デフェラシロクス
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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/08/19 02:33:40」(JST)
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Deferasirox
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| Systematic (IUPAC) name |
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4-[(3Z,5E)-3,5-bis(6-oxo-1-cyclohexa-2,4-
dienylidene)-1,2,4-triazolidin-1-yl]benzoic acid
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| Clinical data |
| License data |
- EU EMA: Exjade
- US FDA: Deferasirox
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Pregnancy
category |
- AU: C
- US: B (No risk in non-human studies)
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Routes of
administration |
Oral |
| Legal status |
| Legal status |
- UK: POM (Prescription only)
- US: ℞-only
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| Pharmacokinetic data |
| Bioavailability |
70% |
| Protein binding |
99% |
| Metabolism |
Hepatic glucuronidation |
| Biological half-life |
8 to 16 hours |
| Excretion |
Fecal (84%) and renal (8%) |
| Identifiers |
| CAS Number |
201530-41-8 Y |
| ATC code |
V03AC03 (WHO) |
| PubChem |
CID 5493381 |
| DrugBank |
DB01609 Y |
| ChemSpider |
4591431 Y |
| UNII |
V8G4MOF2V9 Y |
| KEGG |
D03669 Y |
| ChEMBL |
CHEMBL550348 N |
| Chemical data |
| Formula |
C21H15N3O4 |
| Molar mass |
373.362 g/mol |
SMILES
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O=C4/C=C\C=C/C4=C2\N(N/C(=C1\C(=O)\C=C/C=C1)N2)c3ccc(C(=O)O)cc3
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InChI
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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/h1-12,22-23H,(H,27,28)/b19-15-,20-16+ Y
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Key:FMSOAWSKCWYLBB-VBGLAJCLSA-N Y
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| NY (what is this?) (verify) |
Deferasirox (marketed as Exjade,[1] Desirox, Defrijet, Desifer, Rasiroxpine...) 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.[2][3] It is the first oral medication approved in the USA for this purpose.[4]
It was approved by the United States Food and Drug Administration (FDA) in November 2005.[2][4] According to FDA (May 2007), renal failure and cytopenias have been reported in patients receiving deferasirox oral suspension tablets. It is approved in the European Union by the European Medicines Agency (EMA) for children 6 years and older for chronic iron overload from repeated blood transfusions.[5][6][7]
Contents
- 1 Properties of deferasirox
- 2 Synthesis
- 3 Risks
- 4 References
Properties of deferasirox
Two deferasirox molecules binding iron
The half-life of deferasirox is between 8 and 16 hours allowing once a day dosing. Two molecules of deferasirox are capable of binding to 1 atom of iron which are subsequently eliminated by fecal excretion. Its low molecular weight and high lipophilicity allows the drug to be taken orally unlike deferoxamine which has to be administered by IV route (intravenous infusion). Together with deferiprone, deferasirox seems to be capable of removing iron from cells (cardiac myocytes and hepatocytes) as well as removing iron from the blood.
Synthesis
Deferasirox can be prepared from simple commercially available starting materials (salicylic acid, salicylamide and 4-hydrazinobenzoic acid) in the following two-step synthetic sequence:
The condensation of salicyloyl chloride (formed in situ from salicylic acid and thionyl chloride) with salicylamide under dehydrating reaction conditions results in formation of 2-(2-hydroxyphenyl)-1,3(4H)-benzoxazin-4-one. This intermediate is isolated and reacted with 4-hydrazinobenzoic acid in the presence of base to give 4-(3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl)benzoic acid (Deferasirox).[8]
Risks
Deferasirox was the #2 drug on the list of 'Most frequent suspected drugs in reported patient deaths' compiled by the Institute for Safe Medical Practices in 2009. There were 1320 deaths reported, perhaps explained by an update to the ADE data of Novartis, and a new boxed warning about gastrointestinal haemorrhage as well as kidney and liver failure. [9]
References
- ^ Official manufacturer website including information for health care professionals about indications, dosing, safety and more: http://www.exjade.com/
- ^ a b Choudhry VP, Naithani R (2007). "Current status of iron overload and chelation with deferasirox". Indian J Pediatr. 74 (8): 759–64. doi:10.1007/s12098-007-0134-7. PMID 17785900. Free full text
- ^ Yang LP, Keam SJ, Keating GM (2007). "Deferasirox : a review of its use in the management of transfusional chronic iron overload". Drugs. 67 (15): 2211–30. doi:10.2165/00003495-200767150-00007. PMID 17927285.
