Identification

Summary

Sorafenib is a kinase inhibitor used to treat unresectable liver carcinoma, advanced renal carcinoma, and differentiated thyroid carcinoma.

Brand Names
Nexavar
Generic Name
Sorafenib
DrugBank Accession Number
DB00398
Background

Sorafenib is a bi-aryl urea and an oral multikinase inhibitor. It targets cell surface tyrosine kinase receptors and downstream intracellular kinases that are implicated in tumour cell proliferation and tumour angiogenesis.1 First approved by the FDA and European Commission in 2007 for the treatment of hepatocellular carcinoma, sorafenib is also indicated to treat renal carcinoma and differentiated thyroid carcinoma.3

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 464.825
Monoisotopic: 464.08630272
Chemical Formula
C21H16ClF3N4O3
Synonyms
  • 4-(4-((((4-Chloro-3-(trifluoromethyl)phenyl)amino)carbonyl)amino)phenoxy)-N-methyl-2-pyridinecarboxamide
  • N-(4-Chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea
  • Sorafenib
  • Sorafénib
  • Sorafenibum
External IDs
  • BAY 43-9006
  • BAY-43-9006

Pharmacology

Indication

Sorafenib is indicated for the treatment of unresectable hepatocellular carcinoma and advanced renal cell carcinoma.5,6

In the US, it is also indicated for the treatment of patients with locally recurrent or metastatic, progressive, differentiated thyroid carcinoma that is refractory to radioactive iodine treatment.5

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Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Sorafenib decreases tumour cell proliferation in vitro. It attenuated tumour growth of human tumour xenografts in immunocompromised mice, reduced tumour angiogenesis, and increased tumour apoptosis in models of hepatocellular carcinoma, renal cell carcinoma, and differentiated thyroid carcinoma.1,5 Some studies suggest that sorafenib induces apoptosis in several tumour cell lines, although this effect is inconsistent across cell lines.1 Antiviral effects of sorafenib have been documented, as it was shown to inhibit hepatitis C viral replication in vitro.1

Mechanism of action

Kinases are involved in tumour cell signalling, proliferation, angiogenesis, and apoptosis.3,5 Sorafenib inhibits multiple intracellular serine/threonine kinases in the Ras/mitogen-activated protein kinase (MAPK) signal transduction pathway. Intracellular Raf serine/threonine kinase isoforms inhibited by sorafenib include Raf-1 (or C-Raf), wild-type B-Raf, and mutant B-Raf. Sorafenib inhibits cell surface tyrosine kinase receptors such as KIT, FMS-like tyrosine kinase 3 (FLT-3), RET, RET/PTC, vascular endothelial growth factor receptor-1 (VEGFR-1), VEGFR-2, VEGFR-3, and platelet-derived growth factor receptor-β (PDGFR-β).1,2,3,5

Sorafenib is thought to exhibit a dual mechanism of action: it blocks tumour proliferation and growth by inhibiting the RAF/MEK/extracellular signal-regulated kinase (ERK) pathway on tumour cells, and reduces tumour angiogenesis by inhibiting VEGFR and PDGFR signalling in tumour vasculature.1,4

TargetActionsOrganism
ASerine/threonine-protein kinase B-raf
inhibitor
Humans
ARAF proto-oncogene serine/threonine-protein kinase
inhibitor
Humans
AVascular endothelial growth factor receptor 3
inhibitor
Humans
AVascular endothelial growth factor receptor 2
inhibitor
Humans
AVascular endothelial growth factor receptor 1
inhibitor
Humans
AReceptor-type tyrosine-protein kinase FLT3
inhibitor
Humans
APlatelet-derived growth factor receptor beta
inhibitor
Humans
AMast/stem cell growth factor receptor Kit
antagonist
Humans
AFibroblast growth factor receptor 1
inhibitor
Humans
AProto-oncogene tyrosine-protein kinase receptor Ret
inhibitor
Humans
Absorption

The administration of multiple doses for seven days resulted in a 2.5- to 7-fold accumulation compared to a single dose. Steady-state concentrations were achieved within seven days, with a peak-to-trough ratio of mean concentrations of less than 2. Mean Cmax and AUC increased less than proportionally beyond oral doses of 400 mg administered twice daily. The Tmax is approximately three hours.5

