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Identification
NameAmifostine
Accession NumberDB01143  (APRD00021)
TypeSmall Molecule
GroupsApproved, Investigational
DescriptionA phosphorothioate proposed as a radiation-protective agent. It causes splenic vasodilation and may block autonomic ganglia. [PubChem]
Structure
Thumb
Synonyms
Amifostina
Amifostine
Amifostine Ethiofos
Amifostinum
Aminopropylaminoethyl Thiophosphate
Apaetp
Ethiofos
Ethyol
Gammaphos
SAPEP
WR-1065
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Amifostineinjection, powder, lyophilized, for solution500 mg/10mLintravenousBedford Laboratories2008-04-02Not applicableUs
Ethyol - Pws IV 500mg/vialpowder for solution500 mgintravenousMedimmune Oncology, Inc.1996-12-312008-01-01Canada
Approved Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Amifostineinjection, powder, lyophilized, for solution50 mg/mLintravenousSun Pharma Global FZE2008-03-14Not applicableUs
Amifostineinjection, powder, lyophilized, for solution50 mg/mLintravenousSun Pharmaceutical Industries Limited2008-03-14Not applicableUs
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
EthyolNot Available
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Amifostine trihydrate
112901-68-5
Thumb
  • InChI Key: TXQPXJKRNHJWAX-UHFFFAOYSA-N
  • Monoisotopic Mass: 268.085794576
  • Average Mass: 268.26
DBSALT001833
Categories
UNIIILA426L95O
CAS number20537-88-6
WeightAverage: 214.223
Monoisotopic: 214.054099558
Chemical FormulaC5H15N2O3PS
InChI KeyInChIKey=JKOQGQFVAUAYPM-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.
Related Articles
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 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorNon-inhibitor0.9231
CYP450 2C19 inhibitorNon-inhibitor0.9026
CYP450 3A4 inhibitorNon-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
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
Packagers
Dosage forms
FormRouteStrength
Injection, powder, lyophilized, for solutionintravenous50 mg/mL
Injection, powder, lyophilized, for solutionintravenous500 mg/10mL
Powder for solutionintravenous500 mg
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
Patent NumberPediatric ExtensionApprovedExpires (estimated)
CA2120133 No1998-06-092013-07-30Canada
US5424471 No1995-07-312012-07-31Us
US5994409 No1997-12-082017-12-08Us
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
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot 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 References
  1. Santini V, Giles FJ: The potential of amifostine: from cytoprotectant to therapeutic agent. Haematologica. 1999 Nov;84(11):1035-42. [PubMed:10553165 ]
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
AcebutololAcebutolol may increase the hypotensive activities of Amifostine.
AliskirenAliskiren may increase the hypotensive activities of Amifostine.
AlprenololAlprenolol may increase the hypotensive activities of Amifostine.
AmbrisentanAmbrisentan may increase the hypotensive activities of Amifostine.
AmlodipineAmlodipine may increase the hypotensive activities of Amifostine.
AtenololAtenolol may increase the hypotensive activities of Amifostine.
BenazeprilBenazepril may increase the hypotensive activities of Amifostine.
BendroflumethiazideBendroflumethiazide may increase the hypotensive activities of Amifostine.
BepridilBepridil may increase the hypotensive activities of Amifostine.
BetaxololBetaxolol may increase the hypotensive activities of Amifostine.
BethanidineBethanidine may increase the hypotensive activities of Amifostine.
BimatoprostBimatoprost may increase the hypotensive activities of Amifostine.
BisoprololBisoprolol may increase the hypotensive activities of Amifostine.
BosentanBosentan may increase the hypotensive activities of Amifostine.
BretyliumBretylium may increase the hypotensive activities of Amifostine.
BrimonidineBrimonidine may increase the hypotensive activities of Amifostine.
BupranololBupranolol may increase the hypotensive activities of Amifostine.
CandesartanCandesartan may increase the hypotensive activities of Amifostine.
CandoxatrilCandoxatril may increase the hypotensive activities of Amifostine.
CaptoprilCaptopril may increase the hypotensive activities of Amifostine.
CarteololCarteolol may increase the hypotensive activities of Amifostine.
CarvedilolCarvedilol may increase the hypotensive activities of Amifostine.
CeliprololCeliprolol may increase the hypotensive activities of Amifostine.
ChlorothiazideChlorothiazide may increase the hypotensive activities of Amifostine.
ChlorthalidoneChlorthalidone may increase the hypotensive activities of Amifostine.
CilazaprilCilazapril may increase the hypotensive activities of Amifostine.
