytoin sodium. Phenytoin sodium acts on sodium channels on neuronal cell membranes, limiting the spread of epileptic activity and reducing the propagation of seizures. By promoting sodium ion efflux from neurons, phenytoin sodium helps stabilize the neuronal threshold for overexcitation, preventing overexcitation caused by overstimulation or environmental changes (e.g., reduced membrane sodium gradient). This includes reducing postsynaptic tonic enhancement. Loss of postsynaptic enhancement prevents the spread of cortical epileptic foci to adjacent cortical areas. Toxicity Data
LD50: 156 mg PE/kg (intravenous, mouse) (A308) LD50: 250 mg PE/kg (intravenous, rat) (A308) Interactions For patients regularly taking other liver enzyme inducers (e.g., phenytoin sodium), a single toxic dose or prolonged use of acetaminophen may increase the risk of hepatotoxicity and reduce treatment efficacy. /Phenytoin Anticonvulsants/
Concurrent use of alcohol or central nervous system depressants may enhance the central nervous system depressant effects of phenytoin anticonvulsants. Prolonged alcohol consumption may decrease serum concentrations and efficacy of phenytoin-based drugs; concomitant use of phenytoin anticonvulsants and acute alcohol intake may increase serum phenytoin concentrations. /Phenytoin Anticonvulsants/
Concomitant use of amiodarone with phenytoin sodium and other phenytoin anticonvulsants may increase plasma phenytoin concentrations, thereby enhancing its effects and/or toxicity. /Phenytoin Anticonvulsants/
Concomitant use of coumarin or indanedione derivative anticoagulants, chloramphenicol, cimetidine, disulfiram, influenza virus vaccine, isoniazid, methylphenidate, phenylbutazone, ranitidine, salicylates, or sulfonamides may increase serum phenytoin anticonvulsant concentrations due to slowed metabolism, thereby enhancing its effects and/or toxicity. Dosage adjustment of the anticonvulsant may be necessary. In addition, the anticoagulant effect of coumarin or indanedione derivatives may initially be enhanced, but diminishes with continued combined use. /Phenytoin anticonvulsants/
For more complete data on interactions of fosphenytoin sodium (23 in total), please visit the HSDB record page.

Fosphenytoin sodium is an imidazolidine-2,4-dione compound. Fosphenytoin sodium is a water-soluble prodrug of phenytoin sodium, used only in hospitals to treat seizures. Its mechanism of action is to slow the neural impulses in the brain that trigger seizures. Its primary mechanism is to block frequency-dependent, use-dependent, and voltage-dependent neuronal sodium channels, thereby limiting the repetitive firing of action potentials. Fosphenytoin sodium is an antiepileptic drug. The physiological effects of fosphenytoin sodium are achieved by reducing disordered electrical activity in the central nervous system. Fosphenytoin sodium is a prodrug of phenytoin sodium and is available only in injectable form. Although fosphenytoin sodium does not directly cause drug-induced liver injury, it is converted to phenytoin sodium, which is a known cause of acute specific drug-induced liver disease. Fosphenytoin sodium is a water-soluble phosphate prodrug of phenytoin sodium, a hydantoin derivative with anticonvulsant activity. Fosphenytoin sodium is hydrolyzed to phenytoin sodium by phosphatase. Phenytoin sodium primarily works by promoting sodium ion efflux and stabilizing the neuronal membranes of the motor cortex. This leads to excessive neuronal firing, thereby limiting the spread of seizures. Fosphenytoin sodium is a water-soluble prodrug of phenytoin sodium and is used only in hospitals to treat seizures. Its mechanism of action is to slow the neural impulses in the brain that trigger seizures. Its main mechanism is to block frequency-dependent, use-dependent, and voltage-dependent neuronal sodium channels, thereby limiting the repetitive firing of action potentials. See also: Fosphenytoin sodium (note moved to).

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Drug Indications
Fosphenytoin is indicated for the treatment of generalized tonic-clonic status epilepticus and for the prevention and treatment of seizures occurring during neurosurgery in adult patients. Fosphenytoin may also be used as a short-term alternative to oral phenytoin in patients two years of age and older who are unable to take oral phenytoin.
FDA LabelMechanism of Action
Fosphenytoin is a prodrug of phenytoin; therefore, its anticonvulsant effect is attributed to phenytoin. Phenytoin acts on sodium channels in neuronal cell membranes, limiting the spread of epileptic activity and reducing the propagation of seizures. Phenytoin sodium helps stabilize the neuronal threshold for overexcitation by promoting sodium ion efflux from neurons, preventing overexcitation caused by overstimulation or environmental changes (such as a decrease in the membrane sodium ion gradient). This includes reducing postsynaptic tonic enhancement. Loss of postsynaptic tonic enhancement prevents the spread of cortical epileptic foci to adjacent cortical areas. Its mechanism of action is not fully elucidated, but it is generally believed to involve stabilizing the neuronal membrane at the cell body, axon, and synapse, and limiting the spread of neuronal activity or seizures. In neurons, phenytoin sodium reduces sodium and calcium ion influx by prolonging the channel inactivation time during nerve impulse generation. Phenytoin sodium blocks voltage-dependent sodium channels in neurons, inhibiting calcium ion flow across the neuronal membrane, thereby contributing to neuronal stability. It also reduces synaptic transmission and decreases postsynaptic tonic enhancement. Phenytoin sodium can enhance sodium ATPase activity in neurons and/or glial cells. It can also affect the second messenger system by inhibiting calmodulin phosphorylation and potentially altering the production or metabolism of cyclic nucleotides.

