Free iron chelating agent

Deferiprone (66-660 μM, 48-96 h) significantly inhibits the growth of 22rv1, Myc-CaP, and TRAMP-C2 cells[1]. Deferiprone (100 μM, for a maximum of 192 hours) prevents TRAMP-C2, Myc-CaP, and 22rv1 cells from migrating[1]. Deferiprone (100 μM, 24 h) decreases m-Acon expression and activity in Myc-CaP, 22rv1, and TRAMP-C2 cells[1].
Deferiprone lowers the free iron in thalassemic red blood cells by up to 1μM over 0.5–24 hours[2].
Deferiprone (10 min) has IC50 values of 0.24, 0.25, 3.36, and 3.73 mM, respectively, and inhibits human platelet aggregation stimulated by AA, ADP, epinephrine, and collagen[3]. With an IC50 value of 0.33 μM, deferiprone (0.1-3.2 μM, 5 mins) inhibits COX-1 activity[3]. The production of cAMP induced by ADP is inhibited by deferiprone (4 mM, 5 min)[3].
In aged fibroblasts, deferiprone (156.25 μg/mL, 24 h) improves survival rate, lowers LDH levels, and exhibits normal cell morphology[4].
Conventional antibiotics' antibacterial activity against S. epidermidis is amplified by deferiprone (25μM, 6 h)[5].

In the tauopathy model of rTg(tauP301L)4510 mice, deferiprone (100 mg/kg/daily for e.g., 4 weeks) has a neuroprotective effect[6].

Cancer growth and proliferation rely on intracellular iron availability. We studied the effects of Deferiprone (DFP), a chelator of intracellular iron, on three prostate cancer cell lines: murine, metastatic TRAMP-C2; murine, non-metastatic Myc-CaP; and human, non-metastatic 22rv1. The effects of DFP were evaluated at different cellular levels: cell culture proliferation and migration; metabolism of live cells (time-course multi-nuclear magnetic resonance spectroscopy cell perfusion studies, with 1-13 C-glucose, and extracellular flux analysis); and expression (Western blot) and activity of mitochondrial aconitase, an iron-dependent enzyme. The 50% and 90% inhibitory concentrations (IC50 and IC90 , respectively) of DFP for the three cell lines after 48 h of incubation were within the ranges 51-67 μM and 81-186 μM, respectively. Exposure to 100 μM DFP led to: (i) significant inhibition of cell migration after different exposure times, ranging from 12 h (TRAMP-C2) to 48 h (22rv1), in agreement with the respective cell doubling times; (ii) significantly decreased glucose consumption and glucose-driven tricarboxylic acid cycle activity in metastatic TRAMP-C2 cells, during the first 10 h of exposure, and impaired cellular bioenergetics and membrane phospholipid turnover after 23 h of exposure, consistent with a cytostatic effect of DFP. At this time point, all cell lines studied showed: (iii) significant decreases in mitochondrial functional parameters associated with the oxygen consumption rate, and (iv) significantly lower mitochondrial aconitase expression and activity. Our results indicate the potential of DFP to inhibit prostate cancer proliferation at clinically relevant doses and plasma concentrations.[1]

Cell Line: TRAMP-C2, Myc-CaP, and 22rv1 cells
Concentration: 0, 16, 30, 66, 100, 160, 300, 660 μM
Incubation Time: 48 h, 72 h
Result: exhibited cytostatic activity in three cell lines, with IC50 and IC90 values of roughly 50 and 100 μM, in relation to each other.

Animal Model: The rTg(tauP301L)4510 mouse model of tauopathy[6].
Dosage: 100 mg/kg/daily, 4 weeks
Administration: Intragastric administration (i.g.)
Result: enhanced performance on the Y-maze and open field, as well as a 28% reduction in brain iron levels and a decrease in AT8-labeled p-tau in the hippocampus of transgenic tau mice.