ClonidineClonidine may increase the hypotensive activities of Amifostine.
CryptenamineCryptenamine may increase the hypotensive activities of Amifostine.
CyclothiazideCyclothiazide may increase the hypotensive activities of Amifostine.
DebrisoquinDebrisoquin may increase the hypotensive activities of Amifostine.
DeserpidineDeserpidine may increase the hypotensive activities of Amifostine.
DiazoxideDiazoxide may increase the hypotensive activities of Amifostine.
DiltiazemDiltiazem may increase the hypotensive activities of Amifostine.
DorzolamideDorzolamide may increase the hypotensive activities of Amifostine.
DoxazosinDoxazosin may increase the hypotensive activities of Amifostine.
EfonidipineEfonidipine may increase the hypotensive activities of Amifostine.
EnalaprilEnalapril may increase the hypotensive activities of Amifostine.
EnalaprilatEnalaprilat may increase the hypotensive activities of Amifostine.
EpoprostenolEpoprostenol may increase the hypotensive activities of Amifostine.
EprosartanEprosartan may increase the hypotensive activities of Amifostine.
FelodipineFelodipine may increase the hypotensive activities of Amifostine.
FenoldopamFenoldopam may increase the hypotensive activities of Amifostine.
FosinoprilFosinopril may increase the hypotensive activities of Amifostine.
GuanabenzGuanabenz may increase the hypotensive activities of Amifostine.
GuanadrelGuanadrel may increase the hypotensive activities of Amifostine.
GuanethidineGuanethidine may increase the hypotensive activities of Amifostine.
GuanfacineGuanfacine may increase the hypotensive activities of Amifostine.
HexamethoniumHexamethonium may increase the hypotensive activities of Amifostine.
HydralazineHydralazine may increase the hypotensive activities of Amifostine.
HydrochlorothiazideHydrochlorothiazide may increase the hypotensive activities of Amifostine.
HydroflumethiazideHydroflumethiazide may increase the hypotensive activities of Amifostine.
IndapamideIndapamide may increase the hypotensive activities of Amifostine.
IndenololIndenolol may increase the hypotensive activities of Amifostine.
IndoraminIndoramin may increase the hypotensive activities of Amifostine.
IrbesartanIrbesartan may increase the hypotensive activities of Amifostine.
IsradipineIsradipine may increase the hypotensive activities of Amifostine.
LabetalolLabetalol may increase the hypotensive activities of Amifostine.
LacidipineLacidipine may increase the hypotensive activities of Amifostine.
LatanoprostLatanoprost may increase the hypotensive activities of Amifostine.
LercanidipineLercanidipine may increase the hypotensive activities of Amifostine.
LisinoprilLisinopril may increase the hypotensive activities of Amifostine.
LofexidineLofexidine may increase the hypotensive activities of Amifostine.
LosartanLosartan may increase the hypotensive activities of Amifostine.
MacitentanMacitentan may increase the hypotensive activities of Amifostine.
ManidipineManidipine may increase the hypotensive activities of Amifostine.
MecamylamineMecamylamine may increase the hypotensive activities of Amifostine.
MethyldopaMethyldopa may increase the hypotensive activities of Amifostine.
MetipranololMetipranolol may increase the hypotensive activities of Amifostine.
MetolazoneMetolazone may increase the hypotensive activities of Amifostine.
MetoprololMetoprolol may increase the hypotensive activities of Amifostine.
MibefradilMibefradil may increase the hypotensive activities of Amifostine.
MinoxidilMinoxidil may increase the hypotensive activities of Amifostine.
MoexiprilMoexipril may increase the hypotensive activities of Amifostine.
MoxonidineMoxonidine may increase the hypotensive activities of Amifostine.
NadololNadolol may increase the hypotensive activities of Amifostine.
NebivololNebivolol may increase the hypotensive activities of Amifostine.
NicardipineNicardipine may increase the hypotensive activities of Amifostine.
NicorandilNicorandil may increase the hypotensive activities of Amifostine.
NiguldipineNiguldipine may increase the hypotensive activities of Amifostine.
NilvadipineNilvadipine may increase the hypotensive activities of Amifostine.
NimodipineNimodipine may increase the hypotensive activities of Amifostine.
NisoldipineNisoldipine may increase the hypotensive activities of Amifostine.
NitrendipineNitrendipine may increase the hypotensive activities of Amifostine.
NitroprussideNitroprusside may increase the hypotensive activities of Amifostine.
OlmesartanOlmesartan may increase the hypotensive activities of Amifostine.
OmapatrilatOmapatrilat may increase the hypotensive activities of Amifostine.
