Size | Price | Stock | Qty |
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100mg |
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500mg |
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1g |
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ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
Fosphenytoin at 15 to 20 mg PE/kg infused at 100 to 150 mg PE/min intravenously yields free plasma phenytoin concentrations similar to an equivalent dose of phenytoin sodium administered at 50 mg/min. Single intravenous administration of fosphenytoin shows a linear increase in mean maximum total phenytoin concentration while the mean maximum unbound phenytoin concentrations increase with both dose and infusion rate. Fosphenytoin is rapidly converted to phenytoin following intravenous administration with a half-life of 15 minutes; if administered intramuscularly, the peak plasma phenytoin concentration is not reached until three hours. Phenytoin derived from fosphenytoin administration is excreted in the urine primarily as 5-(p-hydroxyphenyl)-5-phenylhydantoin and its glucuronide. There is little unchanged phenytoin (1%–5% of the administered dose), and essentially no fosphenytoin recovered in urine. The volume of distribution of fosphenytoin increases with dose and rate, ranging between 4.3 and 10.8 L. Bioavailability from either intravenous or intramuscular route is essentially 100%. /Fosphenytoin is/ most likely distributed in humans to heart, kidneys, small intestine, liver, lungs, spleen, where it is hydrolyzed by phosphatases to phenytoin. Predominately distributed in the central (plasma) compartment. The volume of distribution ranges from 4.3 to 10.8 liters, and increases with increasing dose and administration rate of fosphenytoin. Protein binding is very high (95 to 99%); degree of binding is saturable, with the result that the percent bound decreases as the total plasma fosphenytoin concentration increases. For more Absorption, Distribution and Excretion (Complete) data for FOSPHENYTOIN (10 total), please visit the HSDB record page. Metabolism / Metabolites Fosphenytoin is metabolized, likely by phosphatases, to phenytoin, phosphate, and formaldehyde; the formaldehyde is subsequently converted into formate. The phenytoin produced is metabolized hepatically by CYP2C9 and, to a lesser extent, by CYP2C19. Fosphenytoin undergoes rapid hydrolysis to phenytoin. ... Conversion of fosphenytoin also yields two additional metabolites, phosphate and formaldehyde. Formaldehyde is subsequently converted to formate, which in turn is metabolized via a folate-dependent mechanism. ... Phosphatase enzymes probably play a major role in the conversion of fosphenytoin to phenytoin. This investigation was undertaken to identify the structure of a novel immunoreactive metabolite derived from fosphenytoin that has been hypothesized previously as present in sera from renally impaired patients receiving this prodrug. The metabolite was isolated from uremic sera using solid-phase extraction and HPLC. Structural analysis was performed using HPLC-tandem mass spectrometry, nuclear magnetic resonance (NMR), deuterium exchange, and chemical derivatization. Immunoreactivity was evaluated using a fluorescence polarization immunoassay. The metabolite had a parent ion at m/z 457 in the negative-ion mode and fragmented to yield the m/z 251 of phenytoin, as well as other mass fragments of phenytoin. Mass fragments associated with glucuronic acid were also present. The chromatographic peak corresponding to this metabolite demonstrated immunoreactivity sufficient to lead to falsely increased reported values for phenytoin immunoassays. The observed immunoreactivity was also proportional to the relative concentration of the metabolite in collected fractions. Analysis by NMR indicated the presence of phenyl groups with chemical shifts identical to those of phenytoin, as well as the presence of a methylene bridge, which was consistent with the same methylene bridge present on the phosphate ester of fosphenytoin. Comparative analysis of serum samples from renally impaired patients receiving phenytoin vs fosphenytoin using multiple reaction monitoring quantification demonstrated that this metabolite was associated with fosphenytoin administration. A unique immunoreactive oxymethylglucuronide metabolite derived from fosphenytoin has been isolated from sera from uremic patients receiving this prodrug. Fosphenytoin sodium is a hydantoin-derivative anticonvulsant. Fosphenytoin sodium, a water-soluble phosphate ester of phenytoin, is a prodrug and has little, if any, anticonvulsant activity until hydrolyzed in vivo to phenytoin. Pharmacologic effects of fosphenytoin include those of phenytoin. Hepatic. Route of Elimination: Phenytoin derived from administration of Cerebyx is extensively metabolized in the liver and excreted in urine primarily as 5-(p-hydroxyphenyl)-5-phenylhydantoin and its glucuronide; little unchanged phenytoin (1%-5% of the Cerebyx dose) is recovered in urine. Half Life: Fosphenytoin has a half-life of approximately 15 minutes. Biological Half-Life Fosphenytoin has a conversion half-life of approximately 15 minutes. The resulting phenytoin has a wide range of mean total half-life values (12 to 28.9 hours), with longer half-life times at higher administered doses. A single dose of fosphenytoin (250 mg over a period of 30 min) was administered to subjects with hepatic cirrhosis (n = 4), renal disease requiring maintenance hemodialysis (n = 4), and healthy controls (n = 4). The half-life of fosphenytoin was 4.5, 9.2, and 9.5 min for the three groups, respectively. The conversion half-life /of fosphenytoin/ to phenytoin ranges from 8 to 15 minutes. This value is independent of dose, infusion rate, or plasma concentration of either fosphenytoin or phenytoin. The elimination half-life of fosphenytoin after intravenous or intramuscular injection is also independent of dose. |
