Identification

Name
Amifostine
Accession Number
DB01143  (APRD00021)
Type
Small Molecule
Groups
Approved, Investigational
Description

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

Structure
Thumb
Synonyms
  • Amifostina
  • Amifostine
  • Amifostine anhydrous
  • Amifostinum
  • Aminopropylaminoethyl thiophosphate
External IDs
WR-2721 / YM-08310
Product Ingredients
IngredientUNIICASInChI Key
Amifostine trihydrateM487QF2F4V112901-68-5TXQPXJKRNHJWAX-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
AmifostineInjection, powder, lyophilized, for solution500 mg/10mLIntravenousBedford Pharmaceuticals2008-04-022018-12-31Us
EthyolInjection, powder, lyophilized, for solution500 mg/10mLIntravenousMed Immune, Llc1995-12-082012-04-30Us
EthyolInjection, powder, lyophilized, for solution500 mg/10mLIntravenousCumberland Pharmaceuticals Inc.2016-08-01Not applicableUs
Ethyol - Pws IV 500mg/vialPowder, for solution500 mgIntravenousMedimmune Oncology, Inc.1996-12-312008-01-01Canada
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
AmifostineInjection, powder, lyophilized, for solution50 mg/1mLIntravenousSun Pharmaceutical Industries Limited2008-03-142018-05-31Us
AmifostineInjection, powder, lyophilized, for solution50 mg/1mLIntravenousSun Pharma Global FZE2008-03-142013-07-31Us
International/Other Brands
Ethyol
Categories
UNII
ILA426L95O
CAS number
20537-88-6
Weight
Average: 214.223
Monoisotopic: 214.054099558
Chemical Formula
C5H15N2O3PS
InChI Key
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

Pharmacology

Indication

For 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.

Associated Conditions
Pharmacodynamics

Amifostine 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 action

The 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.

TargetActionsOrganism
AAlkaline phosphatase, placental-like
inducer
Human
UEctonucleotide pyrophosphatase/phosphodiesterase family member 1
inducer
Human
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not 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 elimination

