Description
Sorafenib (rINN), marketed as Nexavar by Bayer, is a drug approved for the treatment of advanced renal cell carcinoma (primary kidney cancer). It has also received 'Fast Track' designation by the FDA for the treatment of advanced hepatocellular carcinoma (primary liver cancer), and has since performed well in Phase III trials. Sorafenib is a small molecular inhibitor of Raf kinase, PDGF (platelet-derived growth factor), VEGF receptor 2 & 3 kinases and c Kit the receptor for Stem cell factor. A growing number of drugs target most of these pathways. The originality of Sorafenib lays in its simultaneous targeting of the Raf/Mek/Erk pathway.
Top Gene Interactions
Related Pathways
General Information
- Metabolism: Sorafenib is metabolized primarily in the liver, undergoing oxidative metabolism, mediated by CYP3A4, as well as glucuronidation mediated by UGT1A9. Sorafenib accounts for approximately 70-85% of the circulating analytes in plasma at steady- state. Eight metabolites of sorafenib have been identified, of which five have been detected in plasma. The main circulating metabolite of sorafenib in plasma, the pyridine N-oxide, shows in vitro potency similar to that of sorafenib. This metabolite comprises approximately 9-16% of circulating analytes at steady-state. Route of Elimination: Following oral administration of a 100 mg dose of a solution formulation of sorafenib, 96% of the dose was recovered within 14 days, with 77% of the dose excreted in feces, and 19% of the dose excreted in urine as glucuronidated metabolites. Half Life: 25-48 hours
- Uses/Sources: Sorafenib is indicated for the treatment of unresectable hepatocellular carcinoma and advanced renal cell carcinoma.
- Health Effects: Hand-foot skin reaction and rash represent the most common adverse reactions; may increase the risk of bleeding (L1712)
- Symptoms: The highest dose of sorafenib studied clinically is 800 mg twice daily. The adverse reactions observed at this dose were primarily diarrhea and dermatologic events. No information is available on symptoms of acute overdose in animals because of the saturation of absorption in oral acute toxicity studies conducted in animals.
- Treatment: There is no specific treatment for NEXAVAR (Sorafenib ) overdose. (L1712)
- Route of Exposure: The mean relative bioavailability is 38-49% for the tablet form, when compared to an oral solution. Sorafenib reached peak plasma levels in 3 hours following oral administration. With a high-fat meal, bioavailability is reduced by 29% compared to administration in the fasted state.
Mechanism of Action
Target Name | Mechanism of Action | References |
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5-hydroxytryptamine receptor 2A 5-hydroxytryptamine receptor 2C 5-hydroxytryptamine receptor 1A 5-hydroxytryptamine receptor 2B 5-hydroxytryptamine receptor 7 5-hydroxytryptamine receptor 6 5-hydroxytryptamine receptor 5A Fibroblast growth factor receptor 1 Vascular endothelial growth factor receptor 1 Proto-oncogene tyrosine-protein kinase receptor Ret Serine/threonine-protein kinase PLK2 |
15466206 16507829 17145705 22694093 18183025 19654408 15711537 17655330 22037378 17016424 |
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Serine/threonine-protein kinase B-raf Receptor-type tyrosine-protein kinase FLT3 RAF proto-oncogene serine/threonine-protein kinase Vascular endothelial growth factor receptor 3 Platelet-derived growth factor receptor beta Mast/stem cell growth factor receptor Kit Vascular endothelial growth factor receptor 2 |
Sorafenib interacts with multiple intracellular (CRAF, BRAF and mutant BRAF) and cell surface kinases (KIT, FLT-3, VEGFR-2, VEGFR-3, and PDGFR-ß). Several of these kinases are thought to be involved in angiogenesis, thus sorafenib reduces blood flow to the tumor. |
15975507 17145705 19754199 18183025 19654408 18077425 15711537 21885287 22037378 |