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Identification
NameDeferasirox
Accession NumberDB01609
Typesmall molecule
Groupsapproved, investigational
Description

Deferasirox is an oral iron chelator. Its main use is to reduce chronic iron overload in patients who are receiving long term blood transfusions for conditions such as beta-thalassemia and other chronic anemias. It is the first oral medication approved in the USA for this purpose.

Structure
Thumb
Synonyms
SynonymLanguageCode
DeferasiroxumLatinINN
ICL 670Not AvailableNot Available
SaltsNot Available
Brand names
NameCompany
ExjadeNot Available
Brand mixturesNot Available
Categories
CAS number201530-41-8
WeightAverage: 373.3615
Monoisotopic: 373.106255983
Chemical FormulaC21H15N3O4
InChI KeyBOFQWVMAQOTZIW-UHFFFAOYSA-N
InChI
InChI=1S/C21H15N3O4/c25-17-7-3-1-5-15(17)19-22-20(16-6-2-4-8-18(16)26)24(23-19)14-11-9-13(10-12-14)21(27)28/h1-12,25-26H,(H,27,28)
IUPAC Name
4-[bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl]benzoic acid
SMILES
OC(=O)C1=CC=C(C=C1)N1N=C(N=C1C1=CC=CC=C1O)C1=CC=CC=C1O
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassAzoles
SubclassTriazoles
Direct parentPhenyltriazoles
Alternative parentsAminobenzoic Acid Derivatives; Benzoic Acids; Benzoyl Derivatives; Phenols and Derivatives; Polyols; Carboxylic Acids; Enols; Polyamines; Enolates
Substituentsbenzoic acid; benzoic acid or derivative; benzoyl; phenol derivative; benzene; polyol; enolate; polyamine; enol; carboxylic acid derivative; carboxylic acid; amine; organonitrogen compound
Classification descriptionThis compound belongs to the phenyltriazoles. These are organic aromatic compounds containing a phenyl group sustituted with a triazole ring.
Pharmacology
IndicationFor the treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis) in patients 2 years of age and older.
PharmacodynamicsDeferasirox is an orally active chelator that is selective for iron (as Fe3+). It is a tridentate ligand that binds iron with high affinity in a 2:1 ratio. Although deferasirox has very low affinity for zinc and copper there are variable decreases in the serum concentration of these trace metals after the administration of deferasirox. The clinical significance of these decreases is uncertain.
Mechanism of actionTwo molecules of deferasirox are capable of binding to 1 atom of iron. Deferasirox works in treating iron toxicity by binding trivalent (ferric) iron (for which it has a strong affinity), forming a stable complex which is eliminated via the kidneys.
AbsorptionThe absolute bioavailability (AUC) of deferasirox tablets for oral suspension is 70% compared to an intravenous dose.
Volume of distribution
  • 14.37 ± 2.69 L
Protein bindingDeferasirox is highly (~99%) protein bound almost exclusively to serum albumin.
Metabolism

Hepatic. CYP450-catalyzed (oxidative) metabolism of deferasirox appears to be minor in humans (about 8%). Glucuronidation is the main metabolic pathway for deferasirox, with subsequent biliary excretion.

Route of eliminationDeferasirox and metabolites are primarily (84% of the dose) excreted in the feces. Renal excretion of deferasirox and metabolites is minimal (8% of the administered dose).
Half lifeThe mean elimination half-life ranged from 8 to 16 hours following oral administration.
ClearanceNot Available
ToxicityNot Available
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 + 0.993
Blood Brain Barrier + 0.8508
Caco-2 permeable + 0.5089
P-glycoprotein substrate Non-substrate 0.7808
P-glycoprotein inhibitor I Non-inhibitor 0.894
P-glycoprotein inhibitor II Non-inhibitor 0.8431
Renal organic cation transporter Non-inhibitor 0.8708
CYP450 2C9 substrate Non-substrate 0.7212
CYP450 2D6 substrate Non-substrate 0.8686
CYP450 3A4 substrate Non-substrate 0.6466
CYP450 1A2 substrate Non-inhibitor 0.5802
CYP450 2C9 substrate Non-inhibitor 0.7105
CYP450 2D6 substrate Non-inhibitor 0.8221
CYP450 2C19 substrate Non-inhibitor 0.5918
CYP450 3A4 substrate Non-inhibitor 0.8179
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.5717
Ames test Non AMES toxic 0.6607
Carcinogenicity Non-carcinogens 0.8519
Biodegradation Not ready biodegradable 0.9524
Rat acute toxicity 2.1119 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9684
hERG inhibition (predictor II) Non-inhibitor 0.9072
Pharmacoeconomics
Manufacturers
  • Novartis pharmaceuticals corp
Packagers
Dosage forms
FormRouteStrength
Tablet, for suspensionOral
Prices
Unit descriptionCostUnit
Exjade 500 mg tablet78.61USDtablet
Exjade 250 mg tablet39.3USDtablet
Exjade 125 mg tablet19.65USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States64655041999-04-052019-04-05
United States65967501997-06-242017-06-24
Canada22559512006-10-102017-06-24
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point116-117 °CNot Available
water solubility0.038 mg/mL at 37 °CYALKOWSKY,SH & DANNENFELSER,RM (1992)
logP3.52HANSCH,C ET AL. (1995)
Predicted Properties
PropertyValueSource
water solubility3.43e-02 g/lALOGPS
logP4.01ALOGPS
logP4.74ChemAxon
logS-4ALOGPS
pKa (strongest acidic)4.55ChemAxon
pKa (strongest basic)0.19ChemAxon
physiological charge-1ChemAxon
hydrogen acceptor count6ChemAxon
hydrogen donor count3ChemAxon
polar surface area108.47ChemAxon
rotatable bond count4ChemAxon
refractivity125.32ChemAxon
polarizability38.52ChemAxon
number of rings4ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Rajendra Suryabhan Patil, Kishore Charugundla, Praveen Kumar Neela, Nitin Sharadchandra Pradhan, Jon Valgeirsson, “SUBSTANTIALLY PURE DEFERASIROX AND PROCESSES FOR THE PREPARATION THEREOF.” U.S. Patent US20110171138, issued July 14, 2011.

