Identification

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Name
Ferric cation
Accession Number
DB13949
Type
Small Molecule
Groups
Approved
Description

Iron is a transition metal with a symbol Fe and atomic number 26. By mass, it is the most common element on Earth. Iron is an essential element involved in various metabolic processes, including oxygen transport, deoxyribonucleic acid (DNA) synthesis, and energy production in electron transport 1. Resulting from inadequate supply of iron to cells due to depletion of stores, iron deficiency is the most common nutritional deficiency worldwide, particularly affecting children, women of childbearing age, and pregnant women 8. Iron deficiency may be characterized without the development of anemia, and may result in functional impairments affecting cognitive development and immunity mechanisms, as well as infant or maternal mortality if it occurs during pregnancy 1. The main therapeutic preparation of iron is Ferrous sulfate, and iron-sucrose may also be given intravenously 7.

Iron exists in two oxidation states: the ferrous cation (Fe2+) and ferric cation (Fe3+). Non-haem iron in food is mainly in the ferric state, which is the insoluble form of iron, and must be reduced to the ferrous cation for absorption 7. Ferric citrate (tetraferric tricitrate decahydrate) is a phosphate binder indicated for the control of serum phosphorus levels in patients with chronic kidney disease on dialysis.

Structure
Thumb
Synonyms
  • FE (III) ION
  • Fe(III)
  • Ferric ion
  • iron(3+)
Categories
UNII
91O4LML611
CAS number
20074-52-6
Weight
Average: 55.845
Monoisotopic: 55.934942133
Chemical Formula
Fe
InChI Key
VTLYFUHAOXGGBS-UHFFFAOYSA-N
InChI
InChI=1S/Fe/q+3
IUPAC Name
iron(3+) ion
SMILES
[Fe+3]

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 FhuD
binder
Escherichia coli (strain K12)
ATransferrin receptor protein 1
agonist
Humans
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 DiphosphateFerric cation 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 acidFerric cation 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 Ferric cation resulting in a reduced serum concentration and potentially a decrease in efficacy.
AloglutamolAloglutamol can cause a decrease in the absorption of Ferric cation resulting in a reduced serum concentration and potentially a decrease in efficacy.
AluminiumAluminium can cause a decrease in the absorption of Ferric cation resulting in a reduced serum concentration and potentially a decrease in efficacy.
Aluminium acetoacetateAluminium acetoacetate can cause a decrease in the absorption of Ferric cation resulting in a reduced serum concentration and potentially a decrease in efficacy.
Aluminium glycinateAluminium glycinate can cause a decrease in the absorption of Ferric cation resulting in a reduced serum concentration and potentially a decrease in efficacy.
Aluminium phosphateAluminium phosphate can cause a decrease in the absorption of Ferric cation resulting in a reduced serum concentration and potentially a decrease in efficacy.
Aluminum hydroxideAluminum hydroxide can cause a decrease in the absorption of Ferric cation resulting in a reduced serum concentration and potentially a decrease in efficacy.
AsenapineAsenapine can cause a decrease in the absorption of Ferric cation resulting in a reduced serum concentration and potentially a decrease in efficacy.
Additional Data Available
  • Extended Description
    Extended Description

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  • Severity
    Severity

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  • Evidence Level
    Evidence Level

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  • Action
    Action

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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
Human Metabolome Database
HMDB0012943
KEGG Compound
C14819
ChemSpider
27815
ChEBI
29034
HET
FE
PDB Entries
1a8e / 1a8f / 1ahj / 1aor / 1ar5 / 1aui / 1avm / 1b06 / 1b0l / 1b13
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Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedNot AvailableEnd-Stage Renal Disease (ESRD) / Hyperphosphataemia / Renal Failure Chronic Requiring Hemodialysis1
2CompletedTreatmentAnemia of Chronic Kidney Disease1
2CompletedTreatmentEnd-Stage Renal Disease (ESRD) / Hyperphosphataemia1
2CompletedTreatmentIron Deficiency / Iron Deficiency Anemia (IDA)1
3CompletedTreatmentAnemia of Chronic Kidney Disease1
3CompletedTreatmentChronic Kidney Disease (CKD) / Hyperphosphataemia / Impaired Renal Function / Iron Deficiency Anemia (IDA)1
3CompletedTreatmentEnd Stage Renal Disease (ESRD) / ESRD / Hyperphosphataemia1
3CompletedTreatmentEnd Stage Renal Disease (ESRD) / ESRD / Hyperphosphataemia / Renal Failure1
3CompletedTreatmentESRD / Hyperphosphataemia1
3CompletedTreatmentEnd-Stage Renal Disease (ESRD) / Hyperphosphataemia1
4Active Not RecruitingSupportive CareChronic Kidney Disease (CKD) / End Stage Renal Disease (ESRD)1
4Active Not RecruitingSupportive CareHyperphosphataemia1
4Active Not RecruitingTreatmentChronic Kidney Disease (CKD) / Iron Deficiency Anemia (IDA)1
4CompletedOtherChronic Renal Failure (CRF) / End-Stage Renal Disease (ESRD) / Hyperphosphataemia / Phosphorus Metabolism Disorders1
4RecruitingNot AvailableChronic Inflammation / End Stage Renal Disease (ESRD) / Hyperphosphataemia1
Not AvailableCompletedTreatmentAnemias / Chronic Kidney Disease (CKD) / Iron Deficiency1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
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
Solid
Experimental Properties
PropertyValueSource
melting point (°C)3000MSDS
boiling point (°C)1535MSDS
water solubilityInsolubleMSDS
Predicted Properties
PropertyValueSource
logP-0.77ChemAxon
pKa (Strongest Acidic)4.58ChemAxon
Physiological Charge3ChemAxon
Hydrogen Acceptor Count0ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area0 Å2ChemAxon
Rotatable Bond Count0ChemAxon
Refractivity0 m3·mol-1ChemAxon
Polarizability1.78 Å3ChemAxon
Number of Rings0ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0a4i-9000000000-af3e7aec4f5bd9668683
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0a4i-9000000000-af3e7aec4f5bd9668683
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0a4i-9000000000-af3e7aec4f5bd9668683
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0udi-9000000000-3335fec4c3184739b75e
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0udi-9000000000-3335fec4c3184739b75e
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0udi-9000000000-3335fec4c3184739b75e

Taxonomy

Classification
Not classified

Targets

Kind
Protein
Organism
Escherichia coli (strain K12)
Pharmacological action
Unknown
Actions
Binder
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
Actions
Agonist
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
Actions
Binder
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
Actions
Binder
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
Actions
Binder
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 January 12, 2018 10:15 / Updated on May 01, 2019 11:54