@article {Waldmeier808, author = {Felix Waldmeier and Gerard J. Bruin and Ulrike Glaenzel and Katharine Hazell and Romain Sechaud and Steve Warrington and John B. Porter}, title = {Pharmacokinetics, Metabolism, and Disposition of Deferasirox in β-Thalassemic Patients with Transfusion-Dependent Iron Overload Who Are at Pharmacokinetic Steady State}, volume = {38}, number = {5}, pages = {808--816}, year = {2010}, doi = {10.1124/dmd.109.030833}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Deferasirox (ICL670) is a novel once-daily, orally administered iron chelator to treat chronic iron overload in patients with transfusion-dependent anemias. Absorption, distribution, metabolism, and excretion of [14C]deferasirox at pharmacokinetic steady state was investigated in five adult β-thalassemic patients. Deferasirox (1000 mg) was given orally once daily for 6 days to achieve steady state. On day 7, patients received a single oral 1000-mg dose (\~{}20 mg/kg) of [14C]deferasirox (2.5 MBq). Blood, plasma, feces, and urine samples collected over 7 days were analyzed for radioactivity, deferasirox, its iron complex Fe-[deferasirox]2, and metabolites. Deferasirox was well absorbed. Deferasirox and its iron complex accounted for 87 and 10\%, respectively, of the radioactivity in plasma (area under the curve at steady state). Excretion occurred largely in the feces (84\% of dose), and 60\% of the radioactivity in the feces was identified as deferasirox. Apparently unchanged deferasirox in feces was partly attributable to incomplete intestinal absorption and partly to hepatobiliary elimination of deferasirox (including first-pass elimination) and of its glucuronide. Renal excretion was only 8\% of the dose and included mainly the glucuronide M6. Oxidative metabolism by cytochrome 450 enzymes to M1 [5-hydroxy (OH) deferasirox, presumably by CYP1A] and M4 (5'-OH deferasirox, by CYP2D6) was minor (6 and 2\% of the dose, respectively). Direct and indirect evidence indicates that the main pathway of deferasirox metabolism is via glucuronidation to metabolites M3 (acyl glucuronide) and M6 (2-O-glucuronide). Copyright {\textcopyright} 2010 by The American Society for Pharmacology and Experimental Therapeutics}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/38/5/808}, eprint = {https://dmd.aspetjournals.org/content/38/5/808.full.pdf}, journal = {Drug Metabolism and Disposition} }