The Function of Deferasirox in Iron Overload

2018-08-18

Introduction 

Iron chelating agent is a new type of iron-removing treatment based on the combination of directional and in vivo iron ions, effectively improving iron excretion, reducing iron content in the body and pathological deposition in various organs. It is also the only treatment for iron overload. Deferasirox (DFS) is a kind of iron chelating agent, and it is the first routine oral iron-loading agent approved by the US FDA. Its application greatly reduces the mortality of long-term transfusion patients and improves the quality of their lives.

Pharmacologic Action

Many patients, such as thalassemia, iron erythrocyte anemia, and aplastic anemia, need a long-term blood transfusion therapy, resulting in increased iron deposition in the body, causing blood transfusion-related iron overload. DFS is an active chelator for oral administration and is highly selective with iron (Fe3+). It is a ligand structure with three protrusions, which can get high affinity with iron in blood in a ratio of 2:1, thereby reducing the iron content in the blood. This process relieves iron overload and avoids tissue damage and functional damage to multiple organs. However, excessive intake of DFS can cause many side effects, so the dosage should be strictly controlled.

Function

Deferoxamine (DFO) is also a kind of iron chelating agent, which has long clinical application but has many disadvantages compared with DFC. Cardiac iron overload is the leading cause of death in patients with blood transfusion-dependent anemia. A prospective, multicenter study indicates that DFS has a good reduction and protects heart iron accumulation. Another study showed that DFS 10 mg/(kg·d) stabilized intrahepatic iron concentration (LIC), and 20 mg/(kg·d) can reduce the degree of LIC similar to DFO 40 mg/(kg·d). It does not prolong the QT interval, so there is no need to worry about negative effects on the repolarization of the heart during drug use. If administered in parallel with DFO, the chelation clearance of DFS is 4-5 times than that of the latter. In a multicenter, randomized, open phase III trial, DFS-induced adverse effects were milder, more tolerable, and the efficacy of reducing iron load in patients with sickle cell anemia was similar to DFO.

Pharmacokinetics and Metabolism

Due to the persistence of DFS in plasma, DFS and its Fe complex accounted for 87% and 10% of plasma concentrations respectively, mostly excreted in feces (84%), 60% of which were radioactive DFS. Part of the unaltered DFS in the feces is due to incomplete intestinal absorption, in part because the hepatic bile duct excludes DFS and its glucuronide (including first-pass elimination), and the renal excretion is only 8%. The main component is glucuronide M6. The P450 enzyme catalyzes DFS, and the products are M1 (5-OH DFS) (CYP1A) and M4 (5'-OH DFS) (CYP2D6) with a small content of only 6% and 2%. Direct and indirect results indicate that the main metabolic pathway of DFS is glucuronidation which produces metabolites M3 (acyl-gluconate) and M6 (2-O-glucuronide).

References:

1. Dubey AP, Sudha S, Parakh A. Deferasirox: the new oral iron chelator[J]. Indian Pediatr, 2007, 44(8): 603-607.

2. Pennell DJ, Porter JB, Cappellini MD, et al. Efficacy of deferasirox in reducing and preventing cardiac iron overload in beta thalassemia [J]. Blood, 2010, 115(12): 2364-2371.

Sechaud R, Dumortier T, Balez S. Deferasirox does not induce QT/QT c-prolongation in healthy subjects [J]. Int J Clin Pharmacol Ther, 2009, 47(5): 321-327.

3. Waldmeier FJ, Bruin GJ, Glaenzel U, et al. Pharmacokinetics, metabolism and disposition of deferasisirox in beta-thalassemic patients with transfusion-dependent iron overload who are at pharmacokinetic steady state [J]. Drug Metab Dispos, 2010, 38(5): 808-816.

Creative Peptides has accumulated a huge library of peptide knowledge including frontier peptide articles, application of peptides, useful tools, and more!

 KAI-1678, a synthetic 21-amino acid, is a novel PKC-epsilon (ε-PKC) inhibitor with a molecular weight of 2541 Da ...

 Gonadorelin is a synthetic GnRH, a peptide compound, and a decapeptide whose structure is exactly the same as th ...

 P11 (HSDVHK) is a novel peptide ligand containing a PDZ-binding motif (Ser-Asp-Val) with high affinity to integr ...

 The peptide st-Ht31 P, A-kinase anchoring protein (AKAP) inhibitor, has the negative control for st-Ht31. In DRG ...

 Afamelanotide, a drug for tanning skin, is a synthetic peptide and analogue of α-melanocyte stimulating hormone. ...

Contact Us

USA

Address:

Tel: |

Email:

Germany

Address:

Copyright © 2024 Creative Peptides. All rights reserved.