PT - JOURNAL ARTICLE AU - Felix Waldmeier AU - Gerard J. Bruin AU - Ulrike Glaenzel AU - Katharine Hazell AU - Romain Sechaud AU - Steve Warrington AU - John B. Porter TI - Pharmacokinetics, Metabolism, and Disposition of Deferasirox in β-Thalassemic Patients with Transfusion-Dependent Iron Overload Who Are at Pharmacokinetic Steady State AID - 10.1124/dmd.109.030833 DP - 2010 May 01 TA - Drug Metabolism and Disposition PG - 808--816 VI - 38 IP - 5 4099 - http://dmd.aspetjournals.org/content/38/5/808.short 4100 - http://dmd.aspetjournals.org/content/38/5/808.full SO - Drug Metab Dispos2010 May 01; 38 AB - 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 © 2010 by The American Society for Pharmacology and Experimental Therapeutics