Origin and fate of iron mobilized by the 3-hydroxypyridin-4-one oral chelators: studies in hypertransfused rats by selective radioiron probes of reticuloendothelial and hepatocellular iron stores.
The mechanism of in vivo iron chelation by 3-hydroxypyridin-4-ones (CP compounds) was studied in hypertransfused rats in which the major storage iron pools in hepatocytes and in the reticuloendothelial (RE) system have been labeled by selective radioiron probes. Both dimethyl-3-hydroxypyridin-4-one (CP 20 or L1) and diethyl-3-hydroxypyridine-4-one (CP 94) have an identical and very high (log beta 3 36) binding constant and selective affinity to iron(III), but the lipid solubility of CP 94 is considerably higher than that of CP 20. Both chelators induced an increase in the fecal excretion of hepatocellular iron with no effect on urinary excretion. In contrast, about one third to one half of the iron mobilized from RE cells was excreted in the urine. The chelating efficiency of CP 20 was comparable with that of deferoxamine (DF), whereas CP 94 was up to eight times more effective than DF. Unlike DF, which had no effect by the oral route, the oral and parenteral effectiveness of both CP compounds was identical. These findings indicate that: (1) lipid solubility is an important determinant of in vivo chelating efficiency; (2) urinary iron excretion induced by the CP compounds is derived from RE cells; (3) part of the iron mobilized from RE cells and all of the iron derived from hepatocytes is excreted through the bile; and (4) contrary to previous observations in cell cultures, there is no in vivo evidence for a diminishing chelating efficiency at the lowest doses used.
Zevin
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S
Department of Medicine, Shaare Zedek Medical Center, Jerusalem, Israel.
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Grady
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Hider
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Peter
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Hershko
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D000818:Animals; D000077543:Deferiprone; D005243:Feces / Q000737:chemistry; D005260:Female; D007501:Iron / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D007502:Iron Chelating Agents / Q000378:metabolism* / Q000494:pharmacology; D007504:Iron Radioisotopes; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D012157:Mononuclear Phagocyte System / Q000187:drug effects / Q000378:metabolism*; D011728:Pyridones / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D007502:Iron Chelating Agents; D007504:Iron Radioisotopes; D011728:Pyridones; C068543:1,2-diethyl-3-hydroxypyridin-4-one; D000077543:Deferiprone; D007501:Iron