Pharmacokinetics, distribution, metabolism, and excretion of deferasirox and its iron complex in rats.
Deferasirox (Exjade, ICL670, CGP72670) is an iron-chelating drug for p.o. treatment of transfusional iron overload in patients with beta-thalassemia or sickle cell disease. The pharmacokinetics and disposition of deferasirox were investigated in rats. The animals received single intravenous (10 mg/kg) or p.o. (10 or 100 mg/kg) doses of 14C-radiolabeled deferasirox. Biological samples were analyzed for radioactivity (liquid scintillation counting, quantitative whole-body autoradioluminography), for deferasirox and its iron complex [high-performance liquid chromatography (HPLC)/UV], and for metabolites (HPLC with radiodetection, liquid chromatography/mass spectrometry, 1H and 13C NMR, and two-dimensional NMR techniques). At least 75% of p.o.-dosed deferasirox was absorbed. The p.o. bioavailability was 26% at the 10 mg/kg dose and showed an overproportional increase at the 100 mg/kg dose, probably because of saturation of elimination processes. Deferasirox-related radioactivity was distributed mainly to blood, excretory organs, and gastrointestinal 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 multidrug resistance protein 2. Deferasirox, iron complex, and metabolites were excreted largely via bile and feces (total > or = 90%). Metabolism included glucuronidation at the carboxylate group (acyl glucuronide M3) and at phenolic hydroxy groups, as well as, to a lower degree, cytochrome P450-catalyzed hydroxylations. Two hydroxylated metabolites (M1 and M2) were administered to rats and were shown not to contribute substantially to iron elimination in vivo.
Bruin
Gerard J M
GJ
Novartis Pharma AG, Drug Metabolism and Pharmacokinetics, Novartis Campus, Basel, Switzerland.
Faller
Thomas
T
Wiegand
Hansjörg
H
Schweitzer
Alain
A
Nick
Hanspeter
H
Schneider
Josef
J
Boernsen
K-Olaf
KO
Waldmeier
Felix
F
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000833:Animals, Suckling / Q000378:metabolism; D001565:Benzoates / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*; D001646:Bile / Q000737:chemistry; D001774:Blood Chemical Analysis; D000077588:Deferasirox; D004764:Enterohepatic Circulation; D005243:Feces / Q000737:chemistry; D005260:Female; D005333:Fetus / Q000378:metabolism; D007501:Iron / Q000032:analysis / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008895:Milk, Human / Q000737:chemistry / Q000378:metabolism; D008954:Models, Biological; D015394:Molecular Structure; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D020318:Rats, Long-Evans; D055647:Rats, Transgenic; D017208:Rats, Wistar; D014018:Tissue Distribution; D014230:Triazoles / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*; D014556:Urine / Q000737:chemistry
D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D001565:Benzoates; D007502:Iron Chelating Agents; D014230:Triazoles; D007501:Iron; D000077588:Deferasirox