New concepts of iron and aluminium chelation therapy with oral L1 (deferiprone) and other chelators. A review

Abstract

The introduction of oral chelation therapy with the alpha-ketohydroxypyridine chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1, INN/BAN: deferiprone) in iron- and aluminium-overloaded patients has been initiated in over 15 countries in the last 7 years. Over 600 patients with various conditions, in 26 centres have received L1, in some cases daily for over 5 years. In the vast majority of iron-loaded patients, doses of 55-100 mg kg-1 of L1 resulted in urinary iron excretion levels greater than those accumulating from transfusions (15-35 mg d-1) and also reduction in serum ferritin and liver iron to near normal levels. Urinary iron excretion was related to the iron load of the patients, as well as the dose and frequency of administration of L1. The L1 appears to mobilize iron mainly from a serum iron pool in excess of transferrin saturation, transferrin-bound iron and tissue iron, mainly but not exclusively from the liver. The order of metal binding by L1 at pH 7.4 is Fe > Cu > A1 > Zn. Aluminium removal from aluminium-loaded renal dialysis patients by L1 was also effective at doses similar to those used for iron-loaded patients. Overall toxic side effects include six cases of reversible agranulocytosis, 0-30% incidence of transient musculoskeletal and joint pains, 0-6% of gastric intolerance and 0-2% zinc deficiency. Deferiprone appears to be as effective as desferrioxamine in iron and aluminium removal and has low toxicity. Its oral efficacy and low cost make it more accessible than desferrioxamine for the vast majority of patients needing iron chelation worldwide. The development of other alpha-ketohydroxypyridines is currently in progress.

Redistribution of accumulated cell iron: a modality of chelation with therapeutic implications

“…Labile iron that is likely to be accessible to DFP is assumed to be bound to several possible ligands (eg, citrate, ATP) and to be in dynamic equilibrium between Fe(II) and Fe(III) as dictated by the redox status of the intracellular environment. 38,39 DFP competes effectively for labile cell iron both in vitro and in vivo, 32 and in individuals with normal iron balance it raises serum iron levels, indicating mobilization of tissue iron. 12 This was also observed with isolated cells (Figures 3,4), where DFP readily chelated iron bound to the EDTA analog CALG in endosomes and nuclei and was indicated in other systems.…”

“…14 Yet, despite DFP's brain accessibility, major effects on CNS function have not been reported. 32,44 Whether DFP can alter the iron balance in the brain by shuttling iron across the BBB remains an open question. The absence of iron loading of the CNS in iron-overload conditions indicates that neither transferrin-bound nor non-transferrin-bound iron is able to freely cross the BBB.…”

Methyl‐Hydroxypyridinecarboxylic Acids as Possible Bidentate Chelating Agents for Aluminium(III): Synthesis and Metal–Ligand Solution Chemistry

“…Regarding aluminium() and iron(), there is a need for new, safe, inexpensive, efficient, and orally effective chelators, [1][2][3] because the existing ones, i.e. desferrioxamine and deferiprone, have a number of drawbacks, including oral inefficacy and the high cost for the former, [4][5][6] and several toxic side effects and controversial efficiency for the latter. [5][6][7][8] In a previous work [9] we proposed hydroxypyridinecarboxylic acids (HPs) as new possible chelating agents for aluminium() in view of several promising properties such as their lack of toxicity (references in ref.…”

Desferrioxamine-chelatable iron, a component of serum non–transferrin-bound iron, used for assessing chelation therapy

“…This conclusion was based on the documented capacity of L1 to mobilize Fe in vivo 23 and from cells in vitro 4 and to transfer it to Fl-DFO in vitro ( Figure 5). Moreover, we found that the increase in serum Fe induced by L1 and identified as DCI (Figure 3), was paralleled by an increase in the total serum Fe content measured by the acid-bathophenanthroline method (data not shown).…”