title: Mechanisms for the shuttling of plasma non-transferrin-bound iron (NTBI) onto deferoxamine by deferiprone.
abstract: In iron overload conditions, plasma contains non-transferrin bound iron species, collectively referred to as plasma NTBI. These include iron citrate species, some of which are protein bound. Because NTBI is taken into tissues susceptible to iron loading, its removal by chelation is desirable but only partial using standard deferoxamine (DFO) therapy. Speciation plots suggest that, at clinically achievable concentrations, deferiprone (DFP) will shuttle iron onto DFO to form feroxamine (FO), but whether NTBI chelation by DFO is enhanced to therapeutically relevant rates by DFP is unknown. As FO is highly stable, kinetic measurements of FO formation by high-performance liquid chromatography or by stopped-flow spectrometry are achievable. In serum from thalassemia major patients supplemented with 10 microM DFO, FO formation paralleled NTBI removal but never exceeded 50% of potentially available NTBI; approximately one third of NTBI was chelated rapidly but only 15% of the remainder at 20 h. Addition of DFP increased the magnitude of the slower component, with increments in FO formation equivalent to complete NTBI removal by 8 h. This shuttling effect was absent in serum from healthy control subjects, indicating no transferrin iron removal. Studies with iron citrate solutions also showed biphasic chelation by DFO, the slow component being accelerated by the addition of DFP, with optimal enhancement at 30 microM. Physiological concentrations of albumin also enhanced DFO chelation from iron citrate, and the co-addition of DFP further accelerated this effect. We conclude that at clinically relevant concentrations, DFP enhances plasma NTBI chelation with DFO by rapidly accessing and shuttling NTBI fractions that are otherwise only slowly available to DFO.
authors.affiliation: Department of Hematology, University College London Medical School, London, United Kingdom. patricia.evans@ucl.ac.uk
authors.forename: Patricia
authors.initials: P
authors.lastname: Evans
authors.forename: Reem
authors.initials: R
authors.lastname: Kayyali
authors.forename: Robert C
authors.initials: RC
authors.lastname: Hider
authors.forename: John
authors.initials: J
authors.lastname: Eccleston
authors.forename: John B
authors.initials: JB
authors.lastname: Porter
mesh_terms: D000328:Adult; D002851:Chromatography, High Pressure Liquid; D000077543:Deferiprone; D003676:Deferoxamine / Q000378:metabolism* / Q000627:therapeutic use; D005260:Female; D005290:Ferric Compounds / Q000097:blood / Q000302:isolation & purification; D006801:Humans; D007501:Iron / Q000097:blood* / Q000378:metabolism; D007502:Iron Chelating Agents / Q000378:metabolism / Q000627:therapeutic use; D019190:Iron Overload / Q000097:blood / Q000188:drug therapy / Q000209:etiology; D007700:Kinetics; D008297:Male; D011728:Pyridones / Q000378:metabolism* / Q000627:therapeutic use; D017262:Siderophores / Q000378:metabolism* / Q000627:therapeutic use; D013789:Thalassemia / Q000097:blood / Q000188:drug therapy; D014168:Transferrin / Q000378:metabolism; D065227:Transfusion Reaction
chemical_list: D005290:Ferric Compounds; D007502:Iron Chelating Agents; D011728:Pyridones; D017262:Siderophores; D014168:Transferrin; C000499:ferric oxide; D000077543:Deferiprone; C025314:ferric citrate; D007501:Iron; D003676:Deferoxamine