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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
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Amifostineinjection, powder, lyophilized, for solution500 mg/10mLintravenousBedford Laboratories2008-04-02Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Amifostineinjection, powder, lyophilized, for solution50 mg/mLintravenousSun Pharma Global FZE2008-03-14Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Amifostineinjection, powder, lyophilized, for solution50 mg/mLintravenousSun Pharmaceutical Industries Limited2008-03-14Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Over the Counter ProductsNot Available
International Brands
NameCompany
EthyolNot Available
Brand mixturesNot Available
SaltsNot 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
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as organothiophosphorus compounds. These are organic derivatives of thiophosphonic acid, thiophosphoric acid, dithiophosphoric acid, or phosphorotrithioic acid, or derivatives thereof. Thiophosphonic acid, dithiophosphoric acid, thiophosphoric acid, and phosphorotrithioic acid are thiophosphorus compounds with the formula OP(O)(=S), OP(S)(=S)O, OP(O)(=S)O, and OP(=S)(S)S, respectively.
KingdomOrganic compounds
Super ClassOrganophosphorus compounds
ClassOrganothiophosphorus compounds
Sub ClassNot Available
Direct ParentOrganothiophosphorus compounds
Alternative Parents
Substituents
  • Sulfenyl compound
  • Secondary amine
  • Organothiophosphorus compound
  • Secondary aliphatic amine
  • Hydrocarbon derivative
  • Primary amine
  • Organosulfur compound
  • Organonitrogen compound
  • Primary aliphatic amine
  • Amine
  • Aliphatic acyclic compound
Molecular FrameworkAliphatic acyclic compounds
External Descriptors
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
PropertyValueProbability
Human Intestinal Absorption-0.5944
Blood Brain Barrier-0.8229
Caco-2 permeable-0.6167
P-glycoprotein substrateNon-substrate0.5585
P-glycoprotein inhibitor INon-inhibitor0.9054
P-glycoprotein inhibitor IINon-inhibitor0.9537
Renal organic cation transporterNon-inhibitor0.8451
CYP450 2C9 substrateNon-substrate0.7683
CYP450 2D6 substrateNon-substrate0.7738
CYP450 3A4 substrateNon-substrate0.7689
CYP450 1A2 substrateNon-inhibitor0.9045
CYP450 2C9 substrateNon-inhibitor0.9071
CYP450 2D6 substrateNon-inhibitor0.9231
CYP450 2C19 substrateNon-inhibitor0.9026
CYP450 3A4 substrateNon-inhibitor0.8429
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9592
Ames testNon AMES toxic0.5933
CarcinogenicityNon-carcinogens0.717
BiodegradationReady biodegradable0.6316
Rat acute toxicity2.3829 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.7047
hERG inhibition (predictor II)Non-inhibitor0.7772
Pharmacoeconomics
ManufacturersNot Available
Packagers
Dosage forms
FormRouteStrength
Injection, powder, lyophilized, for solutionintravenous50 mg/mL
Injection, powder, lyophilized, for solutionintravenous500 mg/10mL
Prices
Unit descriptionCostUnit
Ethyol 500 mg vial605.88USD vial
Amifostine 500 mg vial600.0USD vial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
Canada21201331998-06-092013-07-30
United States54244711995-07-312012-07-31
United States59944091997-12-082017-12-08
Properties
StateSolid
Experimental Properties
PropertyValueSource
water solubility1000 mg/mLNot Available
logP-1.9Not Available
Predicted Properties
PropertyValueSource
Water Solubility18.7 mg/mLALOGPS
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 Area95.58 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity51.28 m3·mol-1ChemAxon
Polarizability21.01 Å3ChemAxon
Number of Rings0ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
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
ATC CodesV03AF05
AHFS Codes
  • 92:00.00
PDB EntriesNot Available
FDA labelDownload (45.6 KB)
MSDSDownload (36.1 KB)
Interactions
Drug Interactions
Drug
AcebutololAntihypertensives may enhance the hypotensive effect of Amifostine.
AliskirenAntihypertensives may enhance the hypotensive effect of Amifostine.
AmilorideAntihypertensives may enhance the hypotensive effect of Amifostine.
AmlodipineAntihypertensives may enhance the hypotensive effect of Amifostine.
AtenololAntihypertensives may enhance the hypotensive effect of Amifostine.
Azilsartan medoxomilAntihypertensives may enhance the hypotensive effect of Amifostine.
BenazeprilAntihypertensives may enhance the hypotensive effect of Amifostine.
BendroflumethiazideAntihypertensives may enhance the hypotensive effect of Amifostine.
BisoprololAntihypertensives may enhance the hypotensive effect of Amifostine.
BumetanideAntihypertensives may enhance the hypotensive effect of Amifostine.
