Identification

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Name
Tetraferric tricitrate decahydrate
Commonly known or available as Ferric citrate
Accession Number
DB14520  (DBSALT002619)
Type
Small Molecule
Groups
Approved
Description
Not Available
Structure
Thumb
Synonyms
  • Ferric citrate
  • Ferric citrate hydrate
External IDs
KRX-0502
Active Moieties
NameKindUNIICASInChI Key
Ferric cationionic91O4LML61120074-52-6VTLYFUHAOXGGBS-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
AuryxiaTablet, coated210 mg/1OralKeryx Biopharmaceuticals2014-09-17Not applicableUs
Additional Data Available
  • Application Number
    Application Number

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  • Product Code
    Product Code

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Categories
UNII
Q91187K011
CAS number
Not Available
Weight
Average: 967.803
Monoisotopic: 967.832498
Chemical Formula
C18H32Fe4O31
InChI Key
UISKQNNAQKPSDO-UHFFFAOYSA-E
InChI
InChI=1S/3C6H7O7.4Fe.10H2O/c3*7-3(8)1-6(13,5(11)12)2-4(9)10;;;;;;;;;;;;;;/h3*1-2H2,(H,7,8)(H,9,10)(H,11,12);;;;;10*1H2/q3*-1;4*+3;;;;;;;;;;/p-9
IUPAC Name
tetrairon(3+) tris(2-oxidopropane-1,2,3-tricarboxylate) decahydrate
SMILES
O.O.O.O.O.O.O.O.O.O.[Fe+3].[Fe+3].[Fe+3].[Fe+3].[O-]C(=O)CC([O-])(CC([O-])=O)C([O-])=O.[O-]C(=O)CC([O-])(CC([O-])=O)C([O-])=O.[O-]C(=O)CC([O-])(CC([O-])=O)C([O-])=O

Pharmacology

Indication

For the control of serum phosphorus levels in patients with chronic kidney disease on dialysis, as ferric citrate.

Associated Conditions
Pharmacodynamics

When Fe3+ is converted to soluble Fe2+, it primarily exists in the circulation in the complex forms bound to protein (hemoprotein) as heme compounds (hemoglobin or myoglobin), heme enzymes, or nonheme compounds (flavin-iron enzymes, transferring, and ferritin) 1. Once converted, Fe2+ serves to support various biological functions. Iron promotes the synthesis of oxygen transport proteins such as myoglobin and hemoglobin, and the formation of heme enzymes and other iron-containing enzymes involved in electron transfer and redox reactions 1. It also acts as a cofactor in many non-heme enzymes including hydroxylases and ribonucleotide reductase 8. Iron-containing proteins are responsible in mediating antioxidant actions, energy metabolism, oxygen sensing actions, and DNA replication and repair 8. Saturation of transferrin from high concentrations of unstable iron preparations may elevate the levels of weakly transferrin-bound Fe3+, which may induce oxidative stress by catalyzing lipid peroxidation and reactive oxygen species formation 5.

Mechanism of action

Iron is incorporated into various proteins to serve biological functions as a structural component or cofactor. Once ferric or ferrous cation from intestinal enterocytes or reticuloendothelial macrophages is bound to circulating transferrin, iron-transferrin complex binds to the cell-surface transferrin receptor (TfR) 1, resulting in endocytosis and uptake of the metal cargo. Internalized iron is transported to mitochondria for the synthesis of heme or iron-sulfur clusters, which are integral parts of several metalloproteins 1. Excess iron is stored and detoxified in cytosolic ferritin 1. Internalized Fe2+ exported across the basolateral membrane into the bloodstream via Fe+2 transporter ferroportin, which is coupled by reoxidation to Fe3+ via membrane-bound ferroxidase hephaestin or ceruloplasmin activity 1. Fe+3 is again scavenged by transferrin which maintains the ferric iron in a redox-inert state and delivers it into tissues 1.

Fe3+ participates in the autoxidation reaction, where it can be chelated by DNA. It mainly binds to the backbone phosphate group, whereas at higher metal ion content, the cation binds to both guanine N-7 atom and the backbone phosphate group 2.

