In vitro blood distribution and plasma protein binding of the iron chelator deferasirox (ICL670) and its iron complex Fe-[ICL670]2 for rat, marmoset, rabbit, mouse, dog, and human

Drug Metabolism and Disposition : the Biological Fate of Chemicals
H Markus WeissGerhard Gross

Abstract

Deferasirox (Exjade, ICL670) is an orally active iron chelator. Two molecules of deferasirox can form a complex with ferric iron (Fe-[ICL670]2) that can be excreted, reducing body iron overload. The blood binding parameters across species and the interaction with human serum albumin were analyzed for deferasirox and its iron complex. Both molecules were very highly bound to plasma proteins in all the tested species with unbound fractions in plasma in the range of 0.4 to 1.8% and 0.2 to 1.2% for deferasirox and Fe-[ICL670]2, respectively; binding of the iron complex was either similar or higher in all the species. The high plasma protein binding was in line with a distribution mainly into the plasma fraction of blood; the fraction in plasma was around 100% for Fe-[ICL670]2 in all the species and 65 to 95% for deferasirox depending on the species. Investigations with isolated proteins pointed to serum albumin as the principal binding protein for deferasirox and its iron complex in human plasma. Competition binding experiments indicated that deferasirox at high concentrations displaced markers from the two main drug binding sites of human albumin, whereas Fe-[ICL670]2 displaced only warfarin. In the context of the pharmacokinetic ...Continue Reading

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Citations

Jul 6, 2014·Clinical Pharmacokinetics·Chiaki Tanaka
Jan 19, 2013·The Journal of Antimicrobial Chemotherapy·R A ZanetteJ M Santurio
Jun 19, 2015·Journal of Controlled Release : Official Journal of the Controlled Release Society·Alice GaudinPatrick Couvreur
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Apr 14, 2010·Journal of Controlled Release : Official Journal of the Controlled Release Society·Stephan T SternScott E McNeil
May 21, 2008·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Banu S ZolnikScott E McNeil
Oct 11, 2007·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Ken-ichi KanekoMasaki Otagiri
Sep 9, 2008·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Gerard J M BruinFelix Waldmeier
Mar 7, 2012·Dalton Transactions : an International Journal of Inorganic Chemistry·Tao ZhouRobert C Hider
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Sep 4, 2014·Thrombosis and Haemostasis·Laurens NieuwenhuizenRoger E G Schutgens
Feb 18, 2015·Dalton Transactions : an International Journal of Inorganic Chemistry·Robert C HiderTim Luker

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