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DFO is a water-soluble hexadentate chelator with a molecular weight of 561 Da. The commercial formulation is the mesylate salt with a molecular weight of 657 Da. One mole of DFO binds 1 mole of Fe3+; therefore, 100 mg DFO as the mesylate salt theoretically can bind 8.5 mg Fe3+.
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DFO has a much greater affinity constant for iron (1031) and aluminum (1022) than for zinc, copper, nickel, magnesium, or calcium (102–1014).38 Thus, at physiologic pH, DFO complexes almost exclusively with ferric iron.28,84
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Deferiprone, a bidentate oral iron chelator with a molecular weight of 139 Da, was approved by the US Food and Drug Administration (FDA) in 2011 for the treatment of iron overload in patients with thalassemia in whom current treatment is inadequate.24 Three moles of deferiprone are required to bind one mole of ferric ion to form a stable complex, which is excreted in the urine.32 Inappropriate ratios of drug to iron may be ineffective or even harmful because of the formation of potentially toxic intermediates.32 Preliminary animal studies of the use of deferiprone in acute iron toxicity are contradictory.10,23,36,39 A dose of 75 mg/kg deferiprone produces 60% of the total iron excretion that can be achieved with 50 mg/kg DFO. All of the iron eliminated with deferiprone occurs in the urine, while DFO eliminates iron in the urine and feces.42 It has been proposed that deferiprone is less likely to cause toxicity in patients with low iron stores because it can exchange iron with transferrin. Adverse events include QT prolongation, elevation of hepatic enzymes, gastrointestinal effects, arthralgia, chromaturia. Because of embryofetal toxicity in animals studies it is given an FDA pregnancy category D; DFO also carries a boxed warning for agranulocytosis.24 Deferiprone is now being combined with DFO because studies demonstrate additive or synergistic effects in chronic iron overload syndromes. It is hypothesized that deferiprone, because of its smaller size, can enter and chelate cardiac iron and then transfer it to DFO for elimination.42
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Deferasirox, an oral iron chelator that was FDA approved in 2005, is indicated to treat chronic iron overload caused by blood transfusions or in patients with thalassemia and elevated liver iron concentrations. Deferasirox, a tridentate ligand with a molecular weight of 373 Da, binds ferric iron in a 2:1 ratio. Deferasirox is lipid soluble with high protein binding (~99%). Once bound to iron, the complex is predominantly eliminated in the feces. The serum half-life (19 ± 6.5 hours) is considerably longer than DFO and deferiprone (47–137 minutes). Preliminary studies demonstrate a comparable efficacy to DFO in patients with chronic iron overload.80 One study utilizing deferasirox in a human model of supraphysiologic iron ingestion demonstrated a reduction in serum iron concentrations when compared with placebo.29 However, the dose of iron ingested was 5 mg/kg, and concerns about achieving the effective dose ratio of deferasirox to iron of 2:1 and the effects of acidemia on the binding of deferasirox to iron in a large overdose limit its use in acute iron poisoning at this time.56 In addition, similar to other oral chelators, concerns exist about increasing oral absorption of the deferasirox iron complex, and the toxicity of this complex in the setting of an acute iron overdose.22,63,72 Adverse events include boxed warnings for gastrointestinal hemorrhage, kidney failure, and hepatic failure. Advanced age increases these risks.22
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DFO binds Fe3+ at the 3 N–OH sites, forming an octahedral iron complex (Fig. A7–1). Once bound, the resultant ferrioxamine is very stable. DFO appears to benefit iron-poisoned patients by chelating free iron (non–transferrin plasma iron), iron in transit between transferrin and ferritin (labile chelatable iron pool),32,46,65 and hemosiderin and ferritin, while not directly affecting the iron of transferrin, hemoglobin, and cytochromes.20,38 Although in vitro studies suggest that DFO removes iron from ferritin and transferrin with only very little from hemosiderin,51 in vivo experiments demonstrate that DFO cannot remove iron after the iron is bound to transferrin.4 DFO does bind “free iron,” now referred to as non transferrin bound iron found in the plasma after transferrin saturation, which only occurs acutely after overdose or chronically in iron overload syndromes.32 In vitro studies demonstrate that DFO chelates and inactivates cytoplasmic, lysosomal, and probably mitochondrial iron, preventing disruption of mitochondrial function and injury.27,46 An in vitro study suggests that DFO gains access to cytosol and endosomes through endocytosis rather than passive diffusion.27 In chronic iron overload, DFO chelates iron deposited in the reticuloendothelial cells found in the spleen, liver, and bone marrow and excretes iron in the urine as ferrioxamine.32 Whether DFO actually chelates the iron within the reticuloendothelial cells or after liberation into the plasma is unclear. In vitro studies demonstrate that the liver can donate iron to DFO; thus, chelation may also subsequently lead to biliary iron excretion and fecal elimination.32,50
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Pharmacokinetics/Pharmacodynamics
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The volume of distribution of DFO ranges from 0.6 to 1.33 L/kg.38,43,59 Because DFO is water soluble, entry into most cells is limited except for hepatocytes, in which facilitated uptake takes place.62a,63 The initial distribution half-life of DFO is 5 to 10 minutes.41,71 The terminal elimination half-life of DFO is approximately 6 hours in healthy patients2 but approximately 3 hours in patients with thalassemia. DFO is metabolized in the plasma to several metabolites (A–F), of which metabolite B is believed to be toxic.38,43,59,61 Unchanged DFO undergoes glomerular filtration and tubular secretion.50
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By comparison, ferrioxamine has a smaller volume of distribution than DFO. In nephrectomized dogs, the volume of distribution of ferrioxamine was calculated to be 19% of body weight compared with 50% of body weight for DFO.38 This finding implies that DFO has a more extensive tissue distribution. The different pharmacokinetic patterns may be related to the potential for facilitated penetrance of the straight-chain molecule DFO compared with that of the octahedral ferrioxamine.61 Experiments in dogs with normal kidney function demonstrate that intravenous (IV) ferrioxamine is entirely eliminated by the kidney within 5 hours via glomerular filtration and partial reabsorption.36,50
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The pharmacokinetics of DFO and ferrioxamine differ in healthy compared with iron overloaded patients. Whereas plasma DFO concentrations in healthy patients are approximately twice the concentrations noted in patients with thalassemia major, ferrioxamine concentrations are five times greater in patients with thalassemia major compared with healthy patients.38,73
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The metabolism of DFO is unclear but occurs in the plasma by plasma enzymes and in the liver.20
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DFO is hemodialyzable. Some investigators suggest that DFO can be administered during hemodialysis to remove ferrioxamine.85 Hemodialysis,14,71 particularly high flux hemodialysis78 and hemoperfusion,14 are effective in ferrioxamine removal and are indicated in patients with renal failure.