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Identification
Name Fosphenytoin
Accession Number DB01320
Type small molecule
Groups approved
Description

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.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • (3-Phosphoryloxymethyl)phenytoin
  • Fosfenitoina [inn-spanish]
  • Fosphenytoin sodium
  • Fosphenytoine [inn-french]
  • Fosphenytoinum [inn-latin]
Brand names
  • Cerebyx
  • Prodilantin
Brand name mixtures Not Available
Categories
  • Anticonvulsants
CAS number 93390-81-9
Weight Average: 362.2739
Monoisotopic: 362.066772734
Chemical Formula C16H15N2O6P
InChI Key InChIKey=XWLUWCNOOVRFPX-UHFFFAOYSA-N
InChI
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)
Plain Text
IUPAC Name
[(2,5-dioxo-4,4-diphenylimidazolidin-1-yl)methoxy]phosphonic acid
SMILES
OP(O)(=O)OCN1C(=O)NC(C1=O)(C1=CC=CC=C1)C1=CC=CC=C1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Diphenylmethanes
Substructures
  • Imidazolidinediones
  • Hydroxy Compounds
  • Phosphonic Acids and Derivatives
  • Amino Ketones
  • Organophosphate Esters
  • Benzene and Derivatives
  • Ureas and Derivatives
  • Imidazolidines
  • Diphenylmethanes
  • Phenethylamines
  • Heterocyclic compounds
  • Aromatic compounds
  • Carboxamides and Derivatives
  • Phosphinic Acids and Derivatives
  • Carboxylic Acids and Derivatives
Pharmacology
Indication For 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.
Pharmacodynamics Fosphenytoin is a water-soluble phenytoin prodrug used only in hospitals for the treatment of epileptic seizures. Following parenteral administration of fosphenytoin, fosphenytoin is converted to the anticonvulsant phenytoin by endogenous phosphatases. For every mmol of fosphenytoin administered, one mmol of phenytoin is produced. The pharmacological and toxicological effects of fosphenytoin include those of phenytoin.
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.
Absorption Fosphenytoin is completely bioavailable following lM administration.
Volume of distribution
  • 4.3 to 10.8 L
Protein binding Extensively bound (95% to 99%) to human plasma proteins, primarily albumin.
Metabolism

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.
Clearance Not Available
Toxicity Nausea, vomiting, lethargy, tachycardia, bradycardia, asystole, cardiac arrest, hypotension, syncope, hypocalcemia, metabolic acidosis, and death have been reported in cases of overdosage with fosphenytoin. The median lethal dose of fosphenytoin given intravenously in mice and rats was 156 mg PE/kg and approximately 250 mg PE/kg, or about 0.6 and 2 times, respectively, the maximum human loading dose on a mg/m2 basis. Signs of acute toxicity in animals included ataxia, labored breathing, ptosis, and hypoactivity.
Affected organisms
  • Humans and other mammals
Pathways
Pathway Name SMPDB ID
Smp00326 Fosphenytoin (Antiarrhythmic) Pathway SMP00326
Pharmacoeconomics
Manufacturers
  • Parke davis div warner lambert co
  • Akorn strides llc
  • Apotex inc richmond hill
  • App pharmaceuticals llc
  • Baxter healthcare corp anesthesia and critical care
  • Bedford laboratories div ben venue laboratories inc
  • Hikma farmaceutica (portugal) sa
  • Hospira inc
  • Luitpold pharmaceuticals inc
  • Pharmaforce inc
  • Strides arcolab limited
  • Sun pharma global inc
  • Teva parenteral medicines inc
  • Wockhardt ltd
Packagers
Dosage forms
Form Route Strength
Liquid Intravenous
Liquid Intravenous
Prices
Unit description Cost Unit
Cerebyx 500 mg pe/10 ml vial 8.63 USD ml
Fosphenytoin 500 mg pe/10 ml 0.61 USD ml
Patents Not Available
Properties
State solid
Melting point Not Available
Experimental Properties Not Available
Predicted Properties
Property Value Source
water solubility 1.45e-01 g/l ALOGPS
logP 1.08 ALOGPS
logP 1.67 ChemAxon Molconvert
logS -3.40 ALOGPS
pKa 6.06 ChemAxon Molconvert
hydrogen acceptor count 5 ChemAxon Molconvert
hydrogen donor count 3 ChemAxon Molconvert
polar surface area 116.17 ChemAxon Molconvert
rotatable bond count 5 ChemAxon Molconvert
refractivity 87.05 ChemAxon Molconvert
polarizability 33.23 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Johnson J, Wrenn K: Inappropriate fosphenytoin use in the ED. Am J Emerg Med. 2001 Jul;19(4):293-4. Pubmed
  2. Applebaum J, Levine J, Belmaker RH: Intravenous fosphenytoin in acute mania. J Clin Psychiatry. 2003 Apr;64(4):408-9. Pubmed
  3. McCleane GJ: Intravenous infusion of fosphenytoin produces prolonged pain relief: a case report. J Pain. 2002 Apr;3(2):156-8. Pubmed
  4. Browne TR, Kugler AR, Eldon MA: Pharmacology and pharmacokinetics of fosphenytoin. Neurology. 1996 Jun;46(6 Suppl 1):S3-7. Pubmed 8649612
  5. Luszczki JJ: Third-generation antiepileptic drugs: mechanisms of action, pharmacokinetics and interactions. Pharmacol Rep. 2009 Mar-Apr;61(2):197-216. Pubmed
External Links
Resource Link
KEGG Compound C07840 Link_out
PubChem Compound 56339 Link_out
PubChem Substance 46505168 Link_out
ChemSpider 50839 Link_out
Therapeutic Targets Database DAP000520 Link_out
PharmGKB PA449712 Link_out
Drug Product Database 2230988 Link_out
RxList http://www.rxlist.com/cgi/generic/fosphen.htm Link_out
Drugs.com http://www.drugs.com/cdi/fosphenytoin.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Fosphenytoin Link_out
ATC Codes
  • N03AB05
AHFS Codes
  • 28:12.12
PDB Entries Not Available
FDA label show (820.2 KB)
MSDS Not Available
Interactions
Drug Interactions Not Available
Food Interactions
  • Avoid alcohol.
  • Do not take calcium, aluminum, magnesium or Iron supplements within 2 hours of taking this medication.
  • Take with food.
Targets

