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Identification
NameAmifostine
Accession NumberDB01143  (APRD00021)
Typesmall molecule
Groupsapproved, investigational
Description

A phosphorothioate proposed as a radiation-protective agent. It causes splenic vasodilation and may block autonomic ganglia. [PubChem]

Structure
Thumb
Synonyms
SynonymLanguageCode
AmifostinaNot AvailableNot Available
AmifostineNot AvailableNot Available
Amifostine EthiofosNot AvailableNot Available
AmifostinumNot AvailableNot Available
Aminopropylaminoethyl ThiophosphateNot AvailableNot Available
ApaetpNot AvailableNot Available
EthiofosNot AvailableNot Available
EthyolNot AvailableNot Available
GammaphosNot AvailableNot Available
SAPEPNot AvailableNot Available
WR-1065Not AvailableNot Available
SaltsNot Available
Brand names
NameCompany
EthyolNot Available
Brand mixturesNot Available
Categories
CAS number20537-88-6
WeightAverage: 214.223
Monoisotopic: 214.054099558
Chemical FormulaC5H15N2O3PS
InChI KeyJKOQGQFVAUAYPM-UHFFFAOYSA-N
InChI
InChI=1S/C5H15N2O3PS/c6-2-1-3-7-4-5-12-11(8,9)10/h7H,1-6H2,(H2,8,9,10)
IUPAC Name
({2-[(3-aminopropyl)amino]ethyl}sulfanyl)phosphonic acid
SMILES
NCCCNCCSP(O)(O)=O
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassOrganonitrogen Compounds
ClassAmines
SubclassPolyamines
Direct parentPolyamines
Alternative parentsOrganothiophosphorus Compounds; Dialkylamines; Monoalkylamines
Substituentsprimary aliphatic amine; primary amine
Classification descriptionThis compound belongs to the polyamines. These are compounds containing more than one amine group.
Pharmacology
IndicationFor reduction in the cumulative renal toxicity in patients with ovarian cancer (using cisplatin) and moderate to severe xerostomia in patients undergoing post-operative radiation treatment for head and neck cancer.
PharmacodynamicsAmifostine is an organic thiophosphate cytoprotective agent indicated to reduce the cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian cancer or non-small cell lung cancer and also to reduce the incidence of moderate to severe xerostomia in patients undergoing post-operative radiation treatment for head and neck cancer. Amifostine is a prodrug that is dephosphorylated by alkaline phosphatase in tissues to a pharmacologically active free thiol metabolite, believed to be responsible for the reduction of the cumulative renal toxicity of cisplatin and for the reduction of the toxic effects of radiation on normal oral tissues. Healthy cells are preferentially protected because amifostine and metabolites are present in healthy cells at 100-fold greater concentrations than in tumour cells.
Mechanism of actionThe thiol metabolite is responsible for most of the cytoprotective and radioprotective properties of amifostine. It is readily taken up by cells where it binds to and detoxifies reactive metabolites of platinum and alkylating agents as well as scavenges free radicals. Other possible effects include inhibition of apoptosis, alteration of gene expression and modification of enzyme activity.
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
Metabolism

Amifostine is rapidly dephosphorylated by alkaline phosphatase in tissues primarily to the active free thiol metabolite and, subsequently, to a less active disulfide metabolite.

Route of eliminationAfter a 10-second bolus dose of 150 mg/m2 of ETHYOL, renal excretion of the parent drug and its two metabolites was low during the hour following drug administration, averaging 0.69%, 2.64% and 2.22% of the administered dose for the parent, thiol and disulfide, respectively.
Half life8 minutes
ClearanceNot Available
ToxicityRat LD50: 826 mg/kg
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption - 0.5944
Blood Brain Barrier - 0.8229
Caco-2 permeable - 0.6167
P-glycoprotein substrate Non-substrate 0.5585
P-glycoprotein inhibitor I Non-inhibitor 0.9054
P-glycoprotein inhibitor II Non-inhibitor 0.9537
Renal organic cation transporter Non-inhibitor 0.8451
CYP450 2C9 substrate Non-substrate 0.7683
CYP450 2D6 substrate Non-substrate 0.7738
CYP450 3A4 substrate Non-substrate 0.7689
CYP450 1A2 substrate Non-inhibitor 0.9045
CYP450 2C9 substrate Non-inhibitor 0.9071
CYP450 2D6 substrate Non-inhibitor 0.9231
CYP450 2C19 substrate Non-inhibitor 0.9026
CYP450 3A4 substrate Non-inhibitor 0.8429
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9592
Ames test Non AMES toxic 0.5933
Carcinogenicity Non-carcinogens 0.717
Biodegradation Ready biodegradable 0.6316
Rat acute toxicity 2.3829 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.7047
hERG inhibition (predictor II) Non-inhibitor 0.7772
Pharmacoeconomics
Manufacturers
  • Sun pharma global inc
  • Medimmune
Packagers
Dosage forms
FormRouteStrength
Powder, for solutionIntravenous
Prices
Unit descriptionCostUnit
Ethyol 500 mg vial605.88USDvial
Amifostine 500 mg vial600.0USDvial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States59944091997-12-082017-12-08
United States54244711995-07-312012-07-31
Canada21201331998-06-092013-07-30
Properties
Statesolid
Experimental Properties
PropertyValueSource
water solubility1000 mg/mLNot Available
logP-1.9Not Available
Predicted Properties
PropertyValueSource
water solubility1.87e+01 g/lALOGPS
logP-1.4ALOGPS
logP-3.7ChemAxon
logS-1.1ALOGPS
pKa (strongest acidic)2.06ChemAxon
pKa (strongest basic)11.01ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count5ChemAxon
hydrogen donor count4ChemAxon
polar surface area95.58ChemAxon
rotatable bond count7ChemAxon
refractivity51.28ChemAxon
polarizability21.01ChemAxon
number of rings0ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterNoChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Paul E. Kennedy, Roger A. Rajewski, John M. Baldoni, “Crystalline amifostine compositions and methods of the preparation and use of same.” U.S. Patent US5424471, issued April, 1979.

