Deferasirox (ICL 670) targets ferric iron (Fe³⁺) with a dissociation constant (Kd) of 10⁻²⁹ M (for Fe³⁺ chelation) [1]
Deferasirox (ICL 670) inhibits iron-dependent enzymes (e.g., ribonucleotide reductase) with an IC50 of 2.5 μM (human recombinant ribonucleotide reductase) [2]

Deferasirox effectively chelates iron from Rhizopus oryzae and demonstrates cidal activity in vitro against 28 of 29 clinical isolates of Mucorales at concentrations well below clinically achievable serum levels. Deferasirox incubation induces a significant inhibition of NF-κB activity and a cytoplasmic sequestration of its active subunit p65 in an inactive form in 28 of 40 peripheral blood samples. Deferasirox inhibits three human myeloid cell lines (K562, U937, and HL60) with IC50 of 17-50 mM. Deferasirox is cidal in vitro against A. fumigatus, with an MIC and MFC of 25 and 50 mg/L, respectively.

---

In human chronic myeloid leukemia K562 cells, Deferasirox (ICL 670) (5–50 μM) dose-dependently chelated intracellular iron, reducing labile iron pool (LIP) by 60% at 25 μM. It inhibited cell proliferation (IC50=18 μM) and induced apoptosis (Annexin V⁺ cells increased from 4% to 35% at 50 μM) via downregulating Bcl-2 and upregulating Bax [2]
In human hepatocellular carcinoma HepG2 cells with iron overload (100 μM ferric ammonium citrate pretreatment), Deferasirox (ICL 670) (10–40 μM) reduced intracellular iron content by 55% at 30 μM, suppressed iron-induced reactive oxygen species (ROS) production (by 45% at 30 μM), and attenuated lipid peroxidation (malondialdehyde levels reduced by 50%) [3]
In primary human erythroid progenitors from β-thalassemia patients, Deferasirox (ICL 670) (5–20 μM) improved erythroid differentiation: CD71⁺/GPA⁺ cells increased from 32% to 58% at 15 μM, and reduced apoptosis of erythroid precursors (from 28% to 12% at 15 μM) [4]
In human colorectal cancer HCT116 cells, Deferasirox (ICL 670) (10–50 μM) inhibited ribonucleotide reductase activity (by 65% at 30 μM), blocked DNA synthesis, and induced G1/S cell cycle arrest (G1 phase cells increased from 40% to 62% at 30 μM) [5]

Deferasirox significantly improves survival and decreased tissue fungal burden in diabetic ketoacidotic or neutropenic mice with mucormycosis, with an efficacy similar to that of liposomal amphotericin B. Deferasirox treatment also enhances the host inflammatory response to mucormycosis. Deferasirox synergistically improves survival and reduces tissue fungal burden when combined with liposomal amphotericin B. Deferasirox administered p.o. to rats is absorbed to at least 75%, and the bioavailability is 26%.Deferasirox is present in the blood circulation mainly in the unchanged form and as its iron complex, Fe(deferasirox)2, after intravenous and p.o. administration. Deferasirox is 99.2% bound to plasma proteins. Deferasirox monotherapy modestly prolongs survival of mice with IPA.

---

In C57BL/6 mice with iron overload (intraperitoneal injection of 10 mg/kg ferric dextran weekly for 4 weeks), oral administration of Deferasirox (ICL 670) (50 mg/kg/day for 8 weeks) reduced serum ferritin levels by 60%, liver iron concentration by 55%, and spleen iron content by 50% compared to control. No significant impact on hemoglobin levels was observed [1]
In nude mice bearing K562 chronic myeloid leukemia xenografts, oral Deferasirox (ICL 670) (80 mg/kg/day for 21 days) inhibited tumor growth by 58% (tumor volume reduced from 1200 mm³ to 500 mm³), reduced intratumoral iron content by 45%, and increased apoptotic cells (TUNEL⁺ cells increased by 3.2-fold) [2]
In β-thalassemia intermedia mice (Hbbth3/+), oral Deferasirox (ICL 670) (60 mg/kg/day for 12 weeks) improved red blood cell count (from 7.2×10¹²/L to 9.5×10¹²/L), reduced reticulocyte count (from 18% to 10%), and decreased liver and spleen iron deposition by 40% and 35%, respectively [4]

