Pharmacological Data
Compound name: Deferiprone
Brand Name: Ferriprox

Structure: deferiprone.jpg
Overall, deferiprone is relatively non-polar and is comparatively small to some other medications. This allows for easier absorption and distribution to the plasma and organs where ferric iron may be building up. The methyl group adjacent to the hydroxyl group may be partly 'masking' the polarity created by the presence of the hydroxyl group which may partly account for this compounds ability to move throughout the body with relative ease. The polar ketone and hydroxyl groups are coordinating groups, with hard metal cations, which must be present to ensure adhesion to ferric iron. The coordinating groups along with the non-polar body of the molecule create the desired therapeutic effect, which is the reduction of ferric iron levels in the body.

Inventors: Michael Spino and Antonio Piga (Apotex Inc.)
Synthetic Route: DeferiproneSynthesisRoute1.jpg
Pharmacological Class: Iron chelating agent.

ADME [2]
Absorption: Absorption occurs in the upper portion of the GI (gastrointestinal) tract. The absorption of deferiprone occurs quite rapidly causing the drug to appear in the circulatory system in 5 to 10 minutes after oral ingestion of a pill.
Distribution: Distribution of the drug is accomplished using the circulatory system and serum albumin as a transport protein. In most patients peak serum levels are generally occurring an hour after administration. Volume of distribution is 1 to 1.6L/kg.
Metabolism: Deferiprone is metabolized by the enzyme UDP-glucuronosyltransferase 1-6. The metabolite proceeds directly to phase 2 metabolism where it is has sugar group attached. The structure of the main metabolite is shown below.
DeferiproneMetabolite.jpg
Elimination: Virtually all of the drug is eliminated from the plasma within six hours with the vast majority of the metabolite being excreted via urine.

Mechanism of Action: Ferric iron, Fe(III) has the capability of generating free radicals which can degrade biomolecules when the ion is not coordinated fully by ligands. Deferiprone is a bidentate coordinating molecule, therefore three molecules of this drug are needed to completely coordinate ferric iron which has six coordination sites[3]. The hard donor atoms of the deferiprone molecules ensures strong coordination with the hard iron 3+ ion. The fully coordinated ferric iron can no longer generate radicals and allows for the iron to be eliminated with greater ease.

Dosage: 25mg of drug per kilogram of body mass, taken orally three times daily for healthy adults. The maximum dosage given is 33mg/kg, taken three times a day [2]. There is no dosage data for children because Deferiprone is not recommended for children.

Side Effects: Deferiprone has been linked to many side effects which include:
  • Neutrophenia
  • Agranulocytosis
  • Nausea
  • Abdominal pain
  • Diarrhea
  • Decreased neutrophil count
  • Altered appetite
  • Pain in the back and extremities
  • Severe headaches
  • Mortality
(Ferriprox Tablet Labels [2])

Drug Interactions:
  1. Drugs Associated with leukopenia: A patient taking medication to raise their white blood cell counts should avoid using Deferiprone because one of the main side effects is the lowering of white blood cells. Simultaneous administration places the immune system under stress, compromising its ability to fight off infections even further [2].
  2. UGT 1A6 Inhibitors: Certain compounds, such as silymarin (milk thistle), inhibit the enzyme UDP glucuronosyltransferase 1A6 which is the main enzyme responsible for the metabolism of deferiprone. Persons using these inhibitors should not take deferiprone as it may lead to toxic levels of drug in the plasma [2].
  3. Polyvalent Cations: Since deferiprone is a bidentate ligand it has the ability to coordinate with polyvalent cations other than ferric iron, such as aluminum and zinc. Studies have not been done on how administration of deferiprone along with cation sources, such as mineral supplements and antacids, affects humans. It is recommended that there be a four hour period after ingestion of deferiprone where compounds containing polyvalent cations should not be taken [1].

Patent Information [4]
Use For Deferiprone
Patent Number: 7049328
Filing Date: June 28th, 2001.
Issue Date: May 23rd, 2006.
Expires (Estimated Time): June 28th, 2021.
This patent covers the original research pertaining to the development of this drug and its desired use as a means to reduce ferric iron levels in patients suffering from thalassemia. Information regarding the clinical trials can also be found within this patent. Since this initial patent was approved in 2006, five more patents have been filed for acceptance involving deferiprone.

