Chelator-induced iron excretion in iron-overloaded marmosets.
In order to test new orally active iron chelators in a predictive way, a primate model has been developed. This model makes use of the marmoset monkey (Callithrix jacchus) and its overall design is similar to a previously reported monkey model. However, this new model enables a higher compound throughput and requires lower amounts of test compound because the animals are much easier to handle and have much lower body weights. The marmosets were iron-overloaded by three intraperitoneal injections of iron (III) hydroxide polyisomaltose. For the iron-balance studies, the animals were kept in metabolic cages and were maintained on a low-iron diet in order to reduce faecal background. After compound administration, the excretion of iron in urine and faeces was followed for 2 d. A series of well-known chelators was tested for validation of the model. In particular, comparison of the iron-clearing properties of DFO, L1, CP94 and HBED in marmosets and humans demonstrated the predictive value of the model and justify our expectation that if iron chelators such as CGP65015, ICL670A and CGP75254A are active in marmosets, they will be active in humans as well.
Sergejew
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Novartis Pharma AG, Basle, Switzerland. thomas.sergejew@pharma.novartis.com
Forgiarini
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Schnebli
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HP
D000818:Animals; D001565:Benzoates / Q000627:therapeutic use; D002144:Callithrix; D002428:Cebus; D002614:Chelating Agents / Q000627:therapeutic use*; D000077588:Deferasirox; D004305:Dose-Response Relationship, Drug; D004492:Edetic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use; D005243:Feces / Q000737:chemistry; D005260:Female; D007501:Iron / Q000032:analysis / Q000378:metabolism* / Q000652:urine; D019190:Iron Overload / Q000188:drug therapy* / Q000378:metabolism; D008099:Liver / Q000737:chemistry; D008297:Male; D023421:Models, Animal; D011725:Pyridines / Q000627:therapeutic use; D014230:Triazoles / Q000627:therapeutic use
D001565:Benzoates; C119560:CGP 65015; C114572:CGP 75254A; D002614:Chelating Agents; D011725:Pyridines; D014230:Triazoles; D004492:Edetic Acid; D007501:Iron; D000077588:Deferasirox