Browse views: by Year, by Function, by GLF, by Subfunction, by Conference, by Journal

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

Bruin, Gerardus and Faller, Thomas and Wiegand, Hansjoerg and Schweitzer, Alain and Nick, Hanspeter and Schneider, Josef and 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.

Item Type: Article
Related URLs:
Additional Information: author cannot archive post-print (ie final draft post-refereeing)
Related URLs:
Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15
URI: https://oak.novartis.com/id/eprint/3801

Search

Email Alerts

Register with OAK to receive email alerts for saved searches.