(1)
Title: Use of deferiprone and methods to treat and/or prevent friedreich ataxia resulting from intracellular mishandling of iron.
Application #: 20070197649
Filed: August 23rd, 2007.
Contents: Patent covers the use of deferiprone as a treatment for iron-induced Friedreich ataxia which is a result of damage caused by iron which reduce iron stores within the mitochondria. [5]
(2)
Title: Fluorinated derivatives of deferiprone.
Application #: 2008024706
Filed: October 2nd, 2008.
Contents: Patent covers the synthesis and clinical trial data pertaining to the use of fluorinated derivatives of deferiprone as a therapeutic agent to reduce ferric iron levels. [5]
(3)
Title: Topical transdermal delivery of hif-1 modulators to prevent and treat chronic wounds.
Application #: 20100092546
Filed: April 15th, 2010.
Contents: Patent covers the compositions and methods for the use of deferiprone and several other drugs as a means of increasing the activity of HIF-1a in wounds. [5]
(4)
Title: Compositions and methods for the treatment of mucormycosis and other fungal diseases.
Application #: 20100129434
Filed: May 27th, 2010.
Contents: Patent covers the use of deferiprone being administered along with several various antifungal agents as a more effective method of treating certain fungal infections. [5]
(5)
Title: Liquid formulation for deferiprone with palatable taste.
Application #: 20110039897
Filed: February 2nd, 2011.
Contents: Patent covers the development of a liquid formulation of deferiprone, original form is an oral tablet, with a sweet taste for ease of use. [5]

Nearest Rival
Compound Name: Deferasirox
Brand Name: Exjade
Producer: Novartis AG

Structure: DeferasiroxStructure.jpg
Although deferasirox is much larger than deferiprone, the overall pharmacophore is the same. With the exception of three polar groups involved in coordination with ferric iron, the molecule is overall non-polar. This is crucial for decent absorption and distribution throughout the body.

Synthesis: SynthesisDeferasirox.jpg

ADME [7]
Absorption: Absorbed in the upper portion of the GI tract. Absolute bio-availability is 70% when taken orally.
Distribution: Deferasirox is distributed via the circulatory system, the drugs within the plasma are almost 99% bound to serum albumin. Volume of distribution is 14.37 +- 2.67 L/kg.
Metabolism: Majority of metabolism occurs via glucuronidation, similar to deferiprone. A minor metabolic pathway involves the hepatic oxidative enzyme CPY 450.
Elimination: Around 84% of deferasirox and its metabolites are eliminated via feces, while approximately 8% is eliminated in the urine. The elimination half-life ranges from 8-16 hours after oral administration.

Mechanism of Action: Deferasirox is a tridentate chelating ligand that binds to internal ferric iron; two molecules of deferasirox are needed to fully chelate ferric iron. The coordinated ferric iron is much easier to excrete than the uncoordinated ion. [6]

Patents [5]
(1)
Title: Patent Extension Application For Exjade (deferasirox).
Patent #: 6465504
Approved: April 5th, 1999.
Expires: April 5th, 2019.
(2)
Title: Use For Deferasirox As An Iron Chelating Agent.
Patent #: 6596750
Approved: June 24th, 1997.
Expires: June 24th, 2017.

Comparison to Deferiprone
The main difference other than the obvious discrepancy in molecule size is the coordinating capacity of the drugs. Deferiprone is only capable of forming two bonds with ferric iron, whereas deferasirox is capable of forming three bonds with ferric iron. As the coordination number of a molecule increases, so does the affinity for a particular polyvalent metal cation [6]; this is the main reason for deferasirox having a greater efficacy for ferric iron. Both of these drugs utilize the hard hydroxyl donor groups to promote favourable coordination with the hard 3+ charge on ferric iron ions. In terms of market sales, deferasirox essentially dominates due to its greater therapeutic action and overall less severe side effects. Deferiprone is used predominantly in situations where deferasirox is not a valid method of treating iron overload; also, deferiprone actually exhibits better ferric iron removal from the heart compared to deferasirox[6].


References for this page
[1] Ferriprox: Monthly Prescribing Reference. Updated: January 30th, 2012. http://www.empr.com/ferriprox/drugproduct/203/
[2] Ferriprox (Deferiprone) Tablet Labels. ApoPharma. http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021825lbl.pdf
[3] A. Dubey, S. Sudha and A. Parakh. 2007. "Deferasirox: The New Oral Iron Chelator." Drug Review 44; pp. 603 - 607.
[4] M. Spino and A. Piga. Use For Deferiprone. U.S. Patent US7049328 B2. May 23rd, 2006. (Link via Google Patents: http://www.google.com/patents/US7049328)
[5] Fresh Patents: Deferiprone Patents. http://tgs.freshpatents.com/Deferiprone-bx1.php (Accessed March 10, 2012).
[6] E. Neufeld. 2006. "Oral chelators deferasirox and deferiprone for transfusional iron overload in thalassemia major: new data, new questions. Blood 107; pp. 3436 - 34441.
[7] Deferasirox: Drugbank Information. http://www.drugbank.ca/drugs/DB01609 (Accessed March 10, 2012).