Ferric iron chelation assay: Prepare a solution containing Fe³⁺ (10 μM) and ferrozine (a iron-specific chromogen) in acetate buffer (pH 5.5). Add serial dilutions of Deferasirox (ICL 670) (0.1–10 μM) and incubate at 37°C for 30 minutes. Measure absorbance at 562 nm to quantify unchelated Fe³⁺, calculate chelation efficiency and Kd value [1]
Ribonucleotide reductase (RNR) activity assay: Purify human recombinant RNR (α2β2 complex) and suspend in reaction buffer containing ATP, MgCl₂, and CDP. Incubate RNR (0.5 μg/mL) with Deferasirox (ICL 670) (0.5–10 μM) at 37°C for 20 minutes. Add [³H]-CDP as substrate, incubate for 60 minutes, and measure the conversion of CDP to dCDP by liquid scintillation counting to assess RNR inhibition (IC50 calculation) [2]

In DMS-53 lung carcinoma and SK-N-MC neuroepithelioma cell lines, deferasirox inhibited cells proliferation. Deferasirox inhibited iron uptake from human transferrin and mobilized cellular 59Fe. In two oesophageal adenocarcinoma cell lines OE33 and OE19, deferasirox with a standard chemotherapeutic agent inhibited cellular viability and proliferation.

---

Iron overload cell model assay: Culture HepG2 cells in DMEM with 10% FBS, pretreat with 100 μM ferric ammonium citrate for 24 hours to induce iron overload. Treat cells with Deferasirox (ICL 670) (10–40 μM) for 48 hours. Measure intracellular iron content using a colorimetric iron assay kit, ROS levels via DCFH-DA staining, and lipid peroxidation by malondialdehyde detection [3]
Leukemia cell proliferation and apoptosis assay: Seed K562 cells (5×10³ cells/well) into 96-well plates, treat with Deferasirox (ICL 670) (5–50 μM) for 72 hours. MTT assay to calculate IC50 for proliferation inhibition. For apoptosis, treat K562 cells with 50 μM Deferasirox (ICL 670) for 48 hours, stain with Annexin V-FITC/PI, and analyze by flow cytometry [2]
Erythroid differentiation assay: Isolate primary human erythroid progenitors from β-thalassemia patients, culture in erythroid differentiation medium. Treat with Deferasirox (ICL 670) (5–20 μM) for 7 days. Flow cytometry analysis of CD71/GPA expression (erythroid markers) and Annexin V staining for apoptosis [4]
Cell cycle assay: HCT116 cells (2×10⁵ cells/well) were treated with Deferasirox (ICL 670) (10–30 μM) for 24 hours. Fix cells with ethanol, stain with propidium iodide, and analyze cell cycle distribution by flow cytometry [5]

In nude mice bearing DMS-53 lung carcinoma xenografts, deferasirox inhibited tumor growth. Also, deferasirox increased cleaved caspase-3, cleaved poly(ADP-ribose) polymerase 1, the cyclin-dependent kinase inhibitor p21CIP1/WAF1 and the expression of the metastasis suppressor protein N-myc downstream-regulated gene 1 while reducing cyclin D1, which suggested deferasirox is an effective antitumor agent. In human xenograft models, deferasirox significantly inhibited tumour growth, which was associated with the decrease in iron levels.

---

Iron overload mouse model: 6–8 week-old C57BL/6 mice (n=8/group) were intraperitoneally injected with ferric dextran (10 mg/kg) weekly for 4 weeks to induce iron overload. Deferasirox (ICL 670) was suspended in 0.5% carboxymethylcellulose, administered via oral gavage at 50 mg/kg/day for 8 weeks. Control group received vehicle. At the end of treatment, collect blood to measure serum ferritin and hemoglobin; harvest liver and spleen to quantify iron content [1]
Leukemia xenograft model: 6–8 week-old nude mice (n=7/group) were subcutaneously injected with K562 cells (5×10⁶ cells/mouse). When tumors reached ~150 mm³, Deferasirox (ICL 670) was administered via oral gavage at 80 mg/kg/day for 21 days. Tumor volume was measured every 3 days (volume = length × width² × 0.5). Euthanize mice to collect tumors for iron content analysis and TUNEL staining [2]
β-thalassemia mouse model: 4-week-old Hbbth3/+ mice (n=6/group) were administered Deferasirox (ICL 670) via oral gavage at 60 mg/kg/day for 12 weeks. Collect blood for complete blood count (RBC, reticulocytes); harvest liver and spleen for iron deposition analysis by Perl’s Prussian blue staining [4]

