Pharmacokinetics, Distribution, Metabolism, and Excretion of Deferasirox and its Iron Complex in Rats
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Bruin, Gerardus, Faller, Thomas, Wiegand, Hansjoerg, Schweitzer, Alain, Nick, Hanspeter, Schneider, Josef, Boernsen, K. Olaf and Waldmeier, Felix (2008) Pharmacokinetics, Distribution, Metabolism, and Excretion of Deferasirox and its Iron Complex in Rats. Drug Metabolism and Disposition, 36 (12). pp. 2523-2538. ISSN 1521-009X
Abstract
Deferasirox (Exjade®, ICL670, CGP72670) is an iron-chelating drug for oral treatment of transfusional iron-overload in patients suffering from 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 oral (10 or 100 mg/kg) doses of 14C radio¬labeled deferasirox. Biological samples were analysed for radioactivity (LSC, QWBAL), for deferasirox and its iron complex (HPLC-UV), and for metabolites (HPLC with radiodetection, LC-MS, 1H- and 13C-NMR, and 2-dimensional NMR techniques). At least 75% of orally dosed deferasirox was absorbed. The oral bioavailability was 26% at 10 mg/kg dose, and showed an over-proportional increase at the 100 mg/kg dose, probably due to saturation of elimination processes. Deferasirox-related radioactivity was distributed mainly to blood, excretory organs and GI-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 Mrp2. Deferasirox, iron complex and metabolites were excreted largely via bile and feces (total ≥90%). Metabolism included glucuro¬ni¬da¬tion at the carboxylate group (acyl glucuronide M3) and at phenolic hydroxy groups, as well as, to a lower degree, CYP-catalysed hydroxylations. Two hydroxylated metabolites (M1, M2) were administered to rats and were shown not to contribute substantially to iron elimination in vivo.
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| Additional Information: | author cannot archive post-print (ie final draft post-refereeing) |
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| Date Deposited: | 13 Oct 2015 13:15 |
| Last Modified: | 13 Oct 2015 13:15 |
| URI: | https://oak.novartis.com/id/eprint/3801 |