- ^ a b "FDA Approves First Oral Drug for Chronic Iron Overload" (Press release). United States Food and Drug Administration. November 9, 2005. Retrieved 2007-10-31.
- ^ Exjade - deferasirox, from EMA website
- ^ Turning a blind eye to deferasirox's toxicity? , The Lancet, Volume 381, No. 9873, p1183–1184, 6 April 2013
- ^ Review: Exjade side effects
- ^ Stefan Steinhauser; Uwe Heinz; Mark Bartholomä; Thomas Weyhermüller; Hanspeter Nick; Kaspar Hegetschweiler (2004). "Complex Formation of ICL670 and Related Ligands with FeIII and FeII". European Journal of Inorganic Chemistry. 2004 (21): 4177–4192. doi:10.1002/ejic.200400363. ]
- ^ ISMP (2010). "ISMP QuarterWatch(TM)". 15 (12). ISMP Medication Safety Alert. pp. 1–3.
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Chelating agents / chelation therapy (V03AC, others)
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| Copper |
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| Iron |
- Deferasirox
- Deferiprone
- Deferoxamine#
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| Lead |
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| Thallium |
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| Other |
- ALA
- BAPTA
- DMPS
- DMSA
- DTPA
- EGTA
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- #WHO-EM
- ‡Withdrawn from market
- Clinical trials:
- †Phase III
- §Never to phase III
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UpToDate Contents
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English Journal
- Synthesis, characterization and in vitro anticancer evaluations of two novel derivatives of deferasirox iron chelator.
- Salehi S1, Saljooghi ASh2, Shiri A1.
- European journal of pharmacology.Eur J Pharmacol.2016 Jun 15;781:209-17. doi: 10.1016/j.ejphar.2016.04.026. Epub 2016 Apr 14.
- Iron (Fe) chelation therapy was initially designed to alleviate the toxic effects of excess Fe evident in Fe-overload diseases. However, the novel toxicological properties of some Fe chelator-metal complexes have shifted significant attention to their application in cancer chemotherapy. The present
- PMID 27090924
- Chelation efficacy and erythroid response during deferasirox treatment in patients with myeloproliferative neoplasms in fibrotic phase.
- Latagliata R1, Montagna C1, Porrini R2, Di Veroli A3, Leonetti SC4, Niscola P5, Ciccone F6, Spadea A7, Breccia M1, Maurillo L3, Rago A8, Spirito F9, Cedrone M10, De Muro M11, Montanaro M12, Andriani A13, Bagnato A4, Montefusco E2, Alimena G1.
- European journal of haematology.Eur J Haematol.2016 Jun;96(6):643-9. doi: 10.1111/ejh.12674. Epub 2015 Sep 18.
- At present, very few data are available on deferasirox (DFX) in the treatment of patients with Philadelphia-negative myeloproliferative neoplasms in fibrotic phase (FP-MPN) and transfusion dependence. To address this issue, a retrospective analysis of 28 patients (22 male and 6 female) with FP-MPN a
- PMID 26277477
- Development of a biphasic dissolution test for Deferasirox dispersible tablets and its application in establishing an in vitro-in vivo correlation.
- Al Durdunji A1, AlKhatib HS1, Al-Ghazawi M2.
- European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft für Pharmazeutische Verfahrenstechnik e.V.Eur J Pharm Biopharm.2016 May;102:9-18. doi: 10.1016/j.ejpb.2016.02.006. Epub 2016 Feb 16.
- In a biphasic dissolution medium, the integration of the in vitro dissolution of a drug in an aqueous phase and its subsequent partitioning into an organic phase is hypothesized to simulate the in vivo drug absorption. Such a methodology is expected to improve the probability of achieving a successf
- PMID 26898545
Japanese Journal
- 肝細胞癌に対する内科治療の足跡~革新的治療法の開発
Related Links
- プレスリリース 2005年11月15日 報道関係各位 ノバルティス（スイス）が発表しましたリリースの日本語訳（要約）をご参考までにお届けします。1日1回投与の画期的な経口鉄キレート剤 deferasirox が米国で世界初の承認を取得
- Before taking deferasirox, tell your doctor and pharmacist if you are allergic to deferasirox, any other medications, or any of the ingredients in deferasirox tablets. Ask your doctor or pharmacist for a list of the ingredients. ...
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