Deferasirox

Absorption

The absolute bioavailability (AUC) of deferasirox tablets for oral suspension is 70% compared to an intravenous dose.

Description

Linagliptin was originally discovered at Boehringer Ingelheim as an orally active dipeptidyl peptidase-IV (DPP-4) inhibitor. Eli Lilly and Boehringer Ingelheim co-developed and launched linagliptin for type II diabetes as an adjunct to diet and exercise for the improvement of adult glycemic control. Linagliptin has a superior DPP-4 IC50 value of 1 nM, compared with 19 nM for sitagliptin, 24 nM for alogliptin, 50 nM for saxagliptin and 62 nM for vildagliptin. In addition, linagliptin exhibited prolonged pharmacodynamic activity with long-lasting DPP-4 inhibition in several preclinical species. Linagliptin showed good efficacy in phase II clinical trials with doses as low as 5 mg and no signs of hypoglycemia with doses as high as 600 mg. The prolonged pharmacological effect of DPP-4 activity and the good safety/tolerability profile provided the basis for linagliptin’s approval.

Chemical properties

White to Off-White Solid

Originator

Novartis (Switzerland)

The Uses of Deferasirox

Deferasirox is an orally active tridentate iron chelator with a very high binding affinity for iron. It is primarily used to reduce chronic iron overload in patients undergoing long-term blood transfusions. It can also be used as an internal standard for the quantification of Deferasirox by gas chromatography or liquid chromatography-mass spectrometry.

What are the applications of Application

Deferasirox is a tridentate chelator that binds iron with high affinity, while having low affinity for zinc and copper.

Background

Deferasirox is an iron chelator and the first oral medication FDA approved for chronic iron overload in patients receiving long term blood transfusions.

Indications

For the treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis) in patients 2 years of age and older.

Definition

ChEBI: A member of the class of triazoles, deferasirox is 1,2,4-triazole substituted by a 4-carboxyphenyl group at position 1 and by 2-hydroxyphenyl groups at positions 3 and 5. An orally active iron chelator, it is used to manage chronic iron overload in patient receiving long-term blood transfusions.

brand name

Exjade (Novartis).

Pharmacokinetics

Deferasirox is an orally active chelator that is selective for iron (as Fe3+). It is a tridentate ligand that binds iron with high affinity in a 2:1 ratio. Although deferasirox has very low affinity for zinc and copper there are variable decreases in the serum concentration of these trace metals after the administration of deferasirox. The clinical significance of these decreases is uncertain.

Clinical Use

Treatment of iron overload

Synthesis

Synthesis of deferasirox started with cyclization of salicylamide (26) with salicyloyl chloride (27) by heating at 170 C without any solvents to give 2-(2-hydroxyphenyl)-benz[e]oxazin-4-one (28) in 55% yield. Compound 28 was reacted with 4-hydrazinobenzoic acid (29) in refluxing ethanol for 2 hours to give deferasirox V as colorless crystals.

Drug interactions

Potentially hazardous interactions with other drugs
Aluminium-containing antacids: avoid concomitant use.
Aminophylline and theophylline: concentration of aminophylline and theophylline increased, consider reducing aminophylline and theophylline dose.
Other nephrotoxic agents: avoid concomitant therapy

Metabolism

Metabolism of deferasirox is mainly glucuronidation by uridine diphosphate glucuronosyltransferase (UGT) enzymes. Cytochrome P450 isoenzyme-mediated metabolism appears to be minor. Deconjugation of the glucuronidates in the intestine and subsequent enterohepatic recycling are likely to occur. It is excreted mainly in the faeces via bile, as metabolites and as unchanged drug. About 8% of a dose is excreted in the urine.

Metabolism

Hepatic. CYP450-catalyzed (oxidative) metabolism of deferasirox appears to be minor in humans (about 8%). Glucuronidation is the main metabolic pathway for deferasirox, with subsequent biliary excretion.

Side Effects

Common side effects of Deferasirox include: diarrhoea, dizziness, earache or ear pain, nausea, stomach pain, voice changes and vomiting. A very small percentage of patients experience blindness, vision or hearing changes, and eye pain or discomfort. Other possible side effects include: black tarry stools, bleeding gums, blood in the urine or faeces, dark urine, decreased urine output, feeling tired or weak all over the body, hives, abrasions, rashes, swelling of the face/eyelids/lips/tongue/throat/hands/legs/feet or genitals, pain in the lower back or flanks, pale skin, reddening of the skin, soreness, itching, ulcers, blisters, stomach pain that persists abnormally Bleeding or bruising, unusual drowsiness, sluggishness, tiredness, vomiting blood or material that looks like coffee grounds, yellowing of the eyes or skin.

References

Heinz et al. (1999), 4-[3,5-Bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid: A Novel Efficient and Selective Iron(III) Complexing Agent; Ang. Chem. Int. Ed., 38 2568 Palumbo et al. (2021), From Biology to Clinical Practice: Iron Chelation Therapy With Deferasirox; Front. Oncol., 11 752192 Roatsch et al. (2019), The Clinically Used Iron Chelator Deferasirox Is an Inhibitor of Epigenetic JumonjiC Domain-Containing Histone Demethylases; ACS Chem. Biol., 14 1737 Lui et al. (2015), Targeting cancer by binding iron: Dissecting cellular signaling pathways; Oncotarget, 6 18748 Ibrahim and O’Sullivan (2020), Iron chelators in cancer therapy; Biometals, 33 201 Szymonik et al. (2021), The Impact of Iron Chelators on the Biology of Cancer Stem Cells; Int. J. Mol. Sci., 23 89