OxprenololOxprenolol may increase the hypotensive activities of Amifostine.
PargylinePargyline may increase the hypotensive activities of Amifostine.
PenbutololPenbutolol may increase the hypotensive activities of Amifostine.
PentoliniumPentolinium may increase the hypotensive activities of Amifostine.
PerindoprilPerindopril may increase the hypotensive activities of Amifostine.
PhenoxybenzaminePhenoxybenzamine may increase the hypotensive activities of Amifostine.
PhentolaminePhentolamine may increase the hypotensive activities of Amifostine.
PinacidilPinacidil may increase the hypotensive activities of Amifostine.
PindololPindolol may increase the hypotensive activities of Amifostine.
PolythiazidePolythiazide may increase the hypotensive activities of Amifostine.
PrazosinPrazosin may increase the hypotensive activities of Amifostine.
PropranololPropranolol may increase the hypotensive activities of Amifostine.
QuinaprilQuinapril may increase the hypotensive activities of Amifostine.
RamiprilRamipril may increase the hypotensive activities of Amifostine.
RemikirenRemikiren may increase the hypotensive activities of Amifostine.
RescinnamineRescinnamine may increase the hypotensive activities of Amifostine.
ReserpineReserpine may increase the hypotensive activities of Amifostine.
RiociguatRiociguat may increase the hypotensive activities of Amifostine.
SaprisartanSaprisartan may increase the hypotensive activities of Amifostine.
SelexipagSelexipag may increase the hypotensive activities of Amifostine.
SitaxentanSitaxentan may increase the hypotensive activities of Amifostine.
SpiraprilSpirapril may increase the hypotensive activities of Amifostine.
TelmisartanTelmisartan may increase the hypotensive activities of Amifostine.
TemocaprilTemocapril may increase the hypotensive activities of Amifostine.
TerlipressinTerlipressin may increase the hypotensive activities of Amifostine.
TiboloneTibolone may increase the hypotensive activities of Amifostine.
TicrynafenTicrynafen may increase the hypotensive activities of Amifostine.
TimololTimolol may increase the hypotensive activities of Amifostine.
TolazolineTolazoline may increase the hypotensive activities of Amifostine.
TorasemideTorasemide may increase the hypotensive activities of Amifostine.
TrandolaprilTrandolapril may increase the hypotensive activities of Amifostine.
TravoprostTravoprost may increase the hypotensive activities of Amifostine.
TreprostinilTreprostinil may increase the hypotensive activities of Amifostine.
TrichlormethiazideTrichlormethiazide may increase the hypotensive activities of Amifostine.
TrimazosinTrimazosin may increase the hypotensive activities of Amifostine.
TrimethaphanTrimethaphan may increase the hypotensive activities of Amifostine.
UnoprostoneUnoprostone may increase the hypotensive activities of Amifostine.
ValsartanValsartan may increase the hypotensive activities of Amifostine.
XylometazolineXylometazoline may increase the hypotensive activities of Amifostine.
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inducer
General Function:
Zinc ion binding
Specific Function:
By generating PPi, plays a role in regulating pyrophosphate levels, and functions in bone mineralization and soft tissue calcification. PPi inhibits mineralization by binding to nascent hydroxyapatite (HA) crystals, thereby preventing further growth of these crystals. Preferentially hydrolyzes ATP, but can also hydrolyze other nucleoside 5' triphosphates such as GTP, CTP, TTP and UTP to their c...
Gene Name:
ENPP1
Uniprot ID:
P22413
Molecular Weight:
104923.58 Da
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:17139284 ]
  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:17016423 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inducer
General Function:
Metal ion binding
Specific Function:
Not Available
Gene Name:
ALPPL2
Uniprot ID:
P10696
Molecular Weight:
57376.515 Da
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:10348255 ]
  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:10523712 ]
  3. Santini V, Giles FJ: The potential of amifostine: from cytoprotectant to therapeutic agent. Haematologica. 1999 Nov;84(11):1035-42. [PubMed:10553165 ]
  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:10628381 ]
  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:10995012 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Pyrophosphatase activity
Specific Function:
This isozyme may play a role in skeletal mineralization.
Gene Name:
ALPL
Uniprot ID:
P05186
Molecular Weight:
57304.435 Da
References
  1. Shaw LM, Bonner H, Lieberman R: Pharmacokinetic profile of amifostine. Semin Oncol. 1996 Aug;23(4 Suppl 8):18-22. [PubMed:8783662 ]
Comments
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Drug created on June 13, 2005 07:24 / Updated on September 25, 2016 02:14