Desferri-Exochelin, a lipid-soluble, hexadentate iron chelator, effectively removes tissue iron.
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.
Hodges
Yvonne K
YK
Department of Cardiology, Colorado Health Sciences Center, Denver, CO 80262, USA.
Weinberger
Howard D
HD
Stephens
Janet
J
Horwitz
Marcus A
MA
Horwitz
Lawrence D
LD
D000818:Animals; D001693:Biological Transport, Active; D002908:Chronic Disease; D006321:Heart / Q000187:drug effects; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D019190:Iron Overload / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013154:Spleen / Q000473:pathology; D014018:Tissue Distribution
D007502:Iron Chelating Agents; D010456:Peptides, Cyclic; C410730:desferriexochelin 772SM; D007501:Iron