Pharmacokinetics, metabolism, and disposition of deferasirox in beta-thalassemic patients with transfusion-dependent iron overload who are at pharmacokinetic steady state.
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 beta-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 (approximately 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).
Waldmeier
Felix
F
Novartis Institutes for BioMedical Research-Drug Metabolism and Pharmacokinetics, Novartis Campus, WSJ-210.4.20, Postfach, CH-4056 Basel, Switzerland. felix.waldmeier@novartis.com
Bruin
Gerard J
GJ
Glaenzel
Ulrike
U
Hazell
Katharine
K
Sechaud
Romain
R
Warrington
Steve
S
Porter
John B
JB
D000328:Adult; D000818:Animals; D019540:Area Under Curve; D001192:Arylsulfatases / Q000378:metabolism; D001565:Benzoates / Q000009:adverse effects / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002478:Cells, Cultured; D000077588:Deferasirox; D005243:Feces / Q000737:chemistry; D005260:Female; D005966:Glucuronidase / Q000378:metabolism; D020719:Glucuronides / Q000032:analysis / Q000378:metabolism; D022781:Hepatocytes / Q000201:enzymology; D006801:Humans; D006900:Hydroxylation; D007502:Iron Chelating Agents / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D019190:Iron Overload / Q000188:drug therapy*; D008297:Male; D015394:Molecular Structure; D051381:Rats; D021241:Spectrometry, Mass, Electrospray Ionization; D013463:Sulfuric Acid Esters / Q000032:analysis / Q000378:metabolism; D065227:Transfusion Reaction; D014230:Triazoles / Q000009:adverse effects / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D055815:Young Adult; D017086:beta-Thalassemia / Q000628:therapy*
D001565:Benzoates; D020719:Glucuronides; D007502:Iron Chelating Agents; D013463:Sulfuric Acid Esters; D014230:Triazoles; D001192:Arylsulfatases; D005966:Glucuronidase; D000077588:Deferasirox