Ferric cation

Identification

Summary

Ferric cation is an iron supplement indicated in the treatment of iron deficiency anemia.

Generic Name

Ferric cation

DrugBank Accession Number

DB13949

Background

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.

Type

Small Molecule

Groups

Approved

Structure

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MOLSDFPDBSMILESInChI

Similar Structures

Structure for Ferric cation (DB13949)

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Weight

Average: 55.845
Monoisotopic: 55.934942133

Chemical Formula

Fe

Synonyms

• FE (III) ION
• Fe(III)
• Ferric ion
• iron(3+)

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Pharmacology

Indication

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

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Treatment of	Hyperphosphatemia		••••••••••••
Treatment of	Iron deficiency anemia		••••••••••••

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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.

Target	Actions	Organism
ATransferrin receptor protein 1	agonist	Humans
UIron(3+)-hydroxamate-binding protein FhuD	binder	Escherichia coli (strain K12)

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. Ferritin may also convert ferric to ferrous iron ⁶.

Hover over products below to view reaction partners

• Ferric cation
  • ferrous cation (Fe2+)

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.

Adverse Effects

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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.

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Alendronic acid	Ferric cation can cause a decrease in the absorption of Alendronic acid resulting in a reduced serum concentration and potentially a decrease in efficacy.
Almasilate	Almasilate can cause a decrease in the absorption of Ferric cation resulting in a reduced serum concentration and potentially a decrease in efficacy.
Aluminium phosphate	Aluminium phosphate can cause a decrease in the absorption of Ferric cation resulting in a reduced serum concentration and potentially a decrease in efficacy.
Aluminum hydroxide	Aluminum hydroxide can cause a decrease in the absorption of Ferric cation resulting in a reduced serum concentration and potentially a decrease in efficacy.
Asenapine	Asenapine can cause a decrease in the absorption of Ferric cation resulting in a reduced serum concentration and potentially a decrease in efficacy.

Food Interactions

• Avoid milk and dairy products.
• Take with food. Take ferric cation with or just after meals.

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Mixture Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End	Region	Image
FERIMAX FORT ÇİĞNEME TABLETİ, 30 ADET	Ferric cation (100 mg) + Icosapent (0.35 mg)	Tablet, chewable	Oral	BİLİM İLAÇ SAN. VE TİC. A.Ş.	2009-12-29	Not applicable
MALTOFER FOL 100 MG/0.35 MG TABLET, 30 ADET	Ferric cation (100 mg) + Folic acid (0.35 mg)	Tablet	Oral	ABDİ İBRAHİM İLAÇ SAN. VE TİC. A.Ş.	2002-10-07	Not applicable

Categories

Drug Categories

• Iron Compounds
• Parenteral Iron Replacement
• Phosphate Binder
• Phosphate Chelating Activity
• Polyvalent cation containing laxatives, antacids, oral supplements

Classification

Not classified

Affected organisms

Not Available

Chemical Identifiers

UNII

91O4LML611

CAS number

20074-52-6

InChI Key

VTLYFUHAOXGGBS-UHFFFAOYSA-N

InChI

InChI=1S/Fe/q+3

IUPAC Name

iron(3+) ion

SMILES

[Fe+3]

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. [Article]
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. [Article]
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. [Article]
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. [Article]
5. Geisser P, Burckhardt S: The pharmacokinetics and pharmacodynamics of iron preparations. Pharmaceutics. 2011 Jan 4;3(1):12-33. doi: 10.3390/pharmaceutics3010012. [Article]
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. [Article]
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]
10. TITCK: Ferimax (Ferric Cation) Oral Drops [Link]

External Links

Human Metabolome Database

HMDB0012943

KEGG Compound

C14819

ChemSpider

27815

RxNav

1546357

ChEBI

29034

PDBe Ligand

FE

PDB Entries

1a8e / 1a8f / 1ahj / 1aor / 1ar5 / 1aui / 1avm / 1b06 / 1b0l / 1b13 …

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Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
Not Available	Completed	Not Available	Iron Deficiency (ID)	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Solution	Oral	100 mg/5ml
Solution / drops	Oral	50 mg/ml
Tablet, chewable	Oral
Solution	Oral
Tablet	Oral

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US8846976	No	2014-09-30	2024-02-18
US8093423	No	2012-01-10	2026-04-21
US5753706	No	1998-05-19	2017-02-03
US8338642	No	2012-12-25	2024-02-18
US9050316	No	2015-06-09	2024-02-18
US8901349	No	2014-12-02	2024-02-18
US8754258	No	2014-06-17	2024-02-18
US7767851	No	2010-08-03	2024-02-18
US8754257	No	2014-06-17	2024-02-18
US8609896	No	2013-12-17	2024-02-18
US8299298	No	2012-10-30	2024-02-18
US9387191	No	2016-07-12	2030-07-21
US9328133	No	2016-05-03	2024-02-18
US9757416	No	2017-09-12	2024-02-18

Properties

State

Solid

Experimental Properties

Property	Value	Source
melting point (°C)	3000	MSDS
boiling point (°C)	1535	MSDS
water solubility	Insoluble	MSDS

Predicted Properties

Property	Value	Source
logP	-0.77	Chemaxon
pKa (Strongest Acidic)	4.58	Chemaxon
Physiological Charge	3	Chemaxon
Hydrogen Acceptor Count	0	Chemaxon
Hydrogen Donor Count	0	Chemaxon
Polar Surface Area	0 Å2	Chemaxon
Rotatable Bond Count	0	Chemaxon
Refractivity	0 m3·mol-1	Chemaxon
Polarizability	1.78 Å3	Chemaxon
Number of Rings	0	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	No	Chemaxon
Veber's Rule	Yes	Chemaxon
MDDR-like Rule	No	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Not Available

Chromatographic Properties

Collision Cross Sections (CCS)

Not Available

Targets

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insights and accelerate drug research.

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Details1. Transferrin receptor protein 1

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. [Article]
2. Geisser P, Burckhardt S: The pharmacokinetics and pharmacodynamics of iron preparations. Pharmaceutics. 2011 Jan 4;3(1):12-33. doi: 10.3390/pharmaceutics3010012. [Article]
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. [Article]

Details2. Iron(3+)-hydroxamate-binding protein FhuD

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. [Article]
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. [Article]

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Drug created at January 12, 2018 17:15 / Updated at February 03, 2022 06:26