title: Transport of iron chelators and chelates across MDCK cell monolayers: implications for iron excretion during chelation therapy.
abstract: Iron chelators are effective at removing iron from the body in iron overload, but little is known about the handling of iron chelates by the kidney. We studied the transport of deferoxamine, deferasirox, and three hydroxypyridones, and their iron chelates, in polarized renal epithelial MDCK cells growing on Transwell inserts. Directional iron efflux was also studied in (59)Fe-loaded cells. The chelators were transported at comparable rates in the apical and basolateral directions and moved faster than their corresponding chelates, except for deferoxamine, which did not move from the basolateral to the apical side. In contrast, the chelates were transported faster in the apical-to-basolateral direction. More permeable chelators were more efficient at removing iron from iron-loaded cells compared with deferoxamine. Iron is preferentially removed from the basolateral side, and kinetic modeling suggests facilitated diffusion of chelates in some cases. Basolateral iron efflux is temperature-dependent and partially sensitive to ATP depletion. Polarized transport of chelates suggests the kidney may be involved in reabsorption of iron bound to chelators, with a temperature-sensitive facilitated removal of some iron complexes from the basolateral side. Further studies are warranted to determine if these processes may contribute to the observed nephrotoxicity of some iron chelators.
authors.affiliation: The Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada.
authors.forename: Xi-Ping
authors.initials: XP
authors.lastname: Huang
authors.forename: Jake J
authors.initials: JJ
authors.lastname: Thiessen
authors.forename: Michael
authors.initials: M
authors.lastname: Spino
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Templeton
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001565:Benzoates / Q000737:chemistry / Q000493:pharmacokinetics*; D001692:Biological Transport / Q000502:physiology; D002460:Cell Line; D016764:Cell Polarity / Q000502:physiology; D000077588:Deferasirox; D003676:Deferoxamine / Q000737:chemistry / Q000493:pharmacokinetics*; D004285:Dogs; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005089:Exocytosis / Q000502:physiology; D007501:Iron / Q000493:pharmacokinetics; D007502:Iron Chelating Agents / Q000737:chemistry / Q000493:pharmacokinetics; D019190:Iron Overload / Q000378:metabolism*; D007504:Iron Radioisotopes; D007668:Kidney / Q000166:cytology; D008954:Models, Biological; D011728:Pyridones / Q000737:chemistry / Q000493:pharmacokinetics*; D017262:Siderophores / Q000737:chemistry / Q000493:pharmacokinetics; D013696:Temperature; D014230:Triazoles / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: C487538:1,6-dimethyl-3-hydroxy-4-(1H)-pyridinone-2-carboxy-(N-methyl)-amide hydrochloride; D001565:Benzoates; D007502:Iron Chelating Agents; D007504:Iron Radioisotopes; D011728:Pyridones; D017262:Siderophores; D014230:Triazoles; D000255:Adenosine Triphosphate; D007501:Iron; D003676:Deferoxamine; D000077588:Deferasirox