Recent Insights into Interactions of Deferoxamine with Cellular and Plasma Iron Pools: Implications for Clinical Use

Abstract

Despite the availability of deferoxamine (DFO) for more than three decades, its rates of interaction with cellular iron pools in different tissues, and the effects of its pharmacokinetics on the interaction with plasma iron pools, remain incompletely understood. The positive charge of DFO, together with the negative resting potential in vertebrate cells, favors cellular uptake, whereas the low lipophilicity and high molecular weight counter this effect. The findings presented suggest a facilitated uptake of DFO into hepatocytes, being several hundred-fold faster than into red cells. Antibodies that selectively recognize ferrioxamine (FO) show that initial hepatocellular iron chelation is cytosolic, but later transposes to lysosomal and ultimately canalicular compartments. Strong FO staining is visible in myocytes within 4-8 h after commencing a subcutaneous DFO infusion, indicating effective chelation of myocyte iron. A methodology was developed to study the interaction of DFO and its metabolites with plasma iron pools by stabilizing DFO with aluminum ions, thereby preventing iron shuttling from non-transferrin-bound iron (NTBI) onto DFO after plasma collection. DFO removes only about a third of NTBI rapidly, and NTBI is rarely cleared completely. Increasing DFO dosing does not increase NTBI removal, but instead leads to a greater rebound in NTBI on cessation of intravenous infusion. Thus, intermittent infusions of high-dose DFO are less desirable than continuous infusions at low doses, particularly in high-risk patients. Here the benefits of continuous DFO on heart function occur before changes in T2*-visible storage iron, consistent with early removal of a toxic labile iron pool within myocytes.

Iron Stimulates Urokinase Plasminogen Activator Expression and Activates NF-kappa B in Human Prostate Cancer Cells

“…On the contrary, the likely explanation for the poor outcome of this trial is the intermittent dosing schedule of DFO rather than ineffectiveness of the drug. Recent data suggest that serum NTBI levels are reduced only during active treatment with DFO, and rebound to pre-treatment levels occurs shortly after DFO discontinuation (77). To be useful as a cancer treatment, therefore, continuous exposure to the iron chelator is desirable.…”

Inflammation and oxidant-stress in -thalassemia patients treated with iron chelators deferasirox (ICL670) or deferoxamine: an ancillary study of the Novartis CICL670A0107 trial

“…6,7 NTBI has been suggested to be toxic to the heart and other iron-susceptible tissues. 8,9 Deferasirox (ICL670, Exjade®, Novartis) is an orally administered tridentate iron chelator with a relatively long circulating half-life of 8 to 16 hours 10,11 and documented cellular permeability. 12,13 Deferasirox was approved by the Food and Drug Administration, in late 2005, for treatment of transfusional iron overload in chronic anemias (this approval can be found at:…”

Novel Population Pharmacokinetic Method Compared to the Standard Noncompartmental Approach to Assess Bioequivalence of Iron Gluconate Formulations

“…The model also took into consideration iron lost during each blood sample, as well as iron not bound to transferrin. Although the administration of intravenous iron is not associated with the generation of detectable or dialyzable free iron (3,31), there is evidence that points to the existence of non-transferrin bound iron (NTBI) that is biologically active and labile (9,31,32). This NTBI may even be bound to albumin (32).…”

“…Although the administration of intravenous iron is not associated with the generation of detectable or dialyzable free iron (3,31), there is evidence that points to the existence of non-transferrin bound iron (NTBI) that is biologically active and labile (9,31,32). This NTBI may even be bound to albumin (32). The levels of NTBI estimated in our population were about 46 mcg/dL before any treatment (Period 1) and about 74 mcg/dL before Period 2, which are equivalent to roughly 0.001 and 0.002 mcM and which are well under the 1 M levels normally seen in healthy subjects (1).…”