CandesartanAntihypertensives may enhance the hypotensive effect of Amifostine.
CaptoprilAntihypertensives may enhance the hypotensive effect of Amifostine.
CarvedilolAntihypertensives may enhance the hypotensive effect of Amifostine.
ChlorothiazideAntihypertensives may enhance the hypotensive effect of Amifostine.
ChlorthalidoneAntihypertensives may enhance the hypotensive effect of Amifostine.
CilazaprilAntihypertensives may enhance the hypotensive effect of Amifostine.
ClevidipineAntihypertensives may enhance the hypotensive effect of Amifostine.
ClonidineAntihypertensives may enhance the hypotensive effect of Amifostine.
DiltiazemAntihypertensives may enhance the hypotensive effect of Amifostine.
DoxazosinAntihypertensives may enhance the hypotensive effect of Amifostine.
EnalaprilAntihypertensives may enhance the hypotensive effect of Amifostine.
EplerenoneAntihypertensives may enhance the hypotensive effect of Amifostine.
EprosartanAntihypertensives may enhance the hypotensive effect of Amifostine.
EsmololAntihypertensives may enhance the hypotensive effect of Amifostine.
Ethacrynic acidAntihypertensives may enhance the hypotensive effect of Amifostine.
FelodipineAntihypertensives may enhance the hypotensive effect of Amifostine.
FosinoprilAntihypertensives may enhance the hypotensive effect of Amifostine.
FurosemideAntihypertensives may enhance the hypotensive effect of Amifostine.
GuanfacineAntihypertensives may enhance the hypotensive effect of Amifostine.
HydralazineAntihypertensives may enhance the hypotensive effect of Amifostine.
HydrochlorothiazideAntihypertensives may enhance the hypotensive effect of Amifostine.
IndapamideAntihypertensives may enhance the hypotensive effect of Amifostine.
IrbesartanAntihypertensives may enhance the hypotensive effect of Amifostine.
IsradipineAntihypertensives may enhance the hypotensive effect of Amifostine.
LabetalolAntihypertensives may enhance the hypotensive effect of Amifostine.
LisinoprilAntihypertensives may enhance the hypotensive effect of Amifostine.
LosartanAntihypertensives may enhance the hypotensive effect of Amifostine.
MannitolAntihypertensives may enhance the hypotensive effect of Amifostine.
MethyclothiazideAntihypertensives may enhance the hypotensive effect of Amifostine.
MethyldopaAntihypertensives may enhance the hypotensive effect of Amifostine.
MetolazoneAntihypertensives may enhance the hypotensive effect of Amifostine.
MetoprololAntihypertensives may enhance the hypotensive effect of Amifostine.
MoexiprilAntihypertensives may enhance the hypotensive effect of Amifostine.
NadololAntihypertensives may enhance the hypotensive effect of Amifostine.
NebivololAntihypertensives may enhance the hypotensive effect of Amifostine.
NifedipineAntihypertensives may enhance the hypotensive effect of Amifostine.
NimodipineAntihypertensives may enhance the hypotensive effect of Amifostine.
NisoldipineAntihypertensives may enhance the hypotensive effect of Amifostine.
NitroprussideAntihypertensives may enhance the hypotensive effect of Amifostine.
OlmesartanAntihypertensives may enhance the hypotensive effect of Amifostine.
PenbutololAntihypertensives may enhance the hypotensive effect of Amifostine.
PerindoprilAntihypertensives may enhance the hypotensive effect of Amifostine.
PhenoxybenzamineAntihypertensives may enhance the hypotensive effect of Amifostine.
PhentolamineAntihypertensives may enhance the hypotensive effect of Amifostine.
PindololAntihypertensives may enhance the hypotensive effect of Amifostine.
PrazosinAntihypertensives may enhance the hypotensive effect of Amifostine.
PropranololAntihypertensives may enhance the hypotensive effect of Amifostine.
QuinaprilAntihypertensives may enhance the hypotensive effect of Amifostine.
RamiprilAntihypertensives may enhance the hypotensive effect of Amifostine.
ReserpineAntihypertensives may enhance the hypotensive effect of Amifostine.
SotalolAntihypertensives may enhance the hypotensive effect of Amifostine.
SpironolactoneAntihypertensives may enhance the hypotensive effect of Amifostine.
TelmisartanAntihypertensives may enhance the hypotensive effect of Amifostine.
TerazosinAntihypertensives may enhance the hypotensive effect of Amifostine.
TorasemideAntihypertensives may enhance the hypotensive effect of Amifostine.
TrandolaprilAntihypertensives may enhance the hypotensive effect of Amifostine.
TriamtereneAntihypertensives may enhance the hypotensive effect of Amifostine.
ValsartanAntihypertensives may enhance the hypotensive effect of Amifostine.
Food InteractionsNot Available

Targets

1. 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

2. 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

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