Free iron chelating agent

Deferiprone（66-660 μM，48-96 小时）显着抑制 22rv1、Myc-CaP 和 TRAMP-C2 细胞的生长[1]。 Deferiprone（100 μM，最长 192 小时）可防止 TRAMP-C2、Myc-CaP 和 22rv1 细胞迁移[1]。 Deferiprone（100 μM，24 小时）可降低 Myc-CaP、22rv1 和 TRAMP-C2 细胞中的 m-Acon 表达和活性[1]。
Deferiprone 可在 0.5 小时内将地中海贫血红细胞中的游离铁降低高达 1μM –24 小时[2]。
Deferiprone（10 分钟）的 IC50 值分别为 0.24、0.25、3.36 和 3.73 mM，并抑制 AA、ADP、肾上腺素和胶原蛋白刺激的人血小板聚集[3]。去铁酮（0.1-3.2 μM，5 分钟）抑制 COX-1 活性，IC50 值为 0.33 μM[3]。 ADP 诱导的 cAMP 产生受到去铁酮（4 mM，5 分钟）的抑制[3]。
在衰老的成纤维细胞中，去铁酮（156.25 μg/mL，24 小时）可提高存活率，降低 LDH 水平，并表现出正常的状态细胞形态[4]。
去铁酮（25μM，6 小时）可增强传统抗生素对表皮葡萄球菌的抗菌活性[5]。

在rTg(tauP301L)4510小鼠的tau蛋白病模型中，去铁酮（100 mg/kg/天，例如4周）具有神经保护作用[6]。

癌症的生长和增殖依赖于细胞内铁的供应。我们研究了去铁酮（DFP），一种细胞内铁的螯合剂，对三种前列腺癌症细胞系的影响：小鼠转移性TRAMP-C2；小鼠非转移性Myc-CaP；以及人非转移性22rv1。DFP的作用在不同的细胞水平上进行评估：细胞培养增殖和迁移；活细胞的代谢（时间进程多核磁共振波谱细胞灌注研究，1-13 C-葡萄糖，以及细胞外流量分析）；以及线粒体附子酶（一种铁依赖性酶）的表达（蛋白质印迹）和活性。孵育48小时后，三种细胞系DFP的50%和90%抑制浓度（分别为IC50和IC90）分别在51-67μM和81-186μM范围内。暴露于100μM DFP导致：（i）不同暴露时间后，从12小时（TRAMP-C2）到48小时（22rv1），细胞迁移受到显著抑制，与相应的细胞倍增时间一致；（ii）在暴露的前10小时期间，转移性TRAMP-C2细胞中的葡萄糖消耗和葡萄糖驱动的三羧酸循环活性显著降低，并且暴露23小时后细胞生物能量学和膜磷脂周转受损，这与DFP的细胞抑制作用一致。此时，所研究的所有细胞系都显示：（iii）与耗氧率相关的线粒体功能参数显著降低，以及（iv）线粒体附子酶的表达和活性显著降低。我们的研究结果表明，DFP在临床相关剂量和血浆浓度下抑制前列腺癌症增殖的潜力。[1]

细胞系：TRAMP-C2、Myc-CaP 和 22rv1 细胞
浓度：0、16、30、66、100、160、300、660 μM
孵育时间：48 h、72 h
结果：在三种细胞系中表现出细胞抑制活性，彼此的 IC50 和 IC90 值分别约为 50 和 100 μM。

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

42.23

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)

配方 1 中的溶解度: ≥ 0.71 mg/mL (5.10 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 7.1 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 0.71 mg/mL (5.10 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 7.1mg/mL澄清的DMSO储备液加入到900μL 20％SBE-β-CD生理盐水中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 0.71 mg/mL (5.10 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 7.1 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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配方 4 中的溶解度: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 0.71 mg/mL (5.10 mM)

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配方 5 中的溶解度: 10 mg/mL (71.86 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶.

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。