NOVEL ORALLY-ACTIVE IRON CHELATORS (3-HYDROXYPYRIDIN-4-ONES) ENHANCE THE BILIARY-EXCRETION OF PLASMA NON-TRANSFERRIN-BOUND IRON IN RATS

Background/Aims: It is well documented that levels of plasma non-trans ferrin-bound iron (NTBI), a particularly toxic form of iron, are incre ased in iron overload disorders, In light of the pathogenetic importan ce of NTBI in chronic iron overload, we have studied the ability of ne w orally active iron chelators to promote the biliary excretion of iro n originating as plasma Fe-55-NTBI, Methods: Biliary iron kinetics of plasma Fe-55-labeled NTBI and cumulative recoveries of Fe-55 in bile w ere determined in normal and carbonyl iron-loaded rats receiving a sin gle intragastric dose of iron chelator, These chelators were the novel hydroxypyridin-4-one compounds CP102, CP41, and their respective prod rugs CP117 and CP165. Results: The cumulative recovery of Fe-55 in bil e 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, t hese compounds increased the cumulative recovery by 28.6-, 48.6-, 72.6 -, and 32-fold, respectively, All the chelators had a choleretic effec t, 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-alkyl-hydroxypyridinones such as deferiprone (CP20, L1).