New developments and controversies in iron metabolism and iron chelation therapy

Table 1 Property differences and mode of action of chelating drugs

Recommended doses for the chelating drugs in thalassaemia patients

DF subcutaneously 40-60 mg/kg per day; Oral L1 75-100 mg/kg per day; Oral DFRA 20-40 mg/kg per day

Transfusional iron loaded patient compliance with chelating drugs

Low compliance with DF in comparison to oral L1 and oral DFRA

Increase in iron excretion and route of elimination in iron loaded patients

L1: Urinary iron; DFRA: Faecal iron; DF: Urinary and faecal iron

Effect of chelating drugs on iron absorption

Increase of iron absorption by the lipophilc maltol, 8-hydroxyquinoline and DFRA. Decrease of iron absorption by the hydrophilic DF, EDTA, DTPA and L1

Iron removal from diferric transferrin in iron loaded patients

About 40% at L1 concentrations > 0.1 mmol/L, but not by DF or DFRA

Differential iron removal from various organs of iron loaded patients

L1 preferential iron removal from the heart and DFRA from the liver

DF from the liver or heart. (Efficacy is related to dose for all chelators)

Iron redistribution in diseases of iron metabolism by chelating drugs

L1 and to a lesser extent DF can cause iron redistribution from the reticuloendothelial system to the erythron in anaemic rheumatoid arthritis patients. DFRA may cause redistribution of iron from the liver to other organs in thalassaemia and other iron loaded patients. Enterohepatic circulation by DFRA and metabolites

Increase excretion of metals other than iron, e.g., Zn and Al

Order of increased Zn excretion in iron loaded patients: DTPA > L1 > DF

DF and L1 cause increase Al excretion in renal dialysis patients

DFRA causes an increase in Ca excretion and Al absorption (?)

Iron mobilisation and excretion of chelator metabolite iron complexes

Several DF metabolites have iron chelation potential and increase iron excretion but not L1 glucuronide

Chelating drugs minimising other drug toxicity

L1 but not DFRA, inhibit doxorubicin induced cardiotoxicity

Combination chelation therapy

L1, DF and DFRA combinations are more effective in iron excretion than monotherapy. The ICOC L1 and DF combination causes normalisation of the iron stores in thalassaemia patients

Chelating drug synergism with reducing agents

Ascorbate act synergistically with DF but not L1 for increasing iron excretion

Chelating drug antioxidant effects

L1 and DF have shown antioxidant action in in vitro, in vivo and clinical settings. The antioxidant effects of DFRA are under evaluation

L1: Deferiprone; DF: Deferoxamine; DFRA: Deferasirox; ICOC: International Committee on Chelation; DTPA: Diethylenetriaminepentaacetic acid; EDTA: Ethylenediaminetetraacetic acid.