The mean relative bioavailability was 38–49% following the administration of oral sorafenib tablets. A high-fat meal reduced bioavailability by 29%.5

Volume of distribution

Sorafenib is widely distributed to tissues, indicating that it is lipophilic.1

Protein binding

In vitro, sorafenib is 99.5% bound to human plasma proteins.5

Metabolism

Sorafenib undergoes oxidative metabolism by CYP3A4 in the liver, as well as glucuronidation by UGT1A9 in the liver and kidneys.1,5 At steady-state, sorafenib accounts for 70-85% of the circulating analytes in plasma.1 About eight metabolites of sorafenib have been identified, of which five were detected in plasma. The main circulating metabolite was the pyridine N-oxide form, which comprises approximately 9–16% of the total circulating dose at steady-state: the pharmacological activity of this metabolite was comparable to the parent drug.5

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Route of elimination

Following oral administration of a 100 mg dose of sorafenib, about 96% of the dose was recovered within 14 days, with 77% of the dose being excreted in feces and 19% of the dose being excreted in urine as glucuronidated metabolites. Unchanged sorafenib accounted for 51% of the dose excreted in feces.5

Half-life

The mean elimination half-life of sorafenib was approximately 25 to 48 hours.5

Clearance

Not Available

Adverse Effects
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Toxicity

The oral lowest published toxic dose (Toxic Dose Low, TDLo) is 2.84 mg/kg/21D (intermittent).7 The oral LD50 of sorafenib tosylate in rats is >2000 mg/kg.8

The adverse reactions observed at 800 mg sorafenib twice daily (twice the recommended dose) were primarily diarrhea and dermatologic. 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. The prescribing information recommends the discontinuation of sorafenib treatment and initiation of supportive care in cases of suspected overdose.5

Pathways
PathwayCategory
Sorafenib Metabolism PathwayDrug metabolism
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbacavirThe metabolism of Abacavir can be decreased when combined with Sorafenib.
AbametapirThe serum concentration of Sorafenib can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Sorafenib can be increased when combined with Abatacept.
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Sorafenib.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Sorafenib.
AbirateroneThe serum concentration of Sorafenib can be increased when it is combined with Abiraterone.
AcalabrutinibThe metabolism of Sorafenib can be decreased when combined with Acalabrutinib.
AceclofenacAceclofenac may decrease the excretion rate of Sorafenib which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Sorafenib which could result in a higher serum level.
AcenocoumarolThe risk or severity of bleeding can be increased when Sorafenib is combined with Acenocoumarol.
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Food Interactions
  • Do not take with or immediately after a high-fat meal. Take sorafenib at least 1 hour before or 2 hours after a high-fat meal, as sorafenib absorption can be reduced by a high-fat meal.
  • Exercise caution with grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum levels of sorafenib.
  • Exercise caution with St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce serum levels of sorafenib.
  • Take on an empty stomach. Take sorafenib at least one hour before or two hours after a meal.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Sorafenib tosylate5T62Q3B36J475207-59-1IVDHYUQIDRJSTI-UHFFFAOYSA-N
Product Images
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
NexavarTablet, film coated200 mg/1OralBayer Pharmaceuticals Corporartion2007-02-232007-02-23US flag
NexavarTablet200 mgOralBayer2006-07-31Not applicableCanada flag
NexavarTablet, film coated200 mg/1OralBayer HealthCare Pharmaceuticals Inc.2005-12-20Not applicableUS flag
NexavarTablet, film coated200 mgOralBayer Ag2016-09-08Not applicableEU flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Apo-sorafenibTablet200 mgOralApotex CorporationNot applicableNot applicableCanada flag
SorafenibTablet, film coated200 mg/1OralTeva Pharmaceuticals, Inc.2023-01-03Not applicableUS flag
SorafenibTablet, film coated200 mg/1OralDr.Reddys Laboratories Inc2022-06-08Not applicableUS flag
SorafenibTablet, film coated200 mg/1OralTwi Pharmaceuticals Usa, Inc.2022-12-01Not applicableUS flag
SorafenibTablet, film coated200 mg/1OralYabao Pharmaceutical Co., Ltd. Beijing2021-12-31Not applicableUS flag
Sorafenib TosylateTablet, film coated200 mg/1OralMylan Pharmaceuticals Inc.2022-06-01Not applicableUS flag