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Toxicity/Toxicokinetics |
Toxicity Summary
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. Toxicity Data LD50: 156 mg PE/kg (Intravenous, Mouse) (A308) LD50: 250 mg PE/kg (Intravenous, Rat) (A308) Interactions Risk of hepatotoxicity from a single toxic dose or prolonged use of acetaminophen may be increased and therapeutic efficacy may be decreased in patients regularly taking other hepatic enzyme-inducing agents such as phenytoin. /Hydantoin anticonvulsants/ Concurrent use of alcohol or CNS depression-producing medications with hydantoin anticonvulsants may enhance CNS depression. Chronic use of alcohol may decrease serum concentrations and effectiveness of hydantoins; concurrent use of hydantoin anticonvulsants with acute alcohol intake may increase serum hydantoin concentrations. /Hydantoin anticonvulsants/ Concurrent use of amiodarone with phenytoin and possibly with other hydantoin anticonvulsants may increase plasma concentrations of the hydantoin, resulting in increased effects and/or toxicity. /Hydantoin anticonvulsants/ Concurrent use with coumarin- or indandione-derivative anticoagulants, chloramphenicol, cimetidine, disulfiram, influenza virus vaccine, isoniazid, methylphenidate, phenylbutazone, ranitidine, salicylates, or sulfonamide may increase serum concentrations of hydantoin anticonvulsants because of decreased metabolism, thereby increasing the /hydantoins'/ effects and/or toxicity. Dosage adjustments of the anticonvulsant may be necessary. In addition, the anticoagulant effect of coumarin- or indandione-derivative anticoagulants may be increased initially, but decrease with continued concurrent use. /Hydantoin anticonvulsants/ For more Interactions (Complete) data for FOSPHENYTOIN (23 total), please visit the HSDB record page. |
Additional Infomation |
Fosphenytoin is an imidazolidine-2,4-dione.
Fosphenytoin is a water-soluble phenytoin prodrug used only in hospitals for the treatment of epileptic seizures. It works by slowing down impulses in the brain that cause seizures. Its main mechanism is to block frequency-dependent, use-dependent and voltage-dependent neuronal sodium channels, and therefore limit repetitive firing of action potentials. Fosphenytoin is an Anti-epileptic Agent. The physiologic effect of fosphenytoin is by means of Decreased Central Nervous System Disorganized Electrical Activity. Fosphenytoin is a prodrug of phenytoin available in parenteral forms only. While not specifically associated with cases of drug induced liver injury, fosphenytoin is converted to phenytoin which is a well known cause of acute idiosyncratic drug induced liver disease. Fosphenytoin is a water-soluble phosphate ester prodrug of phenytoin, a hydantoin derivative with anticonvulsant activity. Fosphenytoin is hydrolyzed to phenytoin by phosphatases. Phenytoin exerts its effect mainly by promoting sodium efflux and stabilizes neuronal membranes in the motor cortex. This leads to a suppression of excessive neuronal firing and limits the spread of seizure activity. Fosphenytoin is a water-soluble phenytoin prodrug used only in hospitals for the treatment of epileptic seizures. It works by slowing down impulses in the brain that cause seizures. Its main mechanism is to block frequency-dependent, use-dependent and voltage-dependent neuronal sodium channels, and therefore limit repetitive firing of action potentials. See also: Fosphenytoin Sodium (annotation moved to). Drug Indication 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. It can also be substituted, short-term, for oral phenytoin in patients aged two years and older when oral phenytoin administration is not possible. FDA Label 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. The mechanism of action is not completely known, but it is thought to involve stabilization of neuronal membranes at the cell body, axon, and synapse and limitation of the spread of neuronal or seizure activity. In neurons, phenytoin decreases sodium and calcium ion influx by prolonging channel inactivation time during generation of nerve impulses. Phenytoin blocks the voltage-dependant sodium channels of neurons and inhibits the calcium flux across neuronal membranes, thus helping to stabilize neurons. It also decreases synaptic transmission, and decreases post-tetanic potentiation at the synapse. Phenytoin enhances the sodium ATPase activity of neurons and/or glial cells. It also influences second messenger systems by inhibiting calcium-calmodulin protein phosphorylation and possibly altering cyclic nucleotide production or metabolism. Therapeutic Uses Parenteral fosphenytoin and phenytoin are both indicated for the control of tonic-clonic type status epilepticus. Although parenteral benzodiazepines are often used initially for rapid control of status epilepticus, both fosphenytoin and phenytoin are indicated for sustained control of seizure activity. /Included in US product label/ Fosphenytoin and phenytoin are both indicated for the prevention and treatment of seizures during and following neurosurgery. /Included in US product label/ Hydantoin anticonvulsants are indicated in the suppression and control of tonic-clonic (grand mal) and simple or complex partial (psychomotor or temporal lobe) seizures. /Hydantoin anticonvulsants; Included in US product labeling./ The objective of this case report is to emphasize the analgesic effect of antiepileptic drugs in those