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Identification
- Summary
Amifostine is a cytoprotective adjuvant used for reduction in the cumulative renal toxicity in patients with ovarian cancer and moderate to severe xerostomia in patients undergoing post-operative radiation treatment for head and neck cancer.
- Brand Names
- Ethyol
- Generic Name
- Amifostine
- DrugBank Accession Number
- DB01143
- Background
A phosphorothioate proposed as a radiation-protective agent. It causes splenic vasodilation and may block autonomic ganglia.
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Amifostine (DB01143)
- Weight
- Average: 214.223
Monoisotopic: 214.054099558 - Chemical Formula
- C5H15N2O3PS
- Synonyms
- Amifostina
- Amifostine
- Amifostine anhydrous
- Amifostinum
- Aminopropylaminoethyl thiophosphate
- Ethiofos
- External IDs
- WR-2721
- YM-08310
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.
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Prophylaxis of Radiation proctitis ••• ••••• Prophylaxis of Renal toxicity •••••••••••• Prophylaxis of Xerostomia •••••••••••• - Contraindications & Blackbox Warnings
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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.
Target Actions Organism AAlkaline phosphatase, germ cell type inducerHumans - 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
- Adverse Effects
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Rat LD50: 826 mg/kg
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbaloparatide The risk or severity of adverse effects can be increased when Amifostine is combined with Abaloparatide. Acebutolol Acebutolol may increase the hypotensive activities of Amifostine. Aldesleukin The risk or severity of adverse effects can be increased when Aldesleukin is combined with Amifostine. Aliskiren Aliskiren may increase the hypotensive activities of Amifostine. Ambrisentan Ambrisentan may increase the hypotensive activities of Amifostine. - Food Interactions
- No interactions found.
Products
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Ingredient UNII CAS InChI Key Amifostine trihydrate M487QF2F4V 112901-68-5 TXQPXJKRNHJWAX-UHFFFAOYSA-N - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Amifostine Injection, powder, lyophilized, for solution 500 mg/10mL Intravenous Bedford Pharmaceuticals 2008-04-02 2018-12-31 US 
Ethyol Injection, powder, lyophilized, for solution 500 mg/10mL Intravenous Cumberland Pharmaceuticals Inc. 2016-08-01 2020-10-31 US Ethyol Injection, powder, lyophilized, for solution 500 mg/10mL Intravenous Clinigen Limited 2020-01-01 Not applicable US Ethyol Injection, powder, lyophilized, for solution 500 mg/10mL Intravenous Med Immune, Llc 1995-12-08 2012-04-30 US Ethyol - Pws IV 500mg/vial Powder, for solution 500 mg / vial Intravenous Medimmune Oncology, Inc. 1996-12-31 2008-01-01 Canada 
- Generic Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Amifostine Injection, powder, lyophilized, for solution 50 mg/1mL Intravenous Sun Pharmaceutical Industries Limited 2008-03-14 2012-03-31 US Amifostine Injection, powder, lyophilized, for solution 50 mg/1mL Intravenous Sun Pharma Global FZE 2008-03-14 2013-07-31 US
Categories
- ATC Codes
- V03AF05 — Amifostine
- Drug Categories
- Compounds used in a research, industrial, or household setting
- Cytoprotective Agent
- Detoxifying Agents for Antineoplastic Treatment
- Free Radical Scavenging Activity
- Hypotensive Agents
- Organophosphates
- Organophosphorus Compounds
- Organothiophosphates
- Organothiophosphorus Compounds
- Protective Agents
- Radiation-Protective Agents
- Sulfur Compounds
- Chemical TaxonomyProvided by Classyfire
- 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
- Aliphatic acyclic compound / Amine / Hydrocarbon derivative / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organonitrogen compound / Organopnictogen compound / Organosulfur compound / Organothiophosphorus compound
- Molecular Framework
- Aliphatic acyclic compounds
- External Descriptors
- organic thiophosphate, diamine (CHEBI:2636)
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- ILA426L95O
- CAS number
- 20537-88-6
- 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
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
- Santini V, Giles FJ: The potential of amifostine: from cytoprotectant to therapeutic agent. Haematologica. 1999 Nov;84(11):1035-42. [Article]
- External Links
- Human Metabolome Database
- HMDB0015274
- KEGG Compound
- C06819
- PubChem Compound
- 2141
- PubChem Substance
- 46505305
- ChemSpider
- 2056
- 1545987
- ChEBI
- 2636
- ChEMBL
- CHEMBL1006
- ZINC
- ZINC000021992285
- PharmGKB
- PA448365
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Amifostine
- FDA label
- Download (45.6 KB)
- MSDS
- Download (36.1 KB)
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample dataNot Available Completed Treatment Head And Neck Cancer / Lung Cancer 1 somestatus stop reason just information to hide 4 Completed Prevention Head And Neck Cancer / Lung Cancer / Lymphoma 1 somestatus stop reason just information to hide 4 Completed Supportive Care Drug/Agent Toxicity by Tissue/Organ / Unspecified Adult Solid Tumor, Protocol Specific 1 somestatus stop reason just information to hide 4 Withdrawn Supportive Care Oral Mucositis / Stomatitis 1 somestatus stop reason just information to hide 3 Completed Supportive Care Drug/Agent Toxicity by Tissue/Organ / Lung Cancer / Oral Complications / Radiation Toxicity 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Bedford Labs
- Ben Venue Laboratories Inc.
- Medimmune Inc.
- Sun Pharmaceutical Industries Ltd.
