Deferasirox (also known as CGP-72670, ICL-670) is an orally bioavailable iron chelator used for the treatment of iron-overload disease. 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. 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.

Physicochemical Properties

Molecular Formula	C21H15N3O4
Molecular Weight	373.370
Exact Mass	373.106
Elemental Analysis	C, 67.56; H, 4.05; N, 11.25; O, 17.14
CAS #	201530-41-8
Related CAS #	Deferasirox-d4;1133425-75-8
PubChem CID	214348
Appearance	White to light brown solid powder
Density	1.4±0.1 g/cm3
Boiling Point	672.1±65.0 °C at 760 mmHg
Melting Point	260-262ºC
Flash Point	360.3±34.3 °C
Vapour Pressure	0.0±2.2 mmHg at 25°C
Index of Refraction	1.699
LogP	6.43
Hydrogen Bond Donor Count	3
Hydrogen Bond Acceptor Count	6
Rotatable Bond Count	4
Heavy Atom Count	28
Complexity	540
Defined Atom Stereocenter Count	0
SMILES	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]
InChi Key	BOFQWVMAQOTZIW-UHFFFAOYSA-N
InChi Code	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)
Chemical Name	4-(3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl)benzoic acid
Synonyms	ICL670; IC-L670; ICL 670; ICL-670A; ICL670A; IC L670A; Deferasirox. Brand name: Exjade; Desirox; Defrijet; Desifer.
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

