IRC011, A NEW SYNTHETIC CHELATOR WITH SELECTIVE INTERACTION WITH CATABOLIC RED-BLOOD-CELL IRON - EVALUATION IN HYPERTRANSFUSED RATS WITH HEPATOCELLULAR AND RETICULOENDOTHELIAL RADIOIRON PROBES AND IN IRON-LOADED RAT-HEART CELLS IN CULTURE

A major consideration in the selection of new and improved iron chelat ors for clinical use is preferential interaction with the most toxic i ron compartment. We describe the biologic properties of a new syntheti c hexadentate iron chelator (IRCO11) that is a substituted polyaza com pound. Unlike deferoxamine (DF), the polyaza structure of IRCO11 does not contain any readily hydrolyzable covalent bonds and is anticipated to resist in vivo biotransformation. In the present studies, the abil ity of IRCO11 to remove radioiron from iron-loaded heart cells in vitr o was similar to DF, with a decrease to 20.0 +/- 0.4% and 19.7 +/- 0.5 % of initial values after 24 hours of incubation with 0.3 mmol/L of DF or IRCO11. respectively. The in vivo interaction of IRCO11 with speci fic iron stores was studied in hypertransfused rats using selective la beling of reticuloendothelial (RE) iron stores with Fe-59-heat-denatur ed red blood cells (DRBCs) and of hepatocellular stores with Fe-59-fer ritin. The pattern of radioiron excretion with IRCO11 was quite differ ent from that with DF. Although with both compounds, hepatocellular ir on excretion was through the bile, whereas RE iron excretion was mainl y in the urine, the magnitude of these effects was quite different. Af ter the administration of a single parenteral dose of 200 mg/kg repres enting a 53% higher iron-binding capacity for IRCO11 compared with DF, 48-hour urinary excretion of RE iron with IRCO11 was 22.8% +/- 1.1% ( % of total body Fe-59), but only 6.0% +/- 3.6% with DF. By contrast, t he corresponding biliary excretion of hepatocellular radioiron was 14. 2% +/- 3.2% with DF, but only 0.7% +/- 0.3% with IRCO11. Thus, the new iron chelator IRCO11 is distinguished from DF by the following featur es: (1) a higher affinity to Fe(III), (2) anticipated resistance to in vivo catabolism, (3) preferential interaction with RE iron derived fr om RBC breakdown, and (4) selective renal excretion. Because RBC break down is the most likely source of the toxic nontranferrin plasma iron, IRCO11 may be a useful iron chelator for protecting vital organs from peroxidative damage. (C) 1997 by The American Society of Hematology.