Desferri-Exochelin, a lipid-soluble, hexadentate iron chelator, effectively removes tissue iron

• Published in: Translational research : the journal of laboratory and clinical medicine 2006-08, Vol.148 (2), p.63-71
• Main Authors: Hodges, Yvonne K., Weinberger, Howard D., Stephens, Janet, Horwitz, Marcus A., Horwitz, Lawrence D.
• Format: Article
• Language: English
• Subjects: Animals; Biological Transport, Active; Chronic Disease; Heart - drug effects; Injections, Intraperitoneal; Injections, Intravenous; Iron - metabolism; Iron Chelating Agents - administration & dosage; Iron Chelating Agents - pharmacokinetics; Iron Chelating Agents - pharmacology; Iron Overload - drug therapy; Iron Overload - metabolism; Iron Overload - pathology; Liver - drug effects; Liver - metabolism; Liver - pathology; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Myocardium - metabolism; Myocardium - pathology; Peptides, Cyclic - administration & dosage; Peptides, Cyclic - pharmacokinetics; Peptides, Cyclic - pharmacology; Rats; Rats, Sprague-Dawley; Spleen - pathology; Tissue Distribution
• ISSN: 1931-5244; 1878-1810
• DOI: 10.1016/j.trsl.2006.03.003

Chronic iron-overload is damaging to the heart, liver, and other organs. Better iron chelators are needed to treat this serious medical condition. The uptake and distribution of the lipid-soluble, hexadentate iron chelator desferri-Exochelin 772SM (D-Exo) is studied and its efficacy in removing iron from tissue in rodent models is evaluated. After an intravenous bolus of tritiated D-Exo to rats, counts rapidly disappeared from the blood and rapidly appeared in 15 organs studied, usually peaking within 15 min. There was considerable uptake in the heart and liver, 2 organs especially susceptible to damage from clinical iron overload. To assess actual decreases in cardiac and hepatic iron in response to D-Exo, mice loaded with 42 mg of iron dextran (2100 mg/kg) were studied. Untreated, iron-loaded mice sacrificed 9 weeks later had a 4-fold increase in cardiac iron and a 20-fold increase in hepatic iron compared with controls that were not iron-loaded. In iron-loaded mice treated with 7 mg of D-Exo intraperitoneally (i.p.) 4 days/week for 8 weeks (total 224 mg), tissue iron, measured by atomic absorption, was reduced by 20% in the liver and 25% in the heart ( P < 0.01 for each organ). During the first 8 h after a D-Exo dose, iron was excreted in the urine. Mice treated with D-Exo gained weight normally and showed no evidence of toxicity. In conclusion, in this iron-overload mouse model, D-Exo administered intravenously or i.p. rapidly diffuses into multiple organs, including the heart and liver, and effectively removes iron without apparent toxicity.