ICL670A: a new synthetic oral chelator: evaluation in hypertransfused rats with selective radioiron probes of hepatocellular and reticuloendothelial iron stores and in iron-loaded rat heart cells in culture.
ICL670A (formerly CGP 72 670) or 4-[3,5-bis-(hydroxyphenyl)-1,2,4-triazol-1-yl]- benzoic acid is a tridentate iron-selective synthetic chelator of the bis-hydroxyphenyl-triazole class of compounds. The present studies used selective radioiron probes of hepatocellular and reticuloendothelial (RE) iron stores in hypertransfused rats and iron-loaded heart cells to define the source of iron chelated in vivo by ICL670A and its mode of excretion, to examine its ability to remove iron directly from iron-loaded myocardial cells, and to examine its ability to interact with other chelators through a possible additive or synergistic effect. Results indicate that ICL670A given orally is 4 to 5 times more effective than parenteral deferoxamine (DFO) in promoting the excretion of chelatable iron from hepatocellular iron stores. The pattern of iron excretion produced by ICL670A is quite different from that of DFO and all iron excretion is restricted to the bile regardless of whether it is derived from RE or hepatocellular iron stores. Studies in heart cell cultures have shown a favorable interaction between DFO and ICL670A manifested in improved chelating efficiency of ICL670A, which is most probably explained by an exchange of chelated iron between ICL670A and DFO. These unique chelating properties of ICL670A may have practical implications for current efforts to design better therapeutic strategies for the management of transfusional iron overload.
Hershko
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Department of Medicine, Shaare Zedek Medical Center, Jerusalem, Israel. hershko@szmc.org.il
Konijn
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Nick
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Breuer
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Cabantchik
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Link
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D000818:Animals; D001565:Benzoates / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001646:Bile / Q000378:metabolism; D002478:Cells, Cultured; D000077588:Deferasirox; D003676:Deferoxamine / Q000493:pharmacokinetics / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D017707:Erythrocyte Transfusion; D004913:Erythrocytes, Abnormal; D005243:Feces / Q000737:chemistry; D005260:Female; D005293:Ferritins / Q000493:pharmacokinetics; D006321:Heart / Q000187:drug effects; D022781:Hepatocytes / Q000378:metabolism*; D006358:Hot Temperature; D007275:Injections, Intravenous; D007502:Iron Chelating Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019190:Iron Overload / Q000188:drug therapy* / Q000378:metabolism; D007504:Iron Radioisotopes / Q000493:pharmacokinetics* / Q000652:urine; D008099:Liver / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D012157:Mononuclear Phagocyte System / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D009928:Organ Specificity; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution; D065227:Transfusion Reaction; D014230:Triazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014556:Urine / Q000737:chemistry
D001565:Benzoates; D007502:Iron Chelating Agents; D007504:Iron Radioisotopes; D014230:Triazoles; D005293:Ferritins; D003676:Deferoxamine; D000077588:Deferasirox