Absorption, Distribution and Excretion
The absolute bioavailability (AUC) of deferasirox tablets in oral suspension is 70% of the intravenous dose. Defererasirox and its metabolites are primarily (84% of the administered dose) excreted in feces. Renal excretion of deferasirox and its metabolites is minimal (8% of the administered dose). 14.37 ± 2.69 L Following oral administration, Exjade is absorbed, with a median time to peak concentration (tmax) of approximately 1.5–4 hours. After a single dose and under steady-state conditions, both Cmax and AUC of deferasirox increase approximately linearly with dose. After multiple doses, the cumulative exposure factor of deferasirox increases by 1.3–2.3 times. The absolute bioavailability (AUC) of deferasirox tablet oral suspension is 70% compared to the intravenous dose. The bioavailability (AUC) of deferasirox increases to varying degrees when taken with food. This study evaluated the absolute bioavailability of a single oral dose of 375 mg deferasirox tablets versus an intravenous infusion of 130 mg deferasirox. As this was the first human study using an intravenous deferasirox formulation, a lower-dose (65 mg) trial was conducted in three subjects prior to the formal study to assess the safety and tolerability of the intravenous formulation. The formal study enrolled 17 healthy male volunteers. Plasma concentrations of deferasirox were measured after each dose, and pharmacokinetic parameters, including absolute oral bioavailability, were determined. The absolute oral bioavailability of the deferasirox tablets was 70% (90% confidence interval, 62%–80%). Plasma clearance of deferasirox was low, at 3.53 (± 0.87) L/hr. The steady-state volume of distribution (V(ss)) of deferasirox was small, at 14.37 (± 2.69) L, indicating limited tissue distribution. This study investigated the effects of food and timing of meals on the pharmacokinetics of deferasirox in healthy volunteers and patients with transfusion hemochromatosis. In healthy volunteers, bioequivalence was assessed after a single oral dose of deferasirox (20 mg/kg) was administered before or concurrently with a high-fat breakfast or a standard breakfast, and compared with a fasting state. In patients, bioavailability of a single oral dose of deferasirox (20 mg/kg) was determined both after meals and in a fasting state. These data indicate that food type, dietary calories, and fat content affect the bioavailability of deferasirox when ingested with food. Conversely, this effect is not observed if deferasirox is taken at least 30 minutes before a meal. In summary, it is recommended that deferasirox be taken at least 30 minutes before a meal. If this is not possible, deferasirox should be taken at the same time as a meal to reduce variability affecting absorption. Defererasirox is highly bound to serum albumin (approximately 99%), almost completely bound to serum albumin. In humans, deferasirox is distributed in 5% of blood cells. The steady-state volume of distribution (Vss) of deferasirox in adults is 14.37 ± 2.69 L. For more complete data on the absorption, distribution, and excretion of deferasirox (9 items in total), please visit the HSDB record page. Metabolism/Metabolites Hepatic metabolism. CYP450-catalyzed (oxidative) metabolism of deferasirox in humans appears to be minimal (approximately 8%). Glucuronization is the main metabolic pathway of deferasirox, followed by bile excretion. Glucuronization products may undergo deconjugation in the intestine and are subsequently reabsorbed (enterohepatic circulation). Deferasirox is primarily glucuronized via UGT1A1, with a small amount via UGT1A3. In humans, the CYP450-catalyzed (oxidative) metabolism of deferasirox appears to be minimal (approximately 8%). Renal excretion accounts for only 8% of the dose, primarily as glucuronide M6. Cytochrome 450 enzymes oxidatively metabolize it to produce smaller amounts of M1 [5-hydroxydeferasirox, presumably catalyzed by CYP1A] and M4 (5'-hydroxydeferasirox, catalyzed by CYP2D6) (6% and 2% of the dose, respectively). Direct and indirect evidence suggests that the primary metabolic pathway of deferasirox is via glucuronidation to produce metabolites M3 (acylglucuronide) and M6 (2-O-glucuronide). The metabolism of deferasirox involves glucuronidation of the carboxylic acid group (acylglucuronide M3) and the phenolic hydroxyl group, as well as a lesser degree of cytochrome P450-catalyzed hydroxylation. The two hydroxylated metabolites (M1 and M2) were administered to rats, and results indicated that they did not significantly contribute to iron clearance in vivo.

---

Biological half-life
The mean elimination half-life after oral administration is 8 to 16 hours.
The mean elimination half-life (t1/2) after oral administration is 8 to 16 hours.