ln Vitro	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.
ln Vivo	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.
Cell Assay	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.
Animal Protocol	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.
ADME/Pharmacokinetics	Absorption, Distribution and Excretion The absolute bioavailability (AUC) of deferasirox tablets for oral suspension is 70% compared to an intravenous dose. Deferasirox and metabolites are primarily (84% of the dose) excreted in the feces. Renal excretion of deferasirox and metabolites is minimal (8% of the administered dose). 14.37 ± 2.69 L Exjade is absorbed following oral administration with median times to maximum plasma concentration (tmax) of about 1.5-4 hours. The Cmax and AUC of deferasirox increase approximately linearly with dose after both single administration and under steady-state conditions. Exposure to deferasirox increased by an accumulation factor of 1.3-2.3 after multiple doses. The absolute bioavailability (AUC) of deferasirox tablets for oral suspension is 70% compared to an intravenous dose. The bioavailability (AUC) of deferasirox was variably increased when taken with a meal. ... The current study evaluated the absolute bioavailability of a single 375-mg oral dose of deferasirox administered in the form of tablets compared with a 130-mg intravenous infusion of deferasirox. Since this was a first-in-man study using the deferasirox intravenous (IV) formulation, the safety and tolerability of the IV formulation was evaluated in a pilot phase with a lower dose (65 mg) in 3 subjects prior to the main phase. The main study phase consisted of 17 healthy male volunteers. Plasma concentrations of deferasirox were measured following each treatment, and pharmacokinetic parameters including absolute oral bioavailability were determined. Absolute oral bioavailability of the deferasirox tablets was 70% (90% confidence interval, 62%-80%). Deferasirox was characterized as having a low plasma clearance of 3.53 (+/- 0.87) L/hr. A small volume of distribution of deferasirox at steady state (V(ss)) of 14.37 (+/-2.69 L) was determined, indicating a low tissue distribution. ... The effect of food and time of food intake on the pharmacokinetics of deferasirox was investigated in healthy volunteers and patients with transfusional hemosiderosis. The bioequivalence of a single oral dose of deferasirox (20 mg/kg) was assessed following administration either before a high-fat or standard breakfast or concurrent with a standard breakfast in comparison with fasted conditions in healthy volunteers. The bioavailability of deferasirox was determined following a single oral dose (20 mg/kg) under fed and fasted conditions in patients. These data show that the type of food, caloric content, and fat content of the meal influence the bioavailability of deferasirox when consumed concomitantly. In contrast, this is not the case when deferasirox is administered at least 30 minutes before a meal. In conclusion, it is recommended that deferasirox be administered at least 30 minutes prior to meals. When this is not feasible, deferasirox should be administered consistently at the same time before meals to limit the sources of variability that affect absorption. Deferasirox is highly (approximately 99%) protein bound almost exclusively to serum albumin. The percentage of deferasirox confined to the blood cells was 5% in humans. The volume of distribution at steady state (Vss) of deferasirox is 14.37 +/- 2.69 L in adults. For more Absorption, Distribution and Excretion (Complete) data for Deferasirox (9 total), please visit the HSDB record page. Metabolism / Metabolites Hepatic. CYP450-catalyzed (oxidative) metabolism of deferasirox appears to be minor in humans (about 8%). Glucuronidation is the main metabolic pathway for deferasirox, with subsequent biliary excretion. Glucuronidation is the main metabolic pathway for deferasirox, with subsequent biliary excretion. Deconjugation of glucuronidates in the intestine and subsequent reabsorption (enterohepatic recycling) is likely to occur. Deferasirox is mainly glucuronidated by UGT1A1 and to a lesser extent UGT1A3. CYP450-catalyzed (oxidative) metabolism of deferasirox appears to be minor in humans (about 8%). ... Renal excretion was only 8% of the dose and included mainly the glucuronide M6. Oxidative metabolism by cytochrome 450 enzymes to M1 [5-hydroxy (OH) deferasirox, presumably by CYP1A] and M4 (5'-OH deferasirox, by CYP2D6) was minor (6 and 2% of the dose, respectively). Direct and indirect evidence indicates that the main pathway of deferasirox metabolism is via glucuronidation to metabolites M3 (acyl glucuronide) and M6 (2-O-glucuronide). ... Metabolism /of deferasirox/ included glucuronidation at the carboxylate group (acyl glucuronide M3) and at phenolic hydroxy groups, as well as, to a lower degree, cytochrome P450-catalyzed hydroxylations. Two hydroxylated metabolites (M1 and M2) were administered to rats and were shown not to contribute substantially to iron elimination in vivo. Biological Half-Life The mean elimination half-life ranged from 8 to 16 hours following oral administration. The mean elimination half-life (t1/2) ranged from 8-16 hours following oral administration.
Toxicity/Toxicokinetics	Hepatotoxicity In large clinical trials of deferasirox, elevations in serum aminotransferase levels above 5 times the upper limit of normal (ULN) occurred in 6% of patients and led to drug discontinuation in 1% to 2%. In addition, there have been several single case reports of clinically apparent liver injury arising during deferasirox therapy which was often severe and occasionally fatal. The onset of acute liver injury ranged from a few days to severak years after starting deferasirox but most cases occurred within 1 to 3 months. The pattern of liver injury was typically hepatocellular or mixed with prominent elevations in serum aminotransferase levels. Immunoallergic and autoimmune features were absent. Recovery was usually rapid once deferasirox was stopped, but some cases were associated with progressive liver injury and hepatic failure. Because patients with iron overload often have underlying liver disease, a superimposed acute hepatocellular injury may result in an increased risk of acute liver failure. Deferasirox has a boxed warning regarding hepatotoxicity and regular monitoring of serum bilirubin and aminotransferase levels is recommended. Likelihood score: C (probable cause of clinically apparent liver injury). Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation Deferasirox appears to pass into milk very poorly. Although Australian guidelines recommend against breastfeeding during deferasirox treatment, these were published before a case report of an infant being safely breastfed by a mother with beta-thalassemia receiving deferasirox and finding of no drug in breastmilk. However, since little published information is available on the use of deferasirox during breastfeeding, monitoring of the infant's serum iron is recommended. ◉ Effects in Breastfed Infants A woman with beta-thalassemia was started on deferasirox 2250 mg (35 mg/kg) daily immediately postpartum and exclusively breastfed her infant. Blood samples were taken from the infant at 1, 10 and 30 days postpartum. Serum ferritin levels were 190, 218, and 96 mcg/L, respectively (normal range 22 to 275 mcg/L). Serum iron levels were 101, 77 and 71 mcg/dL, respectively (normal range 60 to 170 mcg/dL). The infant's growth was normal during the first month at the 41st percentile. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding Deferasirox is highly (~99%) protein bound almost exclusively to serum albumin. Interactions Concomitant use of UGT inducers or cholestyramine decreases deferasirox systemic exposure (AUC). Avoid the concomitant use of cholestyramine or potent UGT inducers (eg, rifampicin, phenytoin, phenobarbital, ritonavir) with Exjade. If you must co-administer these agents together, consider increasing the initial dose of Exjade to 30 mg/kg, and monitor serum ferritin levels and clinical responses for further dose modification. The concomitant administration of Exjade and aluminum-containing antacid preparations has not been formally studied. Although deferasirox has a lower affinity for aluminum than for iron, do not administer Exjade with aluminum-containing antacid preparations.
References	[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.
Additional Infomation	Therapeutic Uses Iron Chelating Agents Exjade (deferasirox) is indicated for the treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis) in patients 2 years of age and older. In these patients, Exjade has been shown to reduce liver iron concentration and serum ferritin levels. Clinical trials to demonstrate increased survival or to confirm clinical benefit have not been completed. /Included in US product label/ Drug Warnings /BOXED WARNING/ RENAL FAILURE. Exjade can cause acute renal failure and death, particularly in patients with comorbidities and those who are in the advanced stages of their hematologic disorders. Measure serum creatinine and determine creatinine clearance in duplicate prior to initiation of therapy and monitor renal function at least monthly thereafter. For patients with baseline renal impairment or increased risk of acute renal failure, monitor creatinine weekly for the first month, then at least monthly. Consider dose reduction, interruption, or discontinuation based on increases in serum creatinine. /BOXED WARNING/ HEPATIC FAILURE. Exjade can cause hepatic injury including hepatic failure and death. Measure serum transaminases and bilirubin in all patients prior to initiating treatment, every 2 weeks during the first month, and at least monthly thereafter. Avoid use of Exjade in patients with severe (Child-Pugh C) hepatic impairment and reduce the dose in patients with moderate (Child Pugh B) hepatic impairment. /BOXED WARNING/ GASTROINTESTINAL HEMORRHAGE. Exjade can cause gastrointestinal (GI) hemorrhages, which may be fatal, especially in elderly patients who have advanced hematologic malignancies and/or low platelet counts. Monitor patients and discontinue Exjade for suspected GI ulceration or hemorrhage. Individualize the decision to initiate Exjade therapy based on consideration of the anticipated clinical benefit and risks of the therapy, taking into consideration factors such as the life expectancy and comorbidities of the patient. For more Drug Warnings (Complete) data for Deferasirox (26 total), please visit the HSDB record page. Pharmacodynamics Deferasirox is an orally active chelator that is selective for iron (as Fe3+). It is a tridentate ligand that binds iron with high affinity in a 2:1 ratio. Although deferasirox has very low affinity for zinc and copper there are variable decreases in the serum concentration of these trace metals after the administration of deferasirox. The clinical significance of these decreases is uncertain.

Solubility Data

Solubility (In Vitro)

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

Solubility (In Vivo)

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. 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.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.6783 mL	13.3915 mL	26.7831 mL
	5 mM	0.5357 mL	2.6783 mL	5.3566 mL
	10 mM	0.2678 mL	1.3392 mL	2.6783 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.