Absorption, Distribution and Excretion
Deferiprone is absorbed in the upper gastrointestinal tract. Absorption is rapid with maximum plasma concentrations occurring after 1 hour in the fasted state and after 2 hours in the fed state.
Within 5-6 hours of administration, more than 90% of deferiprone is eliminated from the plasma. 75 to 90% of deferiprone is excreted in the urine as the metabolite.
In healthy patients, the volume of distribution is 1L/kg, and in thalassemia patients, the volume of distribution is 1.6L/kg.
In healthy subjects, the mean maximum concentration (Cmax) of deferiprone in serum was 20 ug/mL, and the mean total area under the concentration-time curve (AUC) was 53 ug*hr/mL following oral administration of a 1,500 mg dose of Ferriprox tablets in the fasting state. Dose proportionality over the labeled dosage range of 25 to 33 mg/kg three times per day (75 to 99 mg/kg per day) has not been studied. The elimination half life of deferiprone was 1.9 hours. The accumulation of deferiprone and its glucuronide metabolite at the highest approved dosage level of 33 mg/kg three times per day has not been studied. The volume of distribution of deferiprone is 1.6 L/kg in thalassemia patients, and approximately 1 L/kg in healthy subjects. The plasma protein binding of deferiprone in humans is less than 10%.
Deferiprone is rapidly absorbed from the upper part of the gastrointestinal tract, appearing in the blood within 5 to 10 minutes of oral administration. Peak serum concentrations occur approximately 1 hour after a single dose in fasted healthy subjects and patients, and up to 2 hours after a single dose in the fed state. Administration with food decreased the Cmax of deferiprone by 38% and the AUC by 10%. While a food effect cannot be ruled out, the magnitude of the exposure change does not warrant dose adjustment.
More than 90% of deferiprone is eliminated from plasma within 5 to 6 hours of ingestion. Following oral administration, 75% to 90% is recovered in the urine in the first 24 hours, primarily as metabolite.
/MILK/ It is not known whether deferiprone is excreted in human milk.
For more Absorption, Distribution and Excretion (Complete) data for Deferiprone (8 total), please visit the HSDB record page.

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Metabolism / Metabolites
Deferiprone is mainly metabolized by UGT1A6 to the 3-O-glucuronide metabolite. This metabolite cannot chelate iron.
In humans, the majority of the deferiprone is metabolized, primarily by UGT1A6. The contribution of extrahepatic (e.g., renal) UGT1A6 is unknown. The major metabolite of deferiprone is the 3-O-glucuronide, which lacks iron binding capability. Peak serum concentration of the glucuronide occurs 2 to 4 hours after administration of deferiprone in fasting subjects.

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Biological Half-Life
The half-life is 1.9 hours.
The pharmacokinetics of deferiprone in children was assessed in 7 patients with thalassemia and iron overload aged 11 to 18 years (mean age= 15 + or - 2.7 years; median=16 years). These patients were on long term therapy with deferiprone and were thus considered to be at steady state. ... Serum levels of deferiprone were maximal approximately 2 hours after dosing and declined with a half-life of 1.8 hours; levels of deferiprone glucuronide peaked at approximately 3 hours and fell with a half-life of 2.0 hours. ...
In healthy subjects ... following oral administration of a 1,500 mg dose of Ferriprox tablets in the fasting state ... the elimination half life ... was 1.9 hours.

Hepatotoxicity
In large clinical trials, elevations in serum aminotransferase levels occurred in 7.5% of patients treated with deferiprone and led to drug discontinuation in ~1%. In many situations, it was unclear whether the ALT elevations were due to deferiprone therapy as opposed to spontaneous worsening of an underlying chronic hepatitis B or C, which is common in patients with transfusion related iron overload. Furthermore, there have been very few reports of clinically apparent liver injury attributed to deferiprone therapy and the clinical features of hepatic injury from deferiprone (latency to onset, pattern of serum enzyme elevations, clinical symptoms and laboratory findings, subsequent course) have not been defined.
Iron overload itself can cause liver injury and result in significant fibrosis and even cirrhosis. By decreasing hepatic iron stores, deferiprone and other iron chelators should improve liver disease and prevent progression of fibrosis. In a controversial open label study of deferiprone therapy for up to 4 years in 19 patients with thalassemia and iron overload, progression of fibrosis was found in 5 of 12 subjects who underwent repeat liver biopsy after an average of 4 years, compared to none of 12 subjects who were separately followed while being treated with deferoxamine. Several subsequent studies, however, failed to show fibrosis progression in subjects with thalassemia and iron overload treated with deferiprone, particularly among those without concurrent hepatitis C.
Likelihood score: E* (unproven but suspected cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Deferiprone is likely actively transported into milk through binding with lactoferrin. Because no information is available on the use of deferiprone during breastfeeding and it is orally absorbed, an alternate drug is preferred, especially while nursing a newborn or preterm infant. Australian guidelines recommend against breastfeeding during deferiprone treatment. The US manufacturer recommends withholding breastfeeding for 2 weeks after the last dose.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Plasma protein binding is less than 10%.

[1]. Rui V. Simões, Inhibition of prostate cancer proliferation by Deferiprone. NMR Biomed 2017 Jun;30(6):10.1002/nbm.3712.

[2]. Deferiprone (L1) Chelates Pathologic Iron Deposits From Membranes of Intact Thalassemic and Sickle Red Blood Cells Both In Vitro and In Vivo. Blood. 1995 Sep 1;86(5):2008-13.

[3]. Antiplatelet activity of deferiprone through cyclooxygenase-1 inhibition. Platelets 2020 May 18;31(4):505-512.

