Charge States of Deferasirox–Ferric Iron Complexes

Abstract

The study of Rafat et al1Rafat C. Fakhouri F. Ribeil J.A. et al.Fanconi syndrome due to deferasirox.Am J Kidney Dis. 2009; 54: 931-934Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar reports a case of deferasirox-induced Fanconi syndrome in an elderly patient receiving multiple transfusions. In the discussion of this article, the authors refer to the properties of the deferasirox–ferric iron complex. Some of these comments are incorrect. A similar error has been made previously, when Neufeld reported that the iron complex of deferasirox is uncharged.2Neufeld E.J. Oral chelators deferasirox and deferiprone for transfusional iron overload in thalassaemia major: new data, new questions.Blood. 2006; 107: 3436-3441Crossref PubMed Scopus (246) Google Scholar As this error may well have a bearing on chelator-associated kidney toxicity, we thought it appropriate to describe the nature of the iron complexes of the 3 chelators in current clinical practice. We summarize the marked differences in the properties of these chelators in Table 1.Table 1Properties of Iron Chelators in Clinical UseChelatorpFe3+,apFe3+ and pZn2+ values are the –log[M] values at pH 7.4 when [M]Total = 1 μM, [ligand]Total = 10 μM. These values offer the most realistic way of comparing ligand affinities for metal ions at neutral pH values (higher value reflects greater tendency to form metal ion complex).pZn2+,apFe3+ and pZn2+ values are the –log[M] values at pH 7.4 when [M]Total = 1 μM, [ligand]Total = 10 μM. These values offer the most realistic way of comparing ligand affinities for metal ions at neutral pH values (higher value reflects greater tendency to form metal ion complex).Major iron(III) complex at pH 7.4Net charge of minor iron(III) complex at pH 7.4cThese minor complexes will usually not be present at pH 7.4. If they do form, they will not exceed 1 μM.Net chargeMW (Da)Passive transportbRate of penetration of membranes by nonfacilitated diffusion.Deferoxamine26.06.011+614SlowNo minor complexDeferasirox22.59.443−796Very slowZwitterionic (1+ and 1−)Deferiprone19.46.240470Fast1+Abbreviations: M, metal; MW, molecular weight.a pFe3+ and pZn2+ values are the –log[M] values at pH 7.4 when [M]Total = 1 μM, [ligand]Total = 10 μM. These values offer the most realistic way of comparing ligand affinities for metal ions at neutral pH values (higher value reflects greater tendency to form metal ion complex).b Rate of penetration of membranes by nonfacilitated diffusion.c These minor complexes will usually not be present at pH 7.4. If they do form, they will not exceed 1 μM. Open table in a new tab Abbreviations: M, metal; MW, molecular weight. Neither of the 2 iron(III) complexes of deferasirox are noncharged and on this basis, neither are predicted to readily penetrate membranes by nonfacilitative diffusion.3Liu Z.D. Hider R.C. Design of clinically useful iron(III)-selective chelators.Med Res Rev. 2002; 22: 26-64Crossref PubMed Scopus (240) Google Scholar Indeed, in a comparative study of the permeability of Caco-2 cell monolayers to the iron complexes of these 3 chelators, only [(deferiprone)3 · Fe]0 was found to be able to cross the monolayer.4Huang X.P. Spino M. Thiessen J.J. Transport kinetics of iron chelators and their chelates in caco-2 cells.Pharm Res. 2006; 23: 280-290Crossref PubMed Scopus (31) Google Scholar Thus although deferasirox is able to readily enter cells because of its lipophilicity, it forms a highly charged (3−) complex with iron, which one would predict will not readily efflux from cells.5Hider R.C. Zhou T. The design of orally active iron chelators.Ann N Y Acad Sci. 2005; 1054: 141-154Crossref PubMed Scopus (61) Google Scholar We suggest that the triple negative charge of the deferasirox-iron complex is likely to strengthen the authors' scientific rationale in explaining the nephrotoxic potential of deferasirox.1Rafat C. Fakhouri F. Ribeil J.A. et al.Fanconi syndrome due to deferasirox.Am J Kidney Dis. 2009; 54: 931-934Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar It is also possibly relevant that deferasirox binds to zinc, forming polymeric complexes6Heinz U. Hegetschweiler K. Acklin P. et al.4-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl] benzoic acid: a novel efficient and selective iron(III) complexing agent.Angew Chem Int Ed Engl. 1999; 38: 2568-2570Crossref PubMed Scopus (114) Google Scholar, 7Ryabukhin Y.I. Shibaeva N.V. Kuzharov A.S. et al.Synthesis and investigation of complex compounds of transition metals with di(o-hydroxyphenyl)-1,2,4-oxadiazole and its 1,2,4-trazole analogues.Sov J Coord Chem. 1988; 13: 493-499Google Scholar; indeed deferasirox has a markedly larger pZn2+ value than either deferoxamine or deferiprone (Table 1). Financial Disclosure: None. Fanconi Syndrome Due to DeferasiroxAmerican Journal of Kidney DiseasesVol. 54Issue 5PreviewDeferasirox is an innovative iron-chelating treatment. However, preliminary data have suggested that kidney toxicity may be a major issue in the management of patients receiving this drug. We report a case of Fanconi syndrome associated with acute renal insufficiency in a patient receiving deferasirox. The latter has to be added to the expanding list of drugs that may induce Fanconi syndrome. Careful monitoring of kidney function and markers of proximal tubular injury are mandatory in patients undergoing treatment with deferasirox. Full-Text PDF