TargetActionsOrganism
UIron(3+)-hydroxamate-binding protein FhuDNot AvailableEscherichia coli (strain K12)
ATransferrin receptor protein 1Not AvailableHumans
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Absorption

Iron absorption and systemic iron homeostasis are regulated by hepcidin, which is a peptide hormone that also regulates the activity of the iron-efflux protein, ferroportin-1 1. Iron is mostly absorbed in the duodenum and upper jejunum 9. Fe3+ displays low solubility at the neutral pH of the intestine and is mainly be converted to ferrous iron (Fe2+) by ferric reductases 7, as ferric salts are only half as well absorbed as ferrous salts 9. Once converted in the intestinal lumen, Fe+2 is transported across the apical membrane of enterocytes 1. The absorption rate of non-haem iron is 2-20% 1. Stored iron may be liberated via ferroportin-mediated efflux, which is coupled by reoxidation of Fe2+ to Fe3+ by ceruloplasmin in the serum or hephaestin in the enterocyte membrane 5. Fe3+ subsequently binds to transferrin, which keeps ferric cation in a redox-inert state and delivers it into tissues 1.

It is proposed that there may be separate cellular uptake pathways for ferrous iron and ferric iron. While ferrous iron is primarily carried by divalent metal transporter-1 (DMAT-1), cellular uptake of ferric iron is predominantly mediated by beta-3 integrin and mobilferrin, which is also referred to as calreticulin in some sources as a homologue 4. However, the most dominant pathway in humans is unclear 4.

Volume of distribution

Less than 65% of iron is stored in the liver, spleen, and bone marrow, mainly as ferritin and haemosiderin 7. The pharmacokinetic properties of ferric compounds vary.

Protein binding

Fe3+ is converted to Fe2+, which is bound and transported in the body via circulating transferrin. In pathogenic Neisseria, ferric iron-binding protein serves as the main periplasmic-protein for ferric iron that has equivalence to human transferrin 3. Once in the cytosol, ferric iron is stored in ferritin where it is associated with hydroxide and phosphate anions 6.

Metabolism

Ferric cation is converted to ferrous iron by duodenal cytochrome B reductase [A32515]. Ferritin may also convert ferric to ferrous iron 6.

Route of elimination

Iron is predominantly conserved in the body with no physiologic mechanism for excretion of excess iron from the body, other than blood loss 1. The pharmacokinetic properties of ferric compounds vary.

Half life

The pharmacokinetic properties of ferric compounds vary.

Clearance

The rate of iron loss is approximately 1 mg/day 1. The pharmacokinetic properties of ferric compounds vary.

Toxicity

The LD50 of ferric compounds vary. High concentrations of ferric iron from unstable and oversaturation of ferritin may lead to adverse events such as hypotension, nausea, vomiting, abdominal and lower back pain, peripheral edema and a metallic taste 5.

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
3-Aza-2,3-Dihydrogeranyl DiphosphateTetraferric tricitrate decahydrate can cause a decrease in the absorption of 3-Aza-2,3-Dihydrogeranyl Diphosphate resulting in a reduced serum concentration and potentially a decrease in efficacy.
Alendronic acidTetraferric tricitrate decahydrate can cause a decrease in the absorption of Alendronic acid resulting in a reduced serum concentration and potentially a decrease in efficacy.
AlmasilateAlmasilate can cause a decrease in the absorption of Tetraferric tricitrate decahydrate resulting in a reduced serum concentration and potentially a decrease in efficacy.
AloglutamolAloglutamol can cause a decrease in the absorption of Tetraferric tricitrate decahydrate resulting in a reduced serum concentration and potentially a decrease in efficacy.
AluminiumAluminium can cause a decrease in the absorption of Tetraferric tricitrate decahydrate resulting in a reduced serum concentration and potentially a decrease in efficacy.
Aluminium acetoacetateAluminium acetoacetate can cause a decrease in the absorption of Tetraferric tricitrate decahydrate resulting in a reduced serum concentration and potentially a decrease in efficacy.
Aluminium glycinateAluminium glycinate can cause a decrease in the absorption of Tetraferric tricitrate decahydrate resulting in a reduced serum concentration and potentially a decrease in efficacy.
Aluminium phosphateAluminium phosphate can cause a decrease in the absorption of Tetraferric tricitrate decahydrate resulting in a reduced serum concentration and potentially a decrease in efficacy.
Aluminum hydroxideAluminum hydroxide can cause a decrease in the absorption of Tetraferric tricitrate decahydrate resulting in a reduced serum concentration and potentially a decrease in efficacy.
AsenapineAsenapine can cause a decrease in the absorption of Tetraferric tricitrate decahydrate resulting in a reduced serum concentration and potentially a decrease in efficacy.
Additional Data Available
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Food Interactions
Not Available