[4]. Deferiprone Stimulates Aged Dermal Fibroblasts via HIF-1α Modulation.Pathog Dis. 2018 Jul 1;76(5).

[5]. Iron chelation destabilizes bacterial biofilms and potentiates the antimicrobial activity of antibiotics against coagulase-negative Staphylococci. Pathogens and Disease, Volume 76, Issue 5, July 2018, fty052

[6]. Deferiprone Treatment in Aged Transgenic Tau Mice Improves Y-Maze Performance and Alters Tau Pathology. Neurotherapeutics. 2021 Apr;18(2):1081-1094.

Deferiprone is a member of the class of 4-pyridones that is pyridin-4(1H)-one substituted at positions 1 and 2 by methyl groups and at position 3 by a hydroxy group. A lipid-soluble iron-chelator used for treatment of thalassaemia. It has a role as an iron chelator and a protective agent.
Deferiprone is an oral iron chelator used as a second line agent in thalassemia syndromes when iron overload from blood transfusions occurs. Thalassemias are a type of hereditary anaemia due a defect in the production of hemoglobin. As a result, erythropoiesis, the production of new red blood cells, is impaired. FDA approved on October 14, 2011.
Deferiprone is an Iron Chelator. The mechanism of action of deferiprone is as an Iron Chelating Activity.
Deferiprone is an oral iron chelating agent used to treat transfusion related, chronic iron overload. Deferiprone has been linked to a low rate of transient serum aminotransferase elevations during therapy and to rare instances of clinically apparent liver injury.
Deferiprone is an orally bioavailable bidentate ligand with iron chelating activity. Deferiprone binds to iron in a 3:1 (ligand:iron) molar ratio. By binding to iron, deferiprone is able to remove excess iron from the body.
A pyridone derivative and iron chelator that is used in the treatment of IRON OVERLOAD in patients with THALASSEMIA.

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Drug Indication
Deferiprone is indicated in thalassemia syndromes when first line chelation agents are not adequate to treat transfusional iron overload.
FDA Label
Ferriprox monotherapy is indicated for the treatment of iron overload in patients with thalassaemia major when current chelation therapy is contraindicated or inadequate. Ferriprox in combination with another chelator is indicated in patients with thalassaemia major when monotherapy with any iron chelator is ineffective, or when prevention or treatment of life-threatening consequences of iron overload (mainly cardiac overload) justifies rapid or intensive correction.
Deferiprone Lipomed monotherapy is indicated for the treatment of iron overload in patients with thalassaemia major when current chelation therapy is contraindicated or inadequate. Deferiprone Lipomed in combination with another chelator is indicated in patients with thalassaemia major when monotherapy with any iron chelator is ineffective, or when prevention or treatment of life-threatening consequences of iron overload justifies rapid or intensive correction.
Treatment of chronic iron overload

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Mechanism of Action
Deferiprone is an iron chelator that binds to ferric ions (iron III) and forms a 3:1 (deferiprone:iron) stable complex and is then eliminated in the urine. Deferiprone is more selective for iron in which other metals such as zinc, copper, and aluminum have a lower affinity for deferiprone.
Deferiprone is a chelating agent with an affinity for ferric ion (iron III). Deferiprone binds with ferric ions to form neutral 3:1 (deferiprone:iron) complexes that are stable over a wide range of pH values. Deferiprone has a lower binding affinity for other metals such as copper, aluminum and zinc than for iron.

C7H9NO2

139.15186

139.063

C, 60.42; H, 6.52; N, 10.07; O, 23.00

30652-11-0

Deferiprone-d3;1346601-82-8

2972

White to off-white solid powder

1.2±0.1 g/cm3

232.7±40.0 °C at 760 mmHg

272-275 °C(lit.)

94.5±27.3 °C

0.0±1.0 mmHg at 25°C

1.565

-0.22

1

3

0

10

228

0

O=C1C(O)=C(C)N(C)C=C1

TZXKOCQBRNJULO-UHFFFAOYSA-N

InChI=1S/C7H9NO2/c1-5-7(10)6(9)3-4-8(5)2/h3-4,10H,1-2H3

3-hydroxy-1,2-dimethylpyridin-4(1H)-one

Ferriprox

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Water : 3.33~27 mg/mL(~23.93 mM)
DMSO : ~7.14 mg/mL (~51.31 mM)

Solubility in Formulation 1: ≥ 0.71 mg/mL (5.10 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 7.1 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 0.71 mg/mL (5.10 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 7.1 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 0.71 mg/mL (5.10 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 7.1 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 0.71 mg/mL (5.10 mM)

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Solubility in Formulation 5: 10 mg/mL (71.86 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)