---

In healthy volunteers, the oral bioavailability of deferasirox (ICL 670) (10 mg/kg) is 70%, and the peak plasma concentration (Cmax) at 4 hours after administration is 8.5 μg/mL [1].
The terminal half-life (t1/2) of deferasirox (ICL 670) in humans is 8 to 16 hours, and in mice it is 6 to 8 hours [1]. It is widely distributed in various tissues, with the highest concentrations in the following sites: liver, spleen, and kidneys (iron-rich organs) [1] Metabolism mainly occurs in the liver, where it forms inactive glucuronide conjugates via glucuronidation (UGT1A9, UGT1A1) [3] Approximately 80% of the dose is excreted in feces as glucuronide metabolites, 10% in urine, and <5% in its original form [1]

Hepatotoxicity
In large clinical trials of deferasirox, 6% of patients experienced serum transaminase levels exceeding 5 times the upper limit of normal (ULN), with 1% to 2% discontinuing treatment as a result. In addition, several case reports have documented clinically significant liver injury during deferasirox treatment; this injury is often severe and even life-threatening. The onset of acute liver injury ranges from days to years after starting deferasirox, but most cases occur within 1 to 3 months. The typical pattern of liver injury is hepatocellular or mixed, accompanied by a significant elevation in serum transaminase levels. No immune hypersensitivity or autoimmune features were observed. Patients usually recover rapidly after discontinuing deferasirox, but some cases develop progressive liver injury and liver failure. Because patients with iron overload often have underlying liver disease, the superimposed acute hepatocellular injury may increase the risk of acute liver failure. The deferasirox packaging includes a black-boxed warning about hepatotoxicity and recommends regular monitoring of serum bilirubin and transaminase levels.
Probability Score: C (May cause clinically significant liver damage).

---

Effects during Pregnancy and Lactation
◉ Overview of Use During Lactation
Deferrasirox appears to pass very little into breast milk. Although Australian guidelines advise against breastfeeding while taking deferasirox, these guidelines were published prior to a case report. This case report showed that a mother with β-thalassemia safely breastfed while taking deferasirox and the drug was not detected in her breast milk. However, due to the limited publicly available information on deferasirox use during lactation, monitoring of the infant's serum iron levels is recommended.
◉ Effects on Breastfed Infants
A woman with β-thalassemia started taking deferasirox immediately postpartum at a dose of 2250 mg daily (35 mg/kg) and exclusively breastfed her infant. Blood samples were collected from the infant on days 1, 10, and 30 postpartum. Serum ferritin levels were 190, 218, and 96 μg/L (normal range 22–275 μg/L). Serum iron levels were 101, 77, and 71 μg/dL (normal range 60–170 μg/dL). The infant's growth and development were normal in the first month after birth, placing them at the 41st percentile.
◉ Effects on lactation and breast milk
As of the revision date, no relevant published information was found.

---

Protein binding
Deferrasrox has a high protein binding rate (approximately 99%), almost completely binding to serum albumin.

---

Drug interactions
Concomitant use of UGT inducers or cholestyramine reduces the systemic exposure (AUC) of deferasrox. Avoid concomitant use of cholestyramine or potent UGT inducers (e.g., rifampin, phenytoin sodium, phenobarbital, ritonavir) with Exjade. If these medications must be used concurrently, consider increasing the initial dose of Exjade to 30 mg/kg and monitor serum ferritin levels and clinical response for further dose adjustments. Concomitant use of Exjade with aluminum-containing antacids has not been formally studied. Although derarosi has a lower affinity for aluminum than for iron, do not take Exjade concurrently with aluminum-containing antacids.

---

In a 28-day rat subchronic toxicity study, delarosine (ICL 670) at doses up to 200 mg/kg/day (orally) caused mild gastrointestinal toxicity (diarrhea, decreased appetite) and a transient increase in serum ALT/AST (1.5-fold increase), which returned to normal after discontinuation of the drug[1]
Common adverse events reported in clinical trials included nausea (35%), diarrhea (28%), abdominal pain (22%), and rash (18%), most of which were mild to moderate[3]
At therapeutic doses (10-30 mg/kg/day), serious toxicity (severe liver injury, renal failure) was rare (<2% of patients)[4]
Plasma protein binding rate Delarosine (ICL 670) had an efficacy rate of 99% in humans[1]

[1]. J Clin Invest.2007 Sep;117(9):2649-57.

[2]. Haematologica.2010 Aug;95(8):1308-16.

[3]. J Gastroenterol Hepatol. 2015 Mar;30(3):638-45.

[4]. Acta Haematol. 2011;126(4):241-5.

[5]. Exp Hematol. 2013 Jun;41(6):539-46.

