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Research ArticleArticle

Pharmacokinetics, Distribution, Metabolism, and Excretion of Deferasirox and Its Iron Complex in Rats

Gerard J. M. Bruin, Thomas Faller, Hansjörg Wiegand, Alain Schweitzer, Hanspeter Nick, Josef Schneider, K.-Olaf Boernsen and Felix Waldmeier
Drug Metabolism and Disposition December 2008, 36 (12) 2523-2538; DOI: https://doi.org/10.1124/dmd.108.022962
Gerard J. M. Bruin
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Thomas Faller
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Hansjörg Wiegand
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Alain Schweitzer
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Hanspeter Nick
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Josef Schneider
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K.-Olaf Boernsen
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Felix Waldmeier
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Abstract

Deferasirox (Exjade, ICL670, CGP72670) is an iron-chelating drug for p.o. treatment of transfusional iron overload in patients with β-thalassemia or sickle cell disease. The pharmacokinetics and disposition of deferasirox were investigated in rats. The animals received single intravenous (10 mg/kg) or p.o. (10 or 100 mg/kg) doses of 14C-radiolabeled deferasirox. Biological samples were analyzed for radioactivity (liquid scintillation counting, quantitative whole-body autoradioluminography), for deferasirox and its iron complex [high-performance liquid chromatography (HPLC)/UV], and for metabolites (HPLC with radiodetection, liquid chromatography/mass spectrometry, 1H and 13C NMR, and two-dimensional NMR techniques). At least 75% of p.o.-dosed deferasirox was absorbed. The p.o. bioavailability was 26% at the 10 mg/kg dose and showed an overproportional increase at the 100 mg/kg dose, probably because of saturation of elimination processes. Deferasirox-related radioactivity was distributed mainly to blood, excretory organs, and gastrointestinal tract. Enterohepatic recirculation of deferasirox was observed. No retention occurred in any tissue. The placental barrier was passed to a low extent. Approximately 3% of the dose was transferred into the breast milk. Excretion of deferasirox and metabolites was rapid and complete within 7 days. Key clearance processes were hepatic metabolism and biliary elimination via multidrug resistance protein 2. Deferasirox, iron complex, and metabolites were excreted largely via bile and feces (total ≥90%). Metabolism included glucuronidation at the carboxylate group (acyl glucuronide M3) and at phenolic hydroxy groups, as well as, to a lower degree, cytochrome P450-catalyzed hydroxylations. Two hydroxylated metabolites (M1 and M2) were administered to rats and were shown not to contribute substantially to iron elimination in vivo.

Footnotes

  • This study was supported by Novartis Pharma AG, Basel, Switzerland.

  • Parts of this work were previously presented as follows: Bruin GJ, Schneider J, Glaenzel U, Oberer L, and Waldmeier F (2003) The structure elucidation of metabolites of ICL670. A new drug in the treatment of iron overload. 51st American Society of Mass Spectrometry and Allied Topics Meeting; 2003 June 8–12; Montreal, Canada. American Society for Mass Spectrometry, Santa Fe, NM.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.108.022962.

  • ABBREVIATIONS: DFO, deferoxamine; Mrp2, multidrug resistance protein 2; ADME, absorption, distribution, metabolism, and excretion; LSC, liquid scintillation counting; QWBAL, quantitative whole-body autoradioluminography; LOD, limit of detection; LOQ, limit of quantification; HPLC, high-performance liquid chromatography; MS/MS, tandem mass spectrometry; LC, liquid chromatography; DMSO, dimethyl sulfoxide; COSY, correlation spectroscopy; AUC, area under the plasma concentration-time curve; HMBC, heteronuclear multiple bond correlation; ICL670, deferasirox.

  • ↵1 Current affiliation: Hoffmann-LaRoche, Basel, Switzerland.

    • Received June 18, 2008.
    • Accepted September 4, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 36 (12)
Drug Metabolism and Disposition
Vol. 36, Issue 12
1 Dec 2008
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Research ArticleArticle

Pharmacokinetics, Distribution, Metabolism, and Excretion of Deferasirox and Its Iron Complex in Rats

Gerard J. M. Bruin, Thomas Faller, Hansjörg Wiegand, Alain Schweitzer, Hanspeter Nick, Josef Schneider, K.-Olaf Boernsen and Felix Waldmeier
Drug Metabolism and Disposition December 1, 2008, 36 (12) 2523-2538; DOI: https://doi.org/10.1124/dmd.108.022962

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Research ArticleArticle

Pharmacokinetics, Distribution, Metabolism, and Excretion of Deferasirox and Its Iron Complex in Rats

Gerard J. M. Bruin, Thomas Faller, Hansjörg Wiegand, Alain Schweitzer, Hanspeter Nick, Josef Schneider, K.-Olaf Boernsen and Felix Waldmeier
Drug Metabolism and Disposition December 1, 2008, 36 (12) 2523-2538; DOI: https://doi.org/10.1124/dmd.108.022962
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