US5424471
General Reference
  1. Santini V, Giles FJ: The potential of amifostine: from cytoprotectant to therapeutic agent. Haematologica. 1999 Nov;84(11):1035-42. Pubmed
External Links
ResourceLink
KEGG CompoundC06819
PubChem Compound2141
PubChem Substance46505305
ChemSpider2056
ChEBI2636
ChEMBLCHEMBL1006
PharmGKBPA448365
Drug Product Database2218054
RxListhttp://www.rxlist.com/cgi/generic/amifostine.htm
Drugs.comhttp://www.drugs.com/cdi/amifostine.html
WikipediaAmifostine
ATC CodesV03AF05
AHFS Codes
  • 92:00.00
PDB EntriesNot Available
FDA labelshow(45.6 KB)
MSDSshow(36.1 KB)
Interactions
Drug Interactions
Drug
Azilsartan medoxomilAzilsartan medoxomil used in combintation with amifostine may lead to hypotension.
ChlorothiazideAntihypertensives may enhance the hypotensive effect of amifostine. When amifostine is used at doses recommended for chemotherapy, antihypertensive medications should be withheld for 24 hours prior to amifostine administration to avoid excessive hypotension during or immediately after infusion. If antihypertensive therapy can not be withheld, then that patient should not receive amifostine. Caution is recommended when using amifostine at the lower doses recommended for radiotherapy, but routine interruption of antihypertensive therapy is not recommended in these patients.
TelmisartanTelmisartan may increase the hypotensive effect of Amifostine. At chemotherapeutic doses of Amifostine, Telmisartan should be withheld for 24 hours prior to Amifostine administration. Use caution at lower doses of Amifostine.
TerazosinTerazosin may increase the hypotensive effect of Amifostine. At chemotherapeutic doses of Amifostine, Terazosin should be withheld for 24 hours prior to Amifostine administration. Use caution at lower doses of Amifostine.
TolazamideAdditive hypotensive effects may occur. At chemotherapeutic doses of Amifostine, Tolazamide should be withheld for 24 hours prior to Amifostine administration. Use caution at lower doses of Amifostine.
TorasemideTorasemide may increase the hypotensive effect of Amifostine. At chemotherapeutic doses of Amifostine, Torasemide should be withheld for 24 hours prior to Amifostine administration. Use caution at lower doses of Amifostine.
TrandolaprilTrandolapril may increase the hypotensive effect of Amifostine. At chemotherapeutic doses of Amifostine, Trandolapril should be withheld for 24 hours prior to Amifostine administration. Use caution at lower doses of Amifostine.
TrichlormethiazideTrichlormethiazide may increase the hypotensive effect of Amifostine. At chemotherapeutic doses of Amifostine, Trichlomethiazide should be withheld for 24 hours prior to Amifostine administration. Use caution at lower doses of Amifostine.
ValsartanAdditive hypotensive effects may occur. At chemotherapeutic doses of Amifostine, Valsartan should be withheld for 24 hours prior to Amifostine administration. Use caution at lower doses of Amifostine.
VerapamilVerapamil may enhance the hypotensive effect of Amifostine. At chemotherapeutic doses of Amifostine, Verapamil should be withheld for 24 hours prior to Amifostine administration. Caution should be used at lower Amifostine doses used during radiotherapy, but routine interruption of Verapamil therapy is not recommended.
Food InteractionsNot Available

Targets

1. Alkaline phosphatase, placental-like

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inducer

Components

Name UniProt ID Details
Alkaline phosphatase, placental-like P10696 Details

References:

  1. Capizzi RL: The preclinical basis for broad-spectrum selective cytoprotection of normal tissues from cytotoxic therapies by amifostine. Semin Oncol. 1999 Apr;26(2 Suppl 7):3-21. Pubmed
  2. Orditura M, De Vita F, Roscigno A, Infusino S, Auriemma A, Iodice P, Ciaramella F, Abbate G, Catalano G: Amifostine: A selective cytoprotective agent of normal tissues from chemo-radiotherapy induced toxicity (Review). Oncol Rep. 1999 Nov-Dec;6(6):1357-62. Pubmed
  3. Santini V, Giles FJ: The potential of amifostine: from cytoprotectant to therapeutic agent. Haematologica. 1999 Nov;84(11):1035-42. Pubmed
  4. Plasswilm L, Hanjalic A, Hoeper J, Cordes N, Tannapfel A: Microvessel density and endothelial cell proliferation after amifostine (Ethyol) administration in vivo. Anticancer Res. 1999 Sep-Oct;19(5B):4241-5. Pubmed
  5. Buschini A, Anceschi E, Carlo-Stella C, Regazzi E, Rizzoli V, Poli P, Rossi C: Amifostine (WR-2721) selective protection against melphalan genotoxicity. Leukemia. 2000 Sep;14(9):1642-51. Pubmed

2. Ectonucleotide pyrophosphatase/phosphodiesterase family member 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inducer

Components

Name UniProt ID Details
Ectonucleotide pyrophosphatase/phosphodiesterase family member 1 P22413 Details

References:

  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed

Enzymes

1. Alkaline phosphatase, tissue-nonspecific isozyme

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
Alkaline phosphatase, tissue-nonspecific isozyme P05186 Details

References:

  1. Shaw LM, Bonner H, Lieberman R: Pharmacokinetic profile of amifostine. Semin Oncol. 1996 Aug;23(4 Suppl 8):18-22. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:13