After 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 life

8 minutes

Clearance
Not Available
Toxicity

Rat LD50: 826 mg/kg

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic Acid1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic Acid may increase the hypotensive activities of Amifostine.
AcebutololAcebutolol may increase the hypotensive activities of Amifostine.
AldesleukinThe risk or severity of adverse effects can be increased when Aldesleukin is combined with 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.
AmilorideThe risk or severity of adverse effects can be increased when Amiloride is combined with Amifostine.
AmiodaroneThe risk or severity of adverse effects can be increased when Amiodarone is combined with Amifostine.
AmlodipineAmlodipine may increase the hypotensive activities of Amifostine.
AmobarbitalAmobarbital may increase the hypotensive activities of Amifostine.
Food Interactions
Not 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
Human Metabolome Database
HMDB0015274
KEGG Compound
C06819
PubChem Compound
2141
PubChem Substance
46505305
ChemSpider
2056
ChEBI
2636
ChEMBL
CHEMBL1006
PharmGKB
PA448365
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Amifostine
ATC Codes
V03AF05 — Amifostine
FDA label
Download (45.6 KB)
MSDS
Download (36.1 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingTreatmentCancer, Breast1
1CompletedSupportive CareDrug/Agent Toxicity by Tissue/Organ / Unspecified Adult Solid Tumor, Protocol Specific1
1CompletedSupportive CareUnspecified Adult Solid Tumor, Protocol Specific1
1CompletedTreatmentDrug/Agent Toxicity by Tissue/Organ / Leukemias1
1CompletedTreatmentLeukemias / Malignant Lymphomas / Unspecified Adult Solid Tumor, Protocol Specific1
1CompletedTreatmentMalignant Pleural Mesothelioma (MPM)1
1CompletedTreatmentRecurrent Melanoma / Renal Cell Cancer, Recurrent / Stage III Melanoma / Stage IV Melanoma / Stage IV Renal Cell Cancer1
1CompletedTreatmentUnspecified Childhood Solid Tumor, Protocol Specific1
1RecruitingTreatmentLung Cancers1
1TerminatedSupportive CareBrain and Central Nervous System Tumors / Cancer of the Ovary / Childhood Germ Cell Tumor / Chordomas / Liver Cancer / Neuroblastomas / Renal Cancers / Retinoblastoma / Sarcomas1
1TerminatedTreatmentDrug/Agent Toxicity by Tissue/Organ / Multiple Myeloma and Plasma Cell Neoplasm1
1Unknown StatusSupportive CareChronic Myeloproliferative Disorders / Drug/Agent Toxicity by Tissue/Organ / Leukemias / Malignant Lymphomas / Multiple Myeloma and Plasma Cell Neoplasm / Myelodysplastic Syndromes / Precancerous Conditions / Unspecified Adult Solid Tumor, Protocol Specific1
1Unknown StatusTreatmentCongenital Hypoplastic Anemia1
1WithdrawnTreatmentCervical Cancers1
1, 2CompletedTreatmentCancer of Head and Neck / Head and Neck Carcinoma / Head Cancer / Neck Cancer / Neoplasms, Neck1
1, 2CompletedTreatmentCancer of the Ovary / Cancer, Breast / Leukemias / Malignant Lymphomas / Neuroblastomas / Sarcomas / Unspecified Adult Solid Tumor, Protocol Specific1
1, 2CompletedTreatmentCancer of the Ovary / Primary Peritoneal Cavity Cancer1
1, 2CompletedTreatmentCarcinoma of Unknown Primary / Head and Neck Carcinoma1
1, 2CompletedTreatmentCervical Cancers / Radiation Toxicity1
1, 2CompletedTreatmentColorectal Cancers1
1, 2CompletedTreatmentDrug/Agent Toxicity by Tissue/Organ / Lung Cancers / Radiation Toxicity1
1, 2CompletedTreatmentHead and Neck Carcinoma / Oral Complications1
1, 2CompletedTreatmentLeukemia Acute Myeloid Leukemia (AML) / Leukemias1
1, 2CompletedTreatmentLeukemias / Myelodysplastic Syndromes1
1, 2Unknown StatusSupportive CareDrug/Agent Toxicity by Tissue/Organ / Head and Neck Carcinoma / Radiation Toxicity1
1, 2Unknown StatusTreatmentDrug/Agent Toxicity by Tissue/Organ / Lung Cancers1
2CompletedPreventionEsophagitis / Non-Small Cell Lung Carcinoma (NSCLC) / Pneumonitis1
2CompletedSupportive CareBrain and Central Nervous System Tumors1
2CompletedSupportive CareCancer of the Ovary / Cancer, Breast / Drug/Agent Toxicity by Tissue/Organ / Lung Cancers / Malignant Lymphomas / Unspecified Adult Solid Tumor, Protocol Specific1
2CompletedSupportive CareCancer of the Ovary / Cancer, Breast / Lung Cancers / Neurologic toxicity / Prostate Cancer / Unspecified Adult Solid Tumor, Protocol Specific1
2CompletedSupportive CareCancer of the Ovary / Lung Cancers / Neurologic toxicity1
2CompletedSupportive CareDrug/Agent Toxicity by Tissue/Organ / Head and Neck Carcinoma / Oral Complications / Radiation Toxicity1
2CompletedSupportive CareMalignant Lymphomas1
2CompletedSupportive CareMyelodysplastic Syndromes1
2CompletedSupportive CareProstatic Neoplasms1
2CompletedTreatmentBladder Cancers / Brain and Central Nervous System Tumors / Cancer of the Ovary / Carcinoma of Unknown Primary / Extragonadal Germ Cell Tumor / Head and Neck Carcinoma / Lung Cancers / Renal Cancers / Sarcomas / Testicular germ cell tumour / Unspecified Adult Solid Tumor, Protocol Specific1
2CompletedTreatmentBladder Cancers / Drug/Agent Toxicity by Tissue/Organ1
2CompletedTreatmentCancer of the Ovary / Childhood Germ Cell Tumor / Drug/Agent Toxicity by Tissue/Organ / Extragonadal Germ Cell Tumor1
2CompletedTreatmentCancer, Breast / Drug/Agent Toxicity by Tissue/Organ1
2CompletedTreatmentChemotherapeutic Agent Toxicity / Head and Neck Carcinoma / Mucositis / Radiation Toxicity / Xerostomia1
2CompletedTreatmentDrug/Agent Toxicity by Tissue/Organ / Lung Cancers1
2CompletedTreatmentDrug/Agent Toxicity by Tissue/Organ / Lung Cancers / Radiation Toxicity1
2CompletedTreatmentEndometrial Cancers1
2CompletedTreatmentHead and Neck Carcinoma2
2CompletedTreatmentHodgkins Disease (HD) / Malignant Lymphomas / Non-Hodgkin's Lymphoma (NHL)1
2CompletedTreatmentMyelodysplastic Syndromes1
2CompletedTreatmentMyelodysplastic Syndromes / Myelodysplastic/Myeloproliferative Neoplasms1
2CompletedTreatmentNeutropenias / Sarcomas1
2CompletedTreatmentProstate Cancer / Radiation Toxicity1
2RecruitingPreventionLocally Advanced Rectal Cancer1
2TerminatedSupportive CareCancer of the Ovary / Cervical Cancers / Endometrial Cancers / Fallopian Tube Cancer / Neurologic toxicity / Primary Peritoneal Cavity Cancer / Sarcomas1
2TerminatedSupportive CareHead and Neck Carcinoma / Mucositis / Swallowing Disorders / Xerostomia1
2TerminatedTreatmentColorectal Cancers1
2TerminatedTreatmentDrug/Agent Toxicity by Tissue/Organ / Head and Neck Carcinoma / Oral Complications / Radiation Toxicity1
2TerminatedTreatmentHead and Neck Carcinoma1
2Unknown StatusPreventionRectal Carcinoma1
2Unknown StatusSupportive CareDrug/Agent Toxicity by Tissue/Organ / Leukemias / Myelodysplastic Syndromes / Neutropenias1
2Unknown StatusSupportive CareDrug/Agent Toxicity by Tissue/Organ / Lung Cancers / Radiation Toxicity1
2Unknown StatusTreatmentAnemias / Myelodysplastic Syndromes1
2Unknown StatusTreatmentHead and Neck Carcinoma1
2Unknown StatusTreatmentLeukemias1
2Unknown StatusTreatmentLeukemias / Myelodysplastic Syndromes1
2Unknown StatusTreatmentMyelodysplastic Syndromes1
3CompletedSupportive CareCancer of the Ovary / Quality of Life1
3CompletedSupportive CareDrug/Agent Toxicity by Tissue/Organ / Lung Cancers / Oral Complications / Radiation Toxicity1
3CompletedSupportive CareGestational Trophoblastic Disease / Neurologic toxicity / Peripheral Neuropathy / Unspecified Adult Solid Tumor, Protocol Specific1
3CompletedTreatmentChildhood Hepatoblastoma / Recurrent Childhood Liver Cancer / Stage I Childhood Liver Cancer1
3CompletedTreatmentHead and Neck Carcinoma1
3CompletedTreatmentRefractory Multiple Myeloma / Stage II Multiple Myeloma / Stage III Multiple Myeloma1
3CompletedTreatmentStage I Lymphoepithelioma of the Nasopharynx / Stage I Squamous Cell Carcinoma of the Nasopharynx / Stage II Lymphoepithelioma of the Nasopharynx / Stage II Squamous Cell Carcinoma of the Nasopharynx / Stage III Lymphoepithelioma of the Nasopharynx / Stage III Squamous Cell Carcinoma of the Nasopharynx / Stage IV Lymphoepithelioma of the Nasopharynx / Stage IV Squamous Cell Carcinoma of the Nasopharynx1
3Unknown StatusTreatmentTrigeminal Neuralgia (TN)1
4CompletedSupportive CareDrug/Agent Toxicity by Tissue/Organ / Unspecified Adult Solid Tumor, Protocol Specific1
4SuspendedSupportive CareOral Mucositis / Vesicular Stomatitis1
Not AvailableCompletedTreatmentHead and Neck Carcinoma / Lung Cancers1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Bedford Labs
  • Ben Venue Laboratories Inc.
  • Medimmune Inc.
  • Sun Pharmaceutical Industries Ltd.
Dosage forms
FormRouteStrength
Injection, powder, lyophilized, for solutionIntravenous50 mg/1mL
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)
US5424471No1995-06-132012-07-31Us
CA2120133No1998-06-092013-07-30Canada
US5994409No1999-11-302017-12-08Us

