title: Novel orally active iron chelators (3-hydroxypyridin-4-ones) enhance the biliary excretion of plasma non-transferrin-bound iron in rats.
abstract: OBJECTIVE
  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 55Fe-NTBI.
  
  
  METHODS
  Biliary iron kinetics of plasma 55Fe-labeled NTBI and cumulative recoveries of 55Fe 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 pro-drugs CP117 and CP165.
  
  
  RESULTS
  The cumulative recovery of 55Fe 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-alkyl-hydroxypyridinones such as deferiprone (CP20, L1).
authors.affiliation: Liver Research Unit, Institut National de la Sante et de la Recherche Médicale INSERM U-49, Pontchaillou University Hospital, Rennes, France. pierre.brissot@univ-rennes1.fr
authors.forename: G
authors.initials: G
authors.lastname: Zanninelli
authors.forename: R
authors.initials: R
authors.lastname: Choudury
authors.forename: O
authors.initials: O
authors.lastname: Loréal
authors.forename: D
authors.initials: D
authors.lastname: Guyader
authors.forename: G
authors.initials: G
authors.lastname: Lescoat
authors.forename: J
authors.initials: J
authors.lastname: Arnaud
authors.forename: R
authors.initials: R
authors.lastname: Verna
authors.forename: B
authors.initials: B
authors.lastname: Cosson
authors.forename: S
authors.initials: S
authors.lastname: Singh
authors.forename: R C
authors.initials: RC
authors.lastname: Hider
authors.forename: P
authors.initials: P
authors.lastname: Brissot
mesh_terms: D000818:Animals; D001646:Bile / Q000378:metabolism*; D007501:Iron / Q000097:blood*; D007502:Iron Chelating Agents / Q000494:pharmacology*; D019266:Iron, Dietary / Q000008:administration & dosage; D008297:Male; D011355:Prodrugs / Q000494:pharmacology*; D011728:Pyridones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014168:Transferrin / Q000378:metabolism*
chemical_list: C105928:CP 117; C108011:CP 165; D007502:Iron Chelating Agents; D019266:Iron, Dietary; D011355:Prodrugs; D011728:Pyridones; D014168:Transferrin; C108010:CP 102; C108009:CP 41; D007501:Iron