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:
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