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Therapeutic Use
Both fosphenytoin sodium for injection and phenytoin sodium are indicated for the control of tonic-clonic status epilepticus. While injectable benzodiazepines are typically used for rapid control of status epilepticus, both fosphenytoin sodium and phenytoin sodium are indicated for sustained control of seizures. /US product label includes/
Both fosphenytoin sodium and phenytoin sodium are indicated for the prevention and treatment of seizures during and after neurosurgical procedures. /US product label includes/
Phenytoin anticonvulsants are indicated for the suppression and control of tonic-clonic (grand mal) and simple or complex partial (psychomotor or temporal lobe) seizures. /Phenytoin anticonvulsants; US product label includes. This case report aims to highlight the analgesic effect of antiepileptic drugs in patients with neuropathic pain, confirming the analgesic properties of fosphenytoin and emphasizing that intravenous infusion of fosphenytoin over 24 hours can produce a good analgesic effect lasting for several weeks. A 37-year-old woman developed neuroma following surgery for endometrial sarcoma, causing neuropathic pain and unresponsiveness to opioids. Pain was effectively relieved 24 hours after intravenous infusion of 1500 phenytoin equivalent units of fosphenytoin. Pain relief lasted 3 to 14 weeks after this and subsequent infusions, accompanied by reduced opioid requirements and improved activities of daily living. Fosphenytoin sodium infusion can provide good analgesia for patients with neuropathic pain.

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Drug Warnings
This drug is contraindicated in patients with known hypersensitivity to fosphenytoin sodium or any component of its formulations, phenytoin sodium, or other hydantoin derivatives.

This medication is contraindicated in patients with sinus bradycardia, sinoatrial block, second- or third-degree atrioventricular block, or Adams-Stokes syndrome (Stokes-Adams disease).
The dosage of fosphenytoin sodium should always be expressed in phenytoin sodium equivalents (PE).
Therefore, the recommended dose should not be adjusted when switching from phenytoin sodium to fosphenytoin sodium or vice versa.
Sudden discontinuation of any antiepileptic drug may lead to an increase in the frequency of seizures or status epilepticus; therefore, if a clinician determines that a dose reduction, discontinuation, or change of antiepileptic drug is necessary, it should be done gradually. However, if an allergic or hypersensitivity reaction occurs during fosphenytoin treatment, it may be necessary to discontinue the drug and switch to another antiepileptic drug (one whose structure is not related to phenytoin derivatives) depending on the severity of the symptoms.
For more complete data on drug warnings for fosphenytoin (20 in total), please visit the HSDB record page.

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Pharmacodynamics
Fosphenytoin is a water-soluble phenytoin prodrug used to treat seizures. After administration via the parenteral route, fosphenytoin is converted to the antiepileptic drug phenytoin by endogenous phosphatases. Each 1.5 mg fosphenytoin sodium dose is equivalent to 1.0 mg phenytoin sodium (PE equivalent); care should be taken to correctly calculate the required PE equivalent dose. Serious adverse reactions may occur, such as drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), and hematopoietic complications, suggesting the use of other antiepileptic drugs. Discontinuation of fosphenytoin sodium may induce seizures; therefore, discontinuation should be gradual.

C16H15N2O6P

362.27400

362.067

93390-81-9

Fosphenytoin disodium;92134-98-0

56339

White crystals from acetone

1.495g/cm3

173-176.5 °C

1.63

1.815

3

6

5

25

547

0

O=C1N(C(NC1(C2=CC=CC=C2)C3=CC=CC=C3)=O)COP(O)(O)=O

XWLUWCNOOVRFPX-UHFFFAOYSA-N

InChI=1S/C16H15N2O6P/c19-14-16(12-7-3-1-4-8-12,13-9-5-2-6-10-13)17-15(20)18(14)11-24-25(21,22)23/h1-10H,11H2,(H,17,20)(H2,21,22,23)

(2,5-dioxo-4,4-diphenylimidazolidin-1-yl)methyl dihydrogen phosphate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)