References

General References
  1. Abbaspour N, Hurrell R, Kelishadi R: Review on iron and its importance for human health. J Res Med Sci. 2014 Feb;19(2):164-74. [PubMed:24778671]
  2. Ouameur AA, Arakawa H, Ahmad R, Naoui M, Tajmir-Riahi HA: A Comparative study of Fe(II) and Fe(III) interactions with DNA duplex: major and minor grooves bindings. DNA Cell Biol. 2005 Jun;24(6):394-401. doi: 10.1089/dna.2005.24.394. [PubMed:15941392]
  3. Chen CY, Berish SA, Morse SA, Mietzner TA: The ferric iron-binding protein of pathogenic Neisseria spp. functions as a periplasmic transport protein in iron acquisition from human transferrin. Mol Microbiol. 1993 Oct;10(2):311-8. doi: 10.1111/j.1365-2958.1993.tb01957.x. [PubMed:7934822]
  4. Conrad ME, Umbreit JN, Moore EG, Hainsworth LN, Porubcin M, Simovich MJ, Nakada MT, Dolan K, Garrick MD: Separate pathways for cellular uptake of ferric and ferrous iron. Am J Physiol Gastrointest Liver Physiol. 2000 Oct;279(4):G767-74. doi: 10.1152/ajpgi.2000.279.4.G767. [PubMed:11005764]
  5. Geisser P, Burckhardt S: The pharmacokinetics and pharmacodynamics of iron preparations. Pharmaceutics. 2011 Jan 4;3(1):12-33. doi: 10.3390/pharmaceutics3010012. [PubMed:24310424]
  6. Waldvogel-Abramowski S, Waeber G, Gassner C, Buser A, Frey BM, Favrat B, Tissot JD: Physiology of iron metabolism. Transfus Med Hemother. 2014 Jun;41(3):213-21. doi: 10.1159/000362888. Epub 2014 May 12. [PubMed:25053935]
  7. 25. (2012). In Rang and Dale's Pharmacology (7th ed., pp. 310-312). Edinburgh: Elsevier/Churchill Livingstone. [ISBN:978-0-7020-3471-8]
  8. Iron [Link]
  9. InChem: Iron [Link]
External Links
ChemSpider
34993203
ChEMBL
CHEMBL3301597
ATC Codes
V03AE08 — Ferric citrate

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Not Yet RecruitingTreatmentEnd Stage Renal Disease (ESRD) / ESRD / Hyperphosphataemia1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Tablet, coatedOral210 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8846976No2014-09-302024-02-18Us
US8093423No2012-01-102026-04-21Us
US5753706No1998-05-192017-02-03Us
US8338642No2012-12-252024-02-18Us
US9050316No2015-06-092024-02-18Us
US8901349No2014-12-022024-02-18Us
US8754258No2014-06-172024-02-18Us
US7767851No2010-08-032024-02-18Us
US8754257No2014-06-172024-02-18Us
US8609896No2013-12-172024-02-18Us
US8299298No2012-10-302024-02-18Us
US9387191No2016-07-122030-07-21Us
US9328133No2016-05-032024-02-18Us
US9757416No2017-09-122024-02-18Us
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

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Properties

State
Not Available
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.503 mg/mLALOGPS
logP1.42ALOGPS
logP-1.3ChemAxon
logS-3.2ALOGPS
pKa (Strongest Acidic)3.05ChemAxon
pKa (Strongest Basic)-4.2ChemAxon
Physiological Charge-3ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area143.45 Å2ChemAxon
Rotatable Bond Count15ChemAxon
Refractivity78.69 m3·mol-1ChemAxon
Polarizability13.97 Å3ChemAxon
Number of Rings0ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Taxonomy

