Tmic
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Record Information
Version2.0
Creation Date2009-07-21 20:28:46 UTC
Update Date2014-12-24 20:25:56 UTC
Accession NumberT3D3036
Identification
Common NameFosphenytoin
ClassSmall Molecule
DescriptionFosphenytoin 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.
Compound Type
  • Amide
  • Amine
  • Anticonvulsant
  • Drug
  • Metabolite
  • Organic Compound
  • Synthetic Compound
Chemical Structure
Thumb
Synonyms
Synonym
(3-Phosphoryloxymethyl)phenytoin
Cerebyx
Fosfenitoina
Fosphenytoine
Fosphenytoinum
Prodilantin
Chemical FormulaC16H15N2O6P
Average Molecular Mass362.274 g/mol
Monoisotopic Mass362.067 g/mol
CAS Registry Number93390-81-9
IUPAC Name[(2,5-dioxo-4,4-diphenylimidazolidin-1-yl)methoxy]phosphonic acid
Traditional Namefosphenytoin
SMILESOC1=NC(C(=O)N1COP(O)(O)=O)(C1=CC=CC=C1)C1=CC=CC=C1
InChI IdentifierInChI=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)
InChI KeyInChIKey=XWLUWCNOOVRFPX-UHFFFAOYSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as diphenylmethanes. Diphenylmethanes are compounds containing a diphenylmethane moiety, which consists of a methane wherein two hydrogen atoms are replaced by two phenyl groups.
KingdomOrganic compounds
Super ClassBenzenoids
ClassBenzene and substituted derivatives
Sub ClassDiphenylmethanes
Direct ParentDiphenylmethanes
Alternative Parents
Substituents
  • Diphenylmethane
  • Alpha-amino acid or derivatives
  • N-acyl urea
  • Ureide
  • Monoalkyl phosphate
  • Imidazolinone
  • Organic phosphoric acid derivative
  • Phosphoric acid ester
  • Alkyl phosphate
  • 2-imidazoline
  • Isourea
  • Azacycle
  • Carboxylic acid derivative
  • Carboximidamide
  • Organoheterocyclic compound
  • Organic 1,3-dipolar compound
  • Propargyl-type 1,3-dipolar organic compound
  • Hydrocarbon derivative
  • Organopnictogen compound
  • Organic nitrogen compound
  • Organonitrogen compound
  • Organic oxygen compound
  • Organooxygen compound
  • Carbonyl group
  • Organic oxide
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Extracellular
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
Pathways
NameSMPDB LinkKEGG Link
Fosphenytoin (Antiarrhythmic) PathwayNot AvailableNot Available
ApplicationsNot Available
Biological RolesNot Available
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Pointv . d . e Anticonvulsants ( N03 )
Boiling PointNot Available
Solubility1.45e-01 g/L
LogPNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.14 g/LALOGPS
logP1.08ALOGPS
logP1.67ChemAxon
logS-3.4ALOGPS
pKa (Strongest Acidic)1.46ChemAxon
pKa (Strongest Basic)-9.7ChemAxon
Physiological Charge-2ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area116.17 ŲChemAxon
Rotatable Bond Count5ChemAxon
Refractivity87.05 m³·mol⁻¹ChemAxon
Polarizability33.23 ųChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash Key
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-00ls-4941000000-7f020f5c4237af5bfb3cView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-03di-0019000000-801dc353a42886feac15View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-03dj-1019000000-954988a4832c09ddde71View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0uy0-5931000000-a2e668ce8b6003249e52View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-03di-2009000000-f100b603f8bec4297f64View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-004i-9100000000-974b8eaa512f665645c7View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-002f-9000000000-edcf929c72670ddaeafeView in MoNA
Toxicity Profile
Route of ExposureFosphenytoin is completely bioavailable following lM administration.
Mechanism of ToxicityFosphenytoin 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.
MetabolismHepatic. 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.
Toxicity ValuesLD50: 156 mg PE/kg (Intravenous, Mouse) (4) LD50: 250 mg PE/kg (Intravenous, Rat) (4)
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesFor the control of generalized convulsive status epilepticus and prevention and treatment of seizures occurring during neurosurgery. It can also be substituted, short-term, for oral phenytoin.
Minimum Risk LevelNot Available
Health EffectsMay cause a potentially dangerous rash that may develop into Stevens Johnson syndrome, an extremely rare but potentially fatal skin disease.
SymptomsNausea, vomiting, lethargy, tachycardia, bradycardia, asystole, cardiac arrest, hypotension, syncope, hypocalcemia, metabolic acidosis, and death have been reported in cases of overdosage with fosphenytoin. Signs of acute toxicity in animals included ataxia, labored breathing, ptosis, and hypoactivity.
TreatmentTreatment is nonspecific since there is no known antidote to Fosphenytoin overdosage. The adequacy of the respiratory and circulatory systems should be carefully observed, and appropriate supportive measures employed. Hemodialysis can be considered since phenytoin is not completely bound to plasma proteins. Total exchange transfusion has been used in the treatment of severe intoxication in children. (7)
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB01320
HMDB IDHMDB15417
PubChem Compound ID56339
ChEMBL IDCHEMBL1201336
ChemSpider ID50839
KEGG IDC07840
UniProt IDNot Available
OMIM ID
ChEBI ID775287
BioCyc IDNot Available
CTD IDNot Available
Stitch IDFosphenytoin
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkFosphenytoin
References
Synthesis Reference

Volker Kirsch, “Process for the preparation of sodium fosphenytoin.” U.S. Patent US20050272706, issued December 08, 2005.

MSDST3D3036.pdf
General References
  1. Johnson J, Wrenn K: Inappropriate fosphenytoin use in the ED. Am J Emerg Med. 2001 Jul;19(4):293-4. [11447516 ]
  2. Applebaum J, Levine J, Belmaker RH: Intravenous fosphenytoin in acute mania. J Clin Psychiatry. 2003 Apr;64(4):408-9. [12716241 ]
  3. McCleane GJ: Intravenous infusion of fosphenytoin produces prolonged pain relief: a case report. J Pain. 2002 Apr;3(2):156-8. [14622802 ]
  4. Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. [18048412 ]
  5. Luszczki JJ: Third-generation antiepileptic drugs: mechanisms of action, pharmacokinetics and interactions. Pharmacol Rep. 2009 Mar-Apr;61(2):197-216. [19443931 ]
  6. Browne TR, Kugler AR, Eldon MA: Pharmacology and pharmacokinetics of fosphenytoin. Neurology. 1996 Jun;46(6 Suppl 1):S3-7. [8649612 ]
  7. RxList: The Internet Drug Index (2009). [Link]
  8. Gaval-Cruz M, Weinshenker D: mechanisms of disulfiram-induced cocaine abstinence: antabuse and cocaine relapse. Mol Interv. 2009 Aug;9(4):175-87. [Link]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

General Function:
Voltage-gated sodium channel activity involved in sa node cell action potential
Specific Function:
This protein mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient. It is a tetrodotoxin-resistant Na(+) channel isoform. This channel is responsible for the initial upstroke of the action potential. Channel inactivation is regulated by intracellular calcium levels.
Gene Name:
SCN5A
Uniprot ID:
Q14524
Molecular Weight:
226937.475 Da
References
  1. Swadron SP, Rudis MI, Azimian K, Beringer P, Fort D, Orlinsky M: A comparison of phenytoin-loading techniques in the emergency department. Acad Emerg Med. 2004 Mar;11(3):244-52. [15001403 ]