Categories

ATC Codes
L01EX02 — Sorafenib
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as diarylethers. These are organic compounds containing the dialkyl ether functional group, with the formula ROR', where R and R' are aryl groups.
Kingdom
Organic compounds
Super Class
Organic oxygen compounds
Class
Organooxygen compounds
Sub Class
Ethers
Direct Parent
Diarylethers
Alternative Parents
Trifluoromethylbenzenes / N-phenylureas / Pyridinecarboxamides / 2-heteroaryl carboxamides / Phenoxy compounds / Phenol ethers / Chlorobenzenes / Aryl chlorides / Heteroaromatic compounds / Secondary carboxylic acid amides
show 10 more
Substituents
2-heteroaryl carboxamide / Alkyl fluoride / Alkyl halide / Aromatic heteromonocyclic compound / Aryl chloride / Aryl halide / Azacycle / Benzenoid / Carbonic acid derivative / Carbonyl group
show 25 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
aromatic ether, ureas, monochlorobenzenes, (trifluoromethyl)benzenes, pyridinecarboxamide (CHEBI:50924)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
9ZOQ3TZI87
CAS number
284461-73-0
InChI Key
MLDQJTXFUGDVEO-UHFFFAOYSA-N
InChI
InChI=1S/C21H16ClF3N4O3/c1-26-19(30)18-11-15(8-9-27-18)32-14-5-2-12(3-6-14)28-20(31)29-13-4-7-17(22)16(10-13)21(23,24)25/h2-11H,1H3,(H,26,30)(H2,28,29,31)
IUPAC Name
4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)phenoxy]-N-methylpyridine-2-carboxamide
SMILES
CNC(=O)C1=NC=CC(OC2=CC=C(NC(=O)NC3=CC(=C(Cl)C=C3)C(F)(F)F)C=C2)=C1

References

Synthesis Reference

Ales Gavenda, Alexandr Jegorov, Pierluigi Rossetto, Peter Lindsay MacDonald, Augusto Canavesi, "POLYMORPHS OF SORAFENIB TOSYLATE AND SORAFENIB HEMI-TOSYLATE, AND PROCESSES FOR PREPARATION THEREOF." U.S. Patent US20090192200, issued July 30, 2009.

US20090192200
General References
  1. Iyer R, Fetterly G, Lugade A, Thanavala Y: Sorafenib: a clinical and pharmacologic review. Expert Opin Pharmacother. 2010 Aug;11(11):1943-55. doi: 10.1517/14656566.2010.496453. [Article]
  2. Keating GM: Sorafenib: A Review in Hepatocellular Carcinoma. Target Oncol. 2017 Apr;12(2):243-253. doi: 10.1007/s11523-017-0484-7. [Article]
  3. Keating GM, Santoro A: Sorafenib: a review of its use in advanced hepatocellular carcinoma. Drugs. 2009;69(2):223-40. doi: 10.2165/00003495-200969020-00006. [Article]
  4. Adnane L, Trail PA, Taylor I, Wilhelm SM: Sorafenib (BAY 43-9006, Nexavar), a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature. Methods Enzymol. 2006;407:597-612. [Article]
  5. FDA Approved Drug Products: NEXAVAR (sorafenib) tablets, for oral use [Link]
  6. EMA Approved Drug Products: Sorafenib Accord Oral Tablets [Link]
  7. Cayman Chemical: Sorafenib MSDS [Link]
  8. CymitQuimica: Sorafenib Tosylate MSDS [Link]
Human Metabolome Database
HMDB0014542
KEGG Drug
D08524
PubChem Compound
216239
PubChem Substance
46505329
ChemSpider
187440
BindingDB
16673
RxNav
495881
ChEBI
50924
ChEMBL
CHEMBL1336
ZINC
ZINC000001493878
Therapeutic Targets Database
DAP000006
PharmGKB
PA7000
PDBe Ligand
BAX
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Sorafenib
PDB Entries
1uwh / 1uwj / 3gcs / 3heg / 3rgf / 3wze / 4asd / 5hi2