Classification
Not classified

Targets

Kind
Protein
Organism
Escherichia coli (strain K12)
Pharmacological action
Unknown
General Function
Not Available
Specific Function
Part of the ABC transporter complex FhuCDB involved in iron(3+)-hydroxamate import. Binds the iron(3+)-hydroxamate complex and transfers it to the membrane-bound permease. Required for the transpor...
Gene Name
fhuD
Uniprot ID
P07822
Uniprot Name
Iron(3+)-hydroxamate-binding protein FhuD
Molecular Weight
32997.965 Da
References
  1. Clarke TE, Rohrbach MR, Tari LW, Vogel HJ, Koster W: Ferric hydroxamate binding protein FhuD from Escherichia coli: mutants in conserved and non-conserved regions. Biometals. 2002 Jun;15(2):121-31. [PubMed:12046920]
  2. Koster W, Braun V: Iron (III) hydroxamate transport into Escherichia coli. Substrate binding to the periplasmic FhuD protein. J Biol Chem. 1990 Dec 15;265(35):21407-10. [PubMed:2254301]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
General Function
Virus receptor activity
Specific Function
Cellular uptake of iron occurs via receptor-mediated endocytosis of ligand-occupied transferrin receptor into specialized endosomes. Endosomal acidification leads to iron release. The apotransferri...
Gene Name
TFRC
Uniprot ID
P02786
Uniprot Name
Transferrin receptor protein 1
Molecular Weight
84870.665 Da
References
  1. Hemadi M, Ha-Duong NT, El Hage Chahine JM: The mechanism of iron release from the transferrin-receptor 1 adduct. J Mol Biol. 2006 May 12;358(4):1125-36. Epub 2006 Mar 13. [PubMed:16564538]
  2. Geisser P, Burckhardt S: The pharmacokinetics and pharmacodynamics of iron preparations. Pharmaceutics. 2011 Jan 4;3(1):12-33. doi: 10.3390/pharmaceutics3010012. [PubMed:24310424]
  3. Waldvogel-Abramowski S, Waeber G, Gassner C, Buser A, Frey BM, Favrat B, Tissot JD: Physiology of iron metabolism. Transfus Med Hemother. 2014 Jun;41(3):213-21. doi: 10.1159/000362888. Epub 2014 May 12. [PubMed:25053935]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Transferrin receptor binding
Specific Function
Transferrins are iron binding transport proteins which can bind two Fe(3+) ions in association with the binding of an anion, usually bicarbonate. It is responsible for the transport of iron from si...
Gene Name
TF
Uniprot ID
P02787
Uniprot Name
Serotransferrin
Molecular Weight
77063.195 Da
References
  1. Abbaspour N, Hurrell R, Kelishadi R: Review on iron and its importance for human health. J Res Med Sci. 2014 Feb;19(2):164-74. [PubMed:24778671]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Virus receptor activity
Specific Function
Integrin alpha-V/beta-3 (ITGAV:ITGB3) is a receptor for cytotactin, fibronectin, laminin, matrix metalloproteinase-2, osteopontin, osteomodulin, prothrombin, thrombospondin, vitronectin and von Wil...
Gene Name
ITGB3
Uniprot ID
P05106
Uniprot Name
Integrin beta-3
Molecular Weight
87056.975 Da
References
  1. Conrad ME, Umbreit JN, Moore EG, Hainsworth LN, Porubcin M, Simovich MJ, Nakada MT, Dolan K, Garrick MD: Separate pathways for cellular uptake of ferric and ferrous iron. Am J Physiol Gastrointest Liver Physiol. 2000 Oct;279(4):G767-74. doi: 10.1152/ajpgi.2000.279.4.G767. [PubMed:11005764]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Zinc ion binding
Specific Function
Calcium-binding chaperone that promotes folding, oligomeric assembly and quality control in the endoplasmic reticulum (ER) via the calreticulin/calnexin cycle. This lectin interacts transiently wit...
Gene Name
CALR
Uniprot ID
P27797
Uniprot Name
Calreticulin
Molecular Weight
48141.2 Da
References
  1. Conrad ME, Umbreit JN, Moore EG, Hainsworth LN, Porubcin M, Simovich MJ, Nakada MT, Dolan K, Garrick MD: Separate pathways for cellular uptake of ferric and ferrous iron. Am J Physiol Gastrointest Liver Physiol. 2000 Oct;279(4):G767-74. doi: 10.1152/ajpgi.2000.279.4.G767. [PubMed:11005764]

Drug created on July 12, 2018 10:50 / Updated on July 13, 2019 01:00