Biological evaluation of some ionophore-polymeric chelator combinations for reducing iron overload.
The potential efficacy of drug combinations that employ an ionophore to mobilize excess hepatic Fe and transport it to the gut for chelation to nonabsorbable polymers and excretion was evaluated in three ways: 1) two-phase partition experiments to assess the ionophoretic capability of lipid-soluble Fe(III)-chelators; 2) in vitro screening with Fe-loaded hepatocyte cultures; and 3) evaluation in Fe-dextran-loaded mice given a low-Fe-containing diet for maximal sensitivity. In the partition experiments, desferal (DF), (desferri)ferrichrome, pyridoxyl isonicotinoyl acid hydrazone hydrochloride (PINH), 2,3-dihydroxybenzoic acid, cholylhydroxamic acid and caffeic acid were effective to varying degrees in transferring Fe(III) from an aqueous to an organic hydrophobic phase. PINH, the most effective, combined with poly[vinylamine-vinyl(2,3-dihydroxybenzenecarboxamide)-vinyl sulfonate sodium salt] (DHBP), increased net 59Fe release from Fe-loaded hepatocytes above the sum of that released by each drug alone and comparable with DF-induced levels. In the mouse bioassay, the combination of PINH (8.1 mg/kg) and DHBP (170 mg/kg 2 times daily) caused a 32% increase in fecal Fe output, comparable with total Fe excretion with DF, but higher doses were toxic and lower doses ineffective. Furthermore, less than 5% of the total Fe load administered was excreted during the 4-day treatment period by either DF or the PINH-DHBP drug combination.
D000818:Animals; D002614:Chelating Agents / Q000008:administration & dosage*; D004338:Drug Combinations; D005243:Feces / Q000032:analysis; D066298:In Vitro Techniques; D007476:Ionophores / Q000008:administration & dosage*; D007501:Iron / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D011108:Polymers / Q000008:administration & dosage*; D051381:Rats; D011919:Rats, Inbred Strains
D002614:Chelating Agents; D004338:Drug Combinations; D007476:Ionophores; D011108:Polymers; D007501:Iron