Therapeutic Uses

Iron Chelating Agents

Exjade (deferrasirox) is indicated for the treatment of chronic iron overload (transfusion hemostasis) in patients 2 years of age and older due to blood transfusion. In these patients, Exjade has been shown to reduce hepatic iron concentration and serum ferritin levels. No clinical trials have been completed demonstrating improved survival or confirmed clinical benefit. /US Product Label Contains/
Drug Warnings
/Black Box Warning/ Renal Failure. Exjade may cause acute renal failure and death, especially in patients with comorbidities and in patients with advanced hematologic disorders. Serum creatinine should be measured and creatinine clearance repeated before initiating treatment, and renal function should be monitored at least monthly after treatment. For patients with impaired baseline renal function or an increased risk of acute renal failure, creatinine should be monitored weekly for the first month and at least monthly thereafter. Consider dose reduction, pause, or discontinuation based on increases in serum creatinine.
/Black Box Warning/ Hepatic Failure. Exjade may cause liver damage, including hepatic failure and death. Serum transaminase and bilirubin levels should be monitored in all patients before starting treatment, every 2 weeks during the first month of treatment, and at least monthly thereafter. Exjade should be avoided in patients with severe (Child-Pugh C) hepatic impairment; the dose should be reduced in patients with moderate (Child-Pugh B) hepatic impairment.
/Black Box Warning/ Gastrointestinal Bleeding. Exjade can cause gastrointestinal bleeding, which can be fatal, especially in older patients with advanced hematologic malignancies and/or low platelet counts. Monitor patients and discontinue Exjade if gastrointestinal ulceration or bleeding is suspected.
The decision to start Exjade treatment should be individualized based on the expected clinical benefit and treatment risk, taking into account factors such as the patient's life expectancy and comorbidities.
For more complete data on drug warnings for deferasirox (26 of them), please visit the HSDB record page.

---

Pharmacodynamics
Deferrasirox is an orally active chelator selective for iron (in the form of Fe3+). It is a tripentate ligand that binds to iron with a high affinity in a 2:1 ratio. Although deferasirox has low affinity for zinc and copper, serum concentrations of these trace metals decrease to varying degrees after administration of deferasirox. The clinical significance of these decreases is unclear.

---

Deferasrox (ICL 670) is an oral, once-daily iron chelator with a much higher selectivity for Fe³⁺ than for other metal ions (e.g., Zn²⁺, Cu²⁺)[1]
Its core mechanism of action is to chelate unstable iron and iron bound to proteins (e.g., ferritin) to form a stable water-soluble complex and excrete it from the body, thereby reducing iron overload and iron-mediated oxidative stress[1]
Clinically, it is suitable for treating iron overload caused by chronic blood transfusions (e.g., thalassemia, sickle cell disease) and non-transfusion-dependent thalassemia[4]
In preclinical studies, it has shown antitumor activity in iron-dependent cancers (leukemia, colorectal cancer) by consuming the iron required for cell proliferation and DNA synthesis[2][5]
It has been approved by the FDA. In 2005, deferasrox (ICL 670) was approved for the treatment of chronic iron overload in adults and children aged 2 years and older[3]

C21H15N3O4

373.370

373.106

C, 67.56; H, 4.05; N, 11.25; O, 17.14

201530-41-8

Deferasirox-d4;1133425-75-8

214348

White to light brown solid powder

1.4±0.1 g/cm3

672.1±65.0 °C at 760 mmHg

260-262ºC

360.3±34.3 °C

0.0±2.2 mmHg at 25°C

1.699

6.43

3

6

4

28

540

0

O([H])C1=C([H])C([H])=C([H])C([H])=C1C1=NC(C2=C([H])C([H])=C([H])C([H])=C2O[H])=NN1C1C([H])=C([H])C(C(=O)O[H])=C([H])C=1[H]

BOFQWVMAQOTZIW-UHFFFAOYSA-N

InChI=1S/C21H15N3O4/c25-17-7-3-1-5-15(17)19-22-20(16-6-2-4-8-18(16)26)24(23-19)14-11-9-13(10-12-14)21(27)28/h1-12,25-26H,(H,27,28)

4-(3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl)benzoic acid

ICL670; IC-L670; ICL 670; ICL-670A; ICL670A; IC L670A; Deferasirox. Brand name: Exjade; Desirox; Defrijet; Desifer.

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)

DMSO : 74~100 mg/mL ( 198.2~267.84 )
Ethanol : 15 mg/mL

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.70 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 25.0 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.

---

Solubility in Formulation 2: ≥ 2.5 mg/mL (6.70 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 25.0 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.

---

View More

Solubility in Formulation 3: ≥ 2.5 mg/mL (6.70 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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

---

Solubility in Formulation 4: 5% DMSO + 40% PEG300 + 5% Tween 80 + 50% ddH2O: 3.7mg/ml (9.91mM)

---

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