title: Biodistribution and predictive hepatic gene expression of intravenous iron sucrose.
abstract: BACKGROUND
  We have examined iron biodistribution and hepatic gene expression in rats following administration of the generic Iron Sucrose Azad (ISA) or the reference iron sucrose drug Venofer®.
  
  
  METHODS
  ISA and Venofer® were administered intravenously to normal, non-anemic, male rats at 15 mg/kg (a supra-therapeutic dose-level). To evaluate biodistribution, tissue iron levels were determined over 28 days for plasma, liver, spleen, bone marrow, heart, kidney, lung and stomach using a validated ICP-MS method. Hepatic gene expression was evaluated by microarray analysis of mRNA from samples taken 24 h after drug administration.
  
  
  RESULTS
  Iron concentration/time profiles for plasma and tissues were quantitatively similar for ISA and Venofer. Following administration, circulating iron levels briefly exceeded transferrin binding capacity and there was a transient increase in hepatic iron. Bone marrow iron levels remained elevated throughout the study. No increases in tissue iron levels were observed in the heart, stomach or lungs. Spleen iron levels increased over the course of the study in treated and control rats. Small, transient increases were recorded in the kidneys of treated rats. The effects of ISA and Venofer® on hepatic gene transcription were similar. Principal components analysis showed that there was no systematic effect of either treatment on transcriptional profiles. Only a small number of genes showed significant modulation of expression. No transcriptional pattern matches with toxicity pathways were found in the ToxFX database for either treatment. No modulation of key genes in apoptosis, inflammation or oxidative stress pathways was detected.
  
  
  CONCLUSIONS
  These findings demonstrated that the biodistribution of administered iron is essentially similar for Iron Sucrose Azad and Venofer®, that iron sucrose partitions predominantly into the liver, spleen and bone marrow, and that hepatic gene expression studies did not provide any evidence of toxicity in animals treated at a supra-therapeutic dose-level.
authors.affiliation: Azad Pharma AG, Bahnhofstrasse 9, CH-3125 Toffen, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Elford
authors.forename: Johanne
authors.initials: J
authors.lastname: Bouchard
authors.forename: Léonore
authors.initials: L
authors.lastname: Jaillet
authors.forename: Nick
authors.initials: N
authors.lastname: Pearson
authors.forename: Alexandra
authors.initials: A
authors.lastname: Rogue
authors.forename: Caroline
authors.initials: C
authors.lastname: Sabadie
authors.forename: Roy
authors.initials: R
authors.lastname: Forster
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D016568:Drugs, Generic / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D005290:Ferric Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D000077605:Ferric Oxide, Saccharated; D005786:Gene Expression Regulation / Q000187:drug effects*; D005937:Glucaric Acid / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D006397:Hematinics / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D007275:Injections, Intravenous; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D025341:Principal Component Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D016568:Drugs, Generic; D005290:Ferric Compounds; D006397:Hematinics; D000077605:Ferric Oxide, Saccharated; D005937:Glucaric Acid
keywords: Anemia; Biodistribution; CS; EMA; European Medicines Agency; Hepatic gene expression; ICP-MS; ISA; Induced Coupled Plasma Tandem Mass Spectrometry; Iron Sucrose Azad; Iron sucrose; KEGG; Kyoto Encyclopedia of Genes and Genomes; NaCl; Partitioning; Predictive toxicity; Rats; Sterile isotonic saline solution; TIBC; Total Iron Binding Capacity; Transferrin Saturation