with neuropathic pain, confirm that fosphenytoin possesses these analgesic properties, and to highlight that intravenous administration of fosphenytoin for 24 hours can produce good quality pain relief that lasts for many weeks. A 37-year-old woman with a neuroma (caused by surgical intervention for an endometrial sarcoma) producing neuropathic pain unresponsive to opiates was successfully treated with intravenous infusion of 1,500 phenytoin equivalent units fosphenytoin for 24 hours. The pain relief after this and subsequent infusions persisted for between 3 and 14 weeks and was associated with a reduced opiate requirement and an increase in activities of daily living. Fosphenytoin infusion can give good quality pain relief in the patient with neuropathic pain. Drug Warnings Known hypersensitivity to fosphenytoin or any ingredient in the formulation, phenytoin, or other hydantoins. Sinus bradycardia, sinoatrial block, second- or third-degree atrioventricular (AV) block, Adams-Stokes syndrome (Stokes-Adams disease). Doses of fosphenytoin sodium should always be expressed in terms of phenytoin sodium equivalents (PE). Therefore, adjustment to the recommended dosage should not be made when switching from phenytoin sodium to fosphenytoin sodium or vice versa. Abrupt withdrawal of any anticonvulsant drug may result in increased seizure frequency or status epilepticus; therefore, if in the clinician's judgment there is a need for dosage reduction, discontinuance, or substitution of an anticonvulsant, this should be done gradually. However, if an allergic or hypersensitivity reaction occurs during fosphenytoin therapy, discontinuance of the drug and institution of alternative anticonvulsant therapy (with a drug structurally unrelated to hydantoin derivatives) may be necessary depending on the severity of the symptoms. For more Drug Warnings (Complete) data for FOSPHENYTOIN (20 total), please visit the HSDB record page. Pharmacodynamics Fosphenytoin is a water-soluble phenytoin prodrug used for the treatment of epileptic seizures. Following parenteral administration of fosphenytoin, fosphenytoin is converted to the anticonvulsant phenytoin by endogenous phosphatases. Each 1.5 mg of fosphenytoin sodium is equivalent to 1.0mg of phenytoin sodium (PE equivalents); care should be taken to calculate the dose required in PE equivalents properly. Serious adverse effects such as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN), and hematopoietic complications may occur and indicate an alternate antiepileptic should be used. Withdrawal of fosphenytoin sodium may precipitate seizures and should be done gradually. |
Molecular Formula |
C16H15N2O6P
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Molecular Weight |
362.27400
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Exact Mass |
362.067
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CAS # |
93390-81-9
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Related CAS # |
Fosphenytoin disodium;92134-98-0
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PubChem CID |
56339
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Appearance |
White crystals from acetone
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Density |
1.495g/cm3
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Melting Point |
173-176.5 °C
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Index of Refraction |
1.63
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LogP |
1.815
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Hydrogen Bond Donor Count |
3
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Hydrogen Bond Acceptor Count |
6
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Rotatable Bond Count |
5
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Heavy Atom Count |
25
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Complexity |
547
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Defined Atom Stereocenter Count |
0
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SMILES |
O=C1N(C(NC1(C2=CC=CC=C2)C3=CC=CC=C3)=O)COP(O)(O)=O
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InChi Key |
XWLUWCNOOVRFPX-UHFFFAOYSA-N
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InChi Code |
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)
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Chemical Name |
(2,5-dioxo-4,4-diphenylimidazolidin-1-yl)methyl dihydrogen phosphate
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HS Tariff Code |
2934.99.9001
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Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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Solubility (In Vitro) |
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
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Solubility (In Vivo) |
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.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80: Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *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). View More
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)] Oral Formulations
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). View More
Oral Formulation 3: Dissolved in PEG400  (Please use freshly prepared in vivo formulations for optimal results.) |
Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
1 mM | 2.7604 mL | 13.8019 mL | 27.6037 mL | |
5 mM | 0.5521 mL | 2.7604 mL | 5.5207 mL | |
10 mM | 0.2760 mL | 1.3802 mL | 2.7604 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration: mg/mL;
Method for preparing DMSO stock solution: mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation::Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.