Properties

State
Solid
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)10.71ChemAxon
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 FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
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)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-0002-0900000000-5350b8c906608c1eb7e4
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-0002-0900000000-bcddc871edb434e577ae
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-0002-2900000000-58ff84f991edcac36e7d
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-05nb-9200000000-ef847b9b156a08e7fa17
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-0a4l-9000000000-c58215f6bca055f13ab7

Taxonomy

Description
This 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.
Kingdom
Organic compounds
Super Class
Organophosphorus compounds
Class
Organothiophosphorus compounds
Sub Class
Not Available
Direct Parent
Organothiophosphorus compounds
Alternative Parents
Sulfenyl compounds / Dialkylamines / Organopnictogen compounds / Organic oxides / Monoalkylamines / Hydrocarbon derivatives
Substituents
Sulfenyl compound / Secondary amine / Organothiophosphorus compound / Secondary aliphatic amine / Organic nitrogen compound / Organic oxygen compound / Organopnictogen compound / Organic oxide / Hydrocarbon derivative / Primary amine
Molecular Framework
Aliphatic acyclic compounds
External Descriptors
organic thiophosphate, diamine (CHEBI:2636)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inducer
General Function
Metal ion binding
Specific Function
Not Available
Gene Name
ALPPL2
Uniprot ID
P10696
Uniprot Name
Alkaline phosphatase, placental-like
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]
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 hydroxyapat...
Gene Name
ENPP1
Uniprot ID
P22413
Uniprot Name
Ectonucleotide pyrophosphatase/phosphodiesterase family member 1
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]

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
Uniprot Name
Alkaline phosphatase, tissue-nonspecific isozyme
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]

Drug created on June 13, 2005 07:24 / Updated on December 14, 2018 12:39