Desferal Mechanism of Action

Chelating agent.
Pharmacology: Mechanism of Action: Desferrioxamine (DFO) forms complexes predominantly with ferric iron and with trivalent aluminium ions: the complex formation constants are 10³¹ and 10²⁵, respectively. The affinity of DFO for divalent ions such as Fe²⁺, Cu²⁺, Zn²⁺, Ca²⁺ is substantially lower (complex formation constants 10¹⁴ or below). Chelation occurs at a 1:1 molar basis, so that 1 g DFO can theoretically bind 85 mg ferric iron or 41 mg Al³⁺.
Owing to its chelating properties, DFO is capable of taking up free iron, either in plasma or in cells thereby forming the complex ferrioxamine (FO). Urinary iron excretion of FO is predominantly a reflection of iron derived from plasma turnover whereas faecal iron reflects mainly intrahepatic iron chelation. Iron may be chelated from ferritin and hemosiderin but is relatively slow at clinically relevant concentrations of DFO. DFO, however, does not remove iron from transferrin or from hemoglobin or from other hemin-containing substances.
DFO can also mobilize and chelate aluminum, forming an aluminoxamine (AlO) complex.
Pharmacodynamics: Since complexes with iron and aluminum are completely excreted, DFO promotes the excretion of iron and aluminum in the urine and feces and thus reduces pathological iron or aluminum deposits in the organs.
Clinical Studies: Desferrioxamine was used as a comparator in a randomized, one-year clinical trial investigating the use of another iron chelator (deferasirox) in patients with beta-thalassemia and transfusional hemosiderosis. A total of 290 patients were treated with subcutaneous desferrioxamine at starting doses of 20 to 60 mg/kg for 5 days per week. The study showed a dose-dependent effect of desferrioxamine on serum ferritin levels, liver iron concentration and iron excretion rate.
Desferrioxamine was also used as a comparator in a second open-label, randomized, one-year trial investigating the use of deferasirox in patients with sickle cell disease and transfusional hemosiderosis. A total of 63 patients were treated with subcutaneous desferrioxamine at starting doses of 20 to 60 mg/kg at least 5 days per week. At the end of the study, the mean change in liver iron concentration (LIC) was -0.7 mg Fe/g dry weight.
Pharmacokinetics: Absorption: DFO is rapidly absorbed after intramuscular bolus injection or slow subcutaneous infusion, but is only poorly absorbed from the gastrointestinal tract in the presence of intact mucosa. The absolute bioavailability is less than 2% after oral administration of 1 g DFO.
During peritoneal dialysis DFO is absorbed if administered in the dialysis fluid.
Distribution: In healthy volunteers peak plasma concentrations of 15.5 micromol/L (8.7 micrograms/mL) were measured 30 minutes after an intramuscular injection of 10 mg/kg DFO. One hour after injection the peak concentration of FO was 3.7 micromol/L (2.3 micrograms/mL). After intravenous infusion of 2 g (about 29 mg/kg) of DFO to healthy volunteers over 2 hours mean steady state concentrations of DFO of 30.5 micromol/L were reached; distribution of DFO is very rapid with a mean distribution half-life of 0.4 hours. Less than 10% of DFO is bound to serum proteins in vitro.
Biotransformation: Four metabolites of DFO were isolated and identified from the urine of patients with iron overload. The following biotransformation reactions were found to occur with DFO: transamination and oxidation yielding an acid metabolite, beta-oxidation also yielding an acid metabolite, decarboxylation and N-hydroxylation yielding neutral metabolites.
Elimination: Both DFO and FO have a biphasic elimination after intramuscular injection in healthy volunteers; for DFO the apparent distribution half-life is 1 hour, and for FO 2.4 hours. The apparent terminal half-life is 6 hours for both. Within six hours of injection, 22% of the dose appears in the urine as DFO and 1% as FO.
Characteristics in patients: In patients with hemochromatosis peak plasma levels of 7.0 micromol/L (3.9 micrograms/mL) were measured for DFO, and 15.7 micromol/L (9.6 micrograms/mL) for FO, 1 hour after an intramuscular injection of 10 mg/kg DFO. These patients eliminated DFO and FO with half-lives of 5.6 and 4.6 hours, respectively. Six hours after the injection 17% of the dose was excreted in the urine as DFO and 12% as FO.
In patients with thalassemia continuous intravenous infusion of 50 mg/kg/24 h of DFO resulted in plasma steady state levels of DFO of 7.4 micromol/L (4.1 micrograms/mL). Elimination of DFO from plasma was biphasic with a mean distribution half-life of 0.28 hours and an apparent terminal half-life of 3.0 hours. The total plasma clearance was 0.5 L/h/kg and the volume of distribution at steady state was estimated at 1.35 L/kg. Exposure to the main iron binding metabolite was around 54% of that of DFO in terms of AUC. The apparent monoexponential elimination half-life of the metabolite was 1.3 hours.
In patients dialyzed for renal failure who received 40 mg/kg DFO infused i.v. within 1 hour, the plasma concentration at the end of the infusion was 152 micromol/L (85.2 micrograms/mL) when the infusion was given between dialysis sessions. Plasma concentrations of DFO were between 13% and 27% lower when the infusion was administered during dialysis. Concentrations of FO were in all cases approx. 7.0 micromol/L (4.3 micrograms/mL); and for AlO 2-3 micromol/L (1.2-1.8 micrograms/mL). After the infusion was discontinued, the plasma concentration of DFO decreased rapidly with a half-life of 20 minutes. A smaller fraction of the dose was eliminated with a longer half-life of 14 hours. The plasma concentrations of AlO continued to increase for up to 48 hours after the infusion and reached values of approx. 7 micromol/L (4 micrograms/mL). Following dialysis the plasma concentration of AlO dropped to 2.2 micromol/L (1.3 micrograms/mL).
Toxicology: Non-Clinical Safety Data: The subcutaneous administration of high doses of DFO to rats, dogs and cats for several weeks caused eye-lens opacity with cataract formation.
DFO did not show evidence for genotoxic/mutagenic effects in in vitro assays (Ames test) and in vivo assay (micronucleus test in rats). Long-term carcinogenicity studies have not been performed.
DFO was not teratogenic in rats and mice. In rabbit fetuses, which were exposed in utero to maternally toxic doses only, some malformations of the axial skeleton were found. Though the results of this study are considered of a preliminary character, DFO-induced teratogenicity in rabbits cannot be excluded under the experimental conditions employed (see Use in Pregnancy & Lactation).