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingTreatmentHepatocellular Carcinoma1
4CompletedTreatmentHepatectomy / Hepatocellular Carcinoma / Sorafenib1
4CompletedTreatmentHepatocellular Carcinoma3
4Enrolling by InvitationTreatmentHepatocellular Carcinoma / Portal Vein Tumor Thrombus1
4RecruitingBasic ScienceHepatocellular Carcinoma1
4TerminatedTreatmentLiver Cancer1
4TerminatedTreatmentRenal Cell Carcinoma1
4Unknown StatusPreventionPortal Vein Tumor Thrombus1
4Unknown StatusTreatmentHepatocellular Carcinoma1
4Unknown StatusTreatmentHepatocellular Carcinoma / Metastatic Cancer1

Pharmacoeconomics

Manufacturers
  • Bayer healthcare pharmaceuticals inc
Packagers
  • Bayer Healthcare
Dosage Forms
FormRouteStrength
TabletOral200 mg
Tablet, coatedOral200 mg
Tablet, film coatedOral200 mg/1
Tablet, film coatedOral274 mg
Tablet, film coatedOral
Tablet, film coatedOral200 MG
Prices
Unit descriptionCostUnit
Nexavar 200 mg tablet66.61USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
CA2315715No2010-06-222018-12-22Canada flag
CA2359510No2007-02-132020-01-12Canada flag
US8618141No2013-12-312023-02-11US flag
US8877933No2014-11-042027-12-24US flag
US8124630No2012-02-282020-01-12US flag
US8841330No2014-09-232020-01-12US flag
US7235576No2007-06-262020-01-12US flag
US7897623No2011-03-012020-01-12US flag
US7351834No2008-04-012020-01-12US flag
US9737488No2017-08-222028-09-10US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)187-226https://static.cymitquimica.com/products/45/pdf/sds-1615876.pdf
water solubility< 0.01 g/Lhttps://static.cymitquimica.com/products/45/pdf/sds-1615876.pdf
Predicted Properties
PropertyValueSource
Water Solubility0.00171 mg/mLALOGPS
logP4.12ALOGPS
logP4.34Chemaxon
logS-5.4ALOGPS
pKa (Strongest Acidic)11.55Chemaxon
pKa (Strongest Basic)3.03Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count3Chemaxon
Hydrogen Donor Count3Chemaxon
Polar Surface Area92.35 Å2Chemaxon
Rotatable Bond Count6Chemaxon
Refractivity114.52 m3·mol-1Chemaxon
Polarizability41.33 Å3Chemaxon
Number of Rings3Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9649
Blood Brain Barrier+0.851
Caco-2 permeable-0.5138
P-glycoprotein substrateNon-substrate0.5086
P-glycoprotein inhibitor INon-inhibitor0.7141
P-glycoprotein inhibitor IINon-inhibitor0.9359
Renal organic cation transporterNon-inhibitor0.8938
CYP450 2C9 substrateNon-substrate0.6569
CYP450 2D6 substrateNon-substrate0.8212
CYP450 3A4 substrateNon-substrate0.5341
CYP450 1A2 substrateInhibitor0.6168
CYP450 2C9 inhibitorNon-inhibitor0.6171
CYP450 2D6 inhibitorNon-inhibitor0.9145
CYP450 2C19 inhibitorInhibitor0.637
CYP450 3A4 inhibitorNon-inhibitor0.7339
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.6629
Ames testNon AMES toxic0.8143
CarcinogenicityNon-carcinogens0.8684
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.7885 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9488
hERG inhibition (predictor II)Non-inhibitor0.6415
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

