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 chelators for clinical use is preferential interaction with the most toxic iron compartment. We describe the biologic properties of a new synthetic hexadentate iron chelator (IRC011) that is a substituted polyaza compound. Unlike deferoxamine (DF ), the polyaza structure of IRC011 does not contain any readily hydrolyzable covalent bonds and is anticipated to resist in vivo biotransformation. In the present studies, the ability of IRC011 to remove radioiron from iron-loaded heart cells in vitro 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 IRC011, respectively. The in vivo interaction of IRC011 with specific iron stores was studied in hypertransfused rats using selective labeling of reticuloendothelial (RE) iron stores with 59Fe-heat-denatured red blood cells (DRBCs) and of hepatocellular stores with 59Fe-ferritin. The pattern of radioiron excretion with IRC011 was quite different from that with DF. Although with both compounds, hepatocellular iron excretion was through the bile, whereas RE iron excretion was mainly in the urine, the magnitude of these effects was quite different. After the administration of a single parenteral dose of 200 mg/kg representing a 53% higher iron-binding capacity for IRC011 compared with DF, 48-hour urinary excretion of RE iron with IRC011 was 22.8% +/- 1.1% (% of total body 59Fe), but only 6.0% +/- 3.6% with DF. By contrast, the corresponding biliary excretion of hepatocellular radioiron was 14.2% +/- 3.2% with DF, but only 0.7% +/- 0.3% with IRC011. Thus, the new iron chelator IRC011 is distinguished from DF by the following features: (1) a higher affinity to Fe(III), (2) anticipated resistance to in vivo catabolism, (3) preferential interaction with RE iron derived from RBC breakdown, and (4) selective renal excretion. Because RBC breakdown is the most likely source of the toxic nontranferrin plasma iron, IRC011 may be a useful iron chelator for protecting vital organs from peroxidative damage.