US20110171138
General ReferenceNot Available
External Links
ResourceLink
KEGG DrugD03669
PubChem Compound5493381
PubChem Substance46506791
ChemSpider4591431
PharmGKBPA164760843
Drug Product Database1926756
RxListhttp://www.rxlist.com/cgi/generic/exjade.htm
Drugs.comhttp://www.drugs.com/cdi/deferasirox.html
WikipediaDeferasirox
ATC CodesV03AC03
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Interactions
Drug Interactions
Drug
AluminiumPossible physicochemical interaction
BivalirudinAnticoagulants increase the risk for gastrointestinal ulceration/irritation and/or GI bleeding. If these two agents must be used, patients need to be closely monitored for signs and symptoms of GI toxicity.
EtravirineEtravirine, when administered concomitantly with deferasirox, may experience a decrease in serum concentration. It is recommended to monitor therapy.
TofacitinibTofacitinib (and other CYP3A4 substrates), when used in combination with deferasirox, may experience a decrease in concentration. It is recommended to monitor therapy.
Food Interactions
  • Dispersion in carbonated drinks or milk is not recommended due to foaming and slow dispersion, respectively.
  • Food causes inconsistent increases in the bioavailability of this product.
  • Tablets should be completely dispersed in water, orange juice or apple juice and the resulting suspension should be ingested immediately (after swallowing the suspension, any residue should be resuspended in a small volume of liquid and swallowed).
  • Tablets should be taken on an empty stomach at least 30 minutes before a meal, preferably at the same time everyday.

Targets

1. Iron

Kind: small molecule

Organism: Human

Pharmacological action: yes

Actions: chelator

Components

Name UniProt ID Details

References:

  1. Wang T, Gao C, Chen BA: [Deferasirox—a new oral iron chelator—review]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2010 Oct;18(5):1359-64. Pubmed
  2. Ibrahim AS, Spellberg B, Edwards J Jr: Iron acquisition: a novel perspective on mucormycosis pathogenesis and treatment. Curr Opin Infect Dis. 2008 Dec;21(6):620-5. Pubmed
  3. Devanur LD, Evans RW, Evans PJ, Hider RC: Chelator-facilitated removal of iron from transferrin: relevance to combined chelation therapy. Biochem J. 2008 Jan 15;409(2):439-47. Pubmed
  4. Lebitasy M, Ampe E, Hecq JD, Karmani L, Nick H, Galanti L: Ability of deferasirox to bind iron during measurement of iron. Clin Chem Lab Med. 2010 Mar;48(3):427-9. Pubmed
  5. Yang LP, Keam SJ, Keating GM: Deferasirox : a review of its use in the management of transfusional chronic iron overload. Drugs. 2007;67(15):2211-30. Pubmed
  6. Choudhry VP, Naithani R: Current status of iron overload and chelation with deferasirox. Indian J Pediatr. 2007 Aug;74(8):759-64. Pubmed

Enzymes

1. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inducer

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. Skerjanec A, Wang J, Maren K, Rojkjaer L: Investigation of the pharmacokinetic interactions of deferasirox, a once-daily oral iron chelator, with midazolam, rifampin, and repaglinide in healthy volunteers. J Clin Pharmacol. 2010 Feb;50(2):205-13. Epub 2009 Nov 25. Pubmed

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Drug created on August 29, 2007 13:21 / Updated on September 16, 2013 17:15