Novel orally active iron chelators (3-hydroxypyridin-4-ones) enhance the biliary excretion of plasma non-transferrin-bound iron in rats
| Autor: | Ruksana Choudury, Surinder Singh, Gérard Lescoat, Bertrand Cosson, Olivier Loréal, Robert C. Hider, Pierre Brissot, Giuliana Zanninelli, Josiane Arnaud, Dominique Guyader, Roberto Verna |
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| Jazyk: | angličtina |
| Rok vydání: | 1997 |
| Předmět: |
Male
medicine.medical_specialty Choleretic Pyridones bile Iron Chelating Agents oral chelation Transaminase Excretion Rats Sprague-Dawley chemistry.chemical_compound iron Internal medicine Metalloprotein medicine Animals Chelation Prodrugs rat iron overload chemistry.chemical_classification hydroxypyridinones non-transferrin-bound iron Hepatology Transferrin Prodrug Rats Endocrinology chemistry Deferiprone Iron Dietary |
| Popis: | Background/Aims: It is well documented that levels of plasma non-transferrin-bound iron (NTBI), a particularly toxic form of iron, are increased in iron overload disorders. In light of the pathogenetic importance of NTBI in chronic iron overload, we have studied the ability of new orally active iron chelators to promote the biliary excretion of iron originating as plasma 55 Fe-NTBI. Methods: Biliary iron kinetics of plasma 55 Fe-labeled NTBI and cumulative recoveries of 55 Fe in bile were determined in normal and carbonyl iron-loaded rats receiving a single intragastric dose of iron, chelator. These chelators were the novel hydroxypyridin-4-one compounds CP102, CP41, and their respective prodrugs CP117 and CP165. Results: The cumulative recovery of 55 Fe in bile of normal rats was increased by 5.2−, 7.9−, 11.5−, and 9.2-fold with CP102, CP117, CP41 and CP165, respectively. In iron overloaded rats, these compounds increased the cumulative recovery by 28.6−, 48.6−, 72.6−, and 32-fold, respectively. All the chelators had a choleretic effect, were metabolized by the liver as demonstrated by HPLC study of bile, and were not cytotoxic since normal plasma transaminase levels were maintained at the end of the experiments. Conclusions: These chelators have potential interest for the treatment of iron overload conditions and may offer advantages over simple N-alky;-hydroxypyridinones such as deferiprone (CP20, L1). |
| Databáze: | OpenAIRE |
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