- Dosage Forms
Form Route Strength Injection, powder, lyophilized, for solution Intravenous 50 mg/1mL Solution Intravenous 500.000 mg Injection Intravenous 375 mg Injection, powder, for solution Intravenous 500 mg Injection, powder, lyophilized, for solution Intravenous 500 mg/10mL Powder, for solution Intravenous 500 mg / vial Injection, powder, lyophilized, for solution Intravenous 500 mg Injection, powder, lyophilized, for solution Parenteral 100 mg Solution Intravenous 500 mg - Prices
Unit description Cost Unit Ethyol 500 mg vial 605.88USD vial Amifostine 500 mg vial 600.0USD vial DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US5424471 No 1995-06-13 2012-07-31 US CA2120133 No 1998-06-09 2013-07-30 Canada US5994409 No 1999-11-30 2017-12-08 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source water solubility 1000 mg/mL Not Available logP -1.9 Not Available - Predicted Properties
Property Value Source Water Solubility 18.7 mg/mL ALOGPS logP -1.4 ALOGPS logP -3.7 Chemaxon logS -1.1 ALOGPS pKa (Strongest Acidic) 2.06 Chemaxon pKa (Strongest Basic) 10.71 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 5 Chemaxon Hydrogen Donor Count 4 Chemaxon Polar Surface Area 95.58 Å2 Chemaxon Rotatable Bond Count 7 Chemaxon Refractivity 51.28 m3·mol-1 Chemaxon Polarizability 21.01 Å3 Chemaxon Number of Rings 0 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - 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 inhibitor Non-inhibitor 0.9071 CYP450 2D6 inhibitor Non-inhibitor 0.9231 CYP450 2C19 inhibitor Non-inhibitor 0.9026 CYP450 3A4 inhibitor 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
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 149.3731798 predictedDarkChem Lite v0.1.0 [M-H]- 136.2305 predictedDeepCCS 1.0 (2019) [M+H]+ 149.6978798 predictedDarkChem Lite v0.1.0 [M+H]+ 139.4081 predictedDeepCCS 1.0 (2019) [M+Na]+ 149.3566798 predictedDarkChem Lite v0.1.0 [M+Na]+ 148.24472 predictedDeepCCS 1.0 (2019)
Targets
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- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inducer
- General Function
- Alkaline phosphatase that can hydrolyze various phosphate compounds
- Specific Function
- alkaline phosphatase activity
- Gene Name
- ALPG
- Uniprot ID
- P10696
- Uniprot Name
- Alkaline phosphatase, germ cell type
- Molecular Weight
- 57376.515 Da
References
- 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. [Article]
- 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. [Article]
- Santini V, Giles FJ: The potential of amifostine: from cytoprotectant to therapeutic agent. Haematologica. 1999 Nov;84(11):1035-42. [Article]
- 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. [Article]
- 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. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Alkaline phosphatase that metabolizes various phosphate compounds and plays a key role in skeletal mineralization and adaptive thermogenesis (PubMed:12162492, PubMed:23688511, PubMed:25982064). Has broad substrate specificity and can hydrolyze a considerable variety of compounds: however, only a few substrates, such as diphosphate (inorganic pyrophosphate; PPi), pyridoxal 5'-phosphate (PLP) and N-phosphocreatine are natural substrates (PubMed:12162492, PubMed:2220817). Plays an essential role in skeletal and dental mineralization via its ability to hydrolyze extracellular diphosphate, a potent mineralization inhibitor, to phosphate: it thereby promotes hydroxyapatite crystal formation and increases inorganic phosphate concentration (PubMed:23688511, PubMed:25982064). Acts in a non-redundant manner with PHOSPHO1 in skeletal mineralization: while PHOSPHO1 mediates the initiation of hydroxyapatite crystallization in the matrix vesicles (MVs), ALPL/TNAP catalyzes the spread of hydroxyapatite crystallization in the extracellular matrix (By similarity). Also promotes dephosphorylation of osteopontin (SSP1), an inhibitor of hydroxyapatite crystallization in its phosphorylated state; it is however unclear whether ALPL/TNAP mediates SSP1 dephosphorylation via a direct or indirect manner (By similarity). Catalyzes dephosphorylation of PLP to pyridoxal (PL), the transportable form of vitamin B6, in order to provide a sufficient amount of PLP in the brain, an essential cofactor for enzymes catalyzing the synthesis of diverse neurotransmitters (PubMed:20049532, PubMed:2220817). Additionally, also able to mediate ATP degradation in a stepwise manner to adenosine, thereby regulating the availability of ligands for purinergic receptors (By similarity). Also capable of dephosphorylating microbial products, such as lipopolysaccharides (LPS) as well as other phosphorylated small-molecules, such as poly-inosine:cytosine (poly I:C) (PubMed:28448526). Acts as a key regulator of adaptive thermogenesis as part of the futile creatine cycle: localizes to the mitochondria of thermogenic fat cells and acts by mediating hydrolysis of N-phosphocreatine to initiate a futile cycle of creatine dephosphorylation and phosphorylation (By similarity). During the futile creatine cycle, creatine and N-phosphocreatine are in a futile cycle, which dissipates the high energy charge of N-phosphocreatine as heat without performing any mechanical or chemical work (By similarity)
- Specific Function
- ADP phosphatase activity
- Gene Name
- ALPL
- Uniprot ID
- P05186
- Uniprot Name
- Alkaline phosphatase, tissue-nonspecific isozyme
- Molecular Weight
- 57304.435 Da
References
- Shaw LM, Bonner H, Lieberman R: Pharmacokinetic profile of amifostine. Semin Oncol. 1996 Aug;23(4 Suppl 8):18-22. [Article]
Drug created at June 13, 2005 13:24 / Updated at December 08, 2022 21:17