1. Sodium channel protein type 5 subunit alpha

Pharmacological action: yes
Actions: inhibitor

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 in the electrocardiogram

Organism class: human
UniProt ID: Q14524 Link_out
Gene: SCN5A Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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. Pubmed
  2. Mantegazza M, Curia G, Biagini G, Ragsdale DS, Avoli M: Voltage-gated sodium channels as therapeutic targets in epilepsy and other neurological disorders. Lancet Neurol. 2010 Apr;9(4):413-24. Pubmed
  3. Lenkowski PW, Ko SH, Anderson JD, Brown ML, Patel MK: Block of human NaV1.5 sodium channels by novel alpha-hydroxyphenylamide analogues of phenytoin. Eur J Pharm Sci. 2004 Apr;21(5):635-44. Pubmed
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
Enzymes

1. Cytochrome P450 2C9

Actions: substrate, inducer

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S- warfarin, diclofenac, phenytoin, tolbutamide and losartan

UniProt ID: P11712 Link_out
Gene: CYP2C9
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Sahi J, Shord SS, Lindley C, Ferguson S, LeCluyse EL: Regulation of cytochrome P450 2C9 expression in primary cultures of human hepatocytes. J Biochem Mol Toxicol. 2009 Jan-Feb;23(1):43-58. Pubmed
  2. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
  3. Goldstein JA: Clinical relevance of genetic polymorphisms in the human CYP2C subfamily. Br J Clin Pharmacol. 2001 Oct;52(4):349-55. Pubmed
  4. Klotz U: The role of pharmacogenetics in the metabolism of antiepileptic drugs: pharmacokinetic and therapeutic implications. Clin Pharmacokinet. 2007;46(4):271-9. Pubmed

2. Cytochrome P450 2C8

Actions: substrate, inducer

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. In the epoxidation of arachidonic acid it generates only 14,15- and 11,12-cis-epoxyeicosatrienoic acids. It is the principal enzyme responsible for the metabolism the anti- cancer drug paclitaxel (taxol)

UniProt ID: P10632 Link_out
Gene: CYP2C8
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Kim KA, Park JY: Inhibitory effect of glyburide on human cytochrome p450 isoforms in human liver microsomes. Drug Metab Dispos. 2003 Sep;31(9):1090-2. Pubmed

3. Cytochrome P450 2C19

Actions: substrate, inducer

Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine

UniProt ID: P33261 Link_out
Gene: CYP2C19 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Anderson GD: Pharmacokinetic, pharmacodynamic, and pharmacogenetic targeted therapy of antiepileptic drugs. Ther Drug Monit. 2008 Apr;30(2):173-80. Pubmed
  2. Hennessy S, Leonard CE, Freeman CP, Metlay JP, Chu X, Strom BL, Bilker WB: CYP2C9, CYP2C19, and ABCB1 genotype and hospitalization for phenytoin toxicity. J Clin Pharmacol. 2009 Dec;49(12):1483-7. Epub 2009 Jul 17. Pubmed
  3. Klotz U: The role of pharmacogenetics in the metabolism of antiepileptic drugs: pharmacokinetic and therapeutic implications. Clin Pharmacokinet. 2007;46(4):271-9. Pubmed

4. Cytochrome P450 3A4

Actions: inducer

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Zhou SF: Drugs behave as substrates, inhibitors and inducers of human cytochrome P450 3A4. Curr Drug Metab. 2008 May;9(4):310-22. Pubmed

5. Cytochrome P450 2B6

Actions: inducer

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics

UniProt ID: P20813 Link_out
Gene: CYP2B6 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Wang H, Faucette S, Moore R, Sueyoshi T, Negishi M, LeCluyse E: Human constitutive androstane receptor mediates induction of CYP2B6 gene expression by phenytoin. J Biol Chem. 2004 Jul 9;279(28):29295-301. Epub 2004 Apr 28. Pubmed
  2. Faucette SR, Wang H, Hamilton GA, Jolley SL, Gilbert D, Lindley C, Yan B, Negishi M, LeCluyse EL: Regulation of CYP2B6 in primary human hepatocytes by prototypical inducers. Drug Metab Dispos. 2004 Mar;32(3):348-58. Pubmed
Carriers

1. Serum albumin

Actions: other/unknown

Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloidal osmotic pressure of blood

UniProt ID: P02768 Link_out
Gene: ALB Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Walker MC, Patsalos PN: Clinical pharmacokinetics of new antiepileptic drugs. Pharmacol Ther. 1995;67(3):351-84. Pubmed
Comments
Drug created on June 30, 2007 11:18 / Updated on June 10, 2011 16:22

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.