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insights and accelerate drug research.
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
Curator comments
It binds to Ras/Raf with an IC50 40 ng/mL.
General Function
Protein serine/threonine kinase activity
Specific Function
Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus. May play a role in the postsynaptic responses of hippocampal neuron. Phosphorylates MAP2K1, a...
Gene Name
BRAF
Uniprot ID
P15056
Uniprot Name
Serine/threonine-protein kinase B-raf
Molecular Weight
84436.135 Da
References
  1. Flaherty KT: Chemotherapy and targeted therapy combinations in advanced melanoma. Clin Cancer Res. 2006 Apr 1;12(7 Pt 2):2366s-2370s. [Article]
  2. Haluska FG, Ibrahim N: Therapeutic targets in melanoma: map kinase pathway. Curr Oncol Rep. 2006 Sep;8(5):400-5. [Article]
  3. Kim S, Yazici YD, Calzada G, Wang ZY, Younes MN, Jasser SA, El-Naggar AK, Myers JN: Sorafenib inhibits the angiogenesis and growth of orthotopic anaplastic thyroid carcinoma xenografts in nude mice. Mol Cancer Ther. 2007 Jun;6(6):1785-92. [Article]
  4. Eisen T, Ahmad T, Flaherty KT, Gore M, Kaye S, Marais R, Gibbens I, Hackett S, James M, Schuchter LM, Nathanson KL, Xia C, Simantov R, Schwartz B, Poulin-Costello M, O'Dwyer PJ, Ratain MJ: Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis. Br J Cancer. 2006 Sep 4;95(5):581-6. Epub 2006 Aug 1. [Article]
  5. Lu X, Tang X, Guo W, Ren T, Zhao H: Sorafenib induces growth inhibition and apoptosis of human chondrosarcoma cells by blocking the RAF/ERK/MEK pathway. J Surg Oncol. 2010 Dec 1;102(7):821-6. doi: 10.1002/jso.21661. [Article]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
  7. Iyer R, Fetterly G, Lugade A, Thanavala Y: Sorafenib: a clinical and pharmacologic review. Expert Opin Pharmacother. 2010 Aug;11(11):1943-55. doi: 10.1517/14656566.2010.496453. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Protein serine/threonine kinase activity
Specific Function
Serine/threonine-protein kinase that acts as a regulatory link between the membrane-associated Ras GTPases and the MAPK/ERK cascade, and this critical regulatory link functions as a switch determin...
Gene Name
RAF1
Uniprot ID
P04049
Uniprot Name
RAF proto-oncogene serine/threonine-protein kinase
Molecular Weight
73051.025 Da
References
  1. Adnane L, Trail PA, Taylor I, Wilhelm SM: Sorafenib (BAY 43-9006, Nexavar), a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature. Methods Enzymol. 2006;407:597-612. [Article]
  2. Gollob JA, Wilhelm S, Carter C, Kelley SL: Role of Raf kinase in cancer: therapeutic potential of targeting the Raf/MEK/ERK signal transduction pathway. Semin Oncol. 2006 Aug;33(4):392-406. [Article]
  3. Huether A, Hopfner M, Baradari V, Schuppan D, Scherubl H: Sorafenib alone or as combination therapy for growth control of cholangiocarcinoma. Biochem Pharmacol. 2007 May 1;73(9):1308-17. Epub 2007 Jan 5. [Article]
  4. Cascone T, Gridelli C, Ciardiello F: Combined targeted therapies in non-small cell lung cancer: a winner strategy? Curr Opin Oncol. 2007 Mar;19(2):98-102. [Article]
  5. Gridelli C, Maione P, Del Gaizo F, Colantuoni G, Guerriero C, Ferrara C, Nicolella D, Comunale D, De Vita A, Rossi A: Sorafenib and sunitinib in the treatment of advanced non-small cell lung cancer. Oncologist. 2007 Feb;12(2):191-200. [Article]
  6. Lu X, Tang X, Guo W, Ren T, Zhao H: Sorafenib induces growth inhibition and apoptosis of human chondrosarcoma cells by blocking the RAF/ERK/MEK pathway. J Surg Oncol. 2010 Dec 1;102(7):821-6. doi: 10.1002/jso.21661. [Article]
  7. Smalley KS, Xiao M, Villanueva J, Nguyen TK, Flaherty KT, Letrero R, Van Belle P, Elder DE, Wang Y, Nathanson KL, Herlyn M: CRAF inhibition induces apoptosis in melanoma cells with non-V600E BRAF mutations. Oncogene. 2009 Jan 8;28(1):85-94. doi: 10.1038/onc.2008.362. Epub 2008 Sep 15. [Article]
  8. Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M: Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther. 2008 Oct;7(10):3129-40. doi: 10.1158/1535-7163.MCT-08-0013. [Article]
  9. Iyer R, Fetterly G, Lugade A, Thanavala Y: Sorafenib: a clinical and pharmacologic review. Expert Opin Pharmacother. 2010 Aug;11(11):1943-55. doi: 10.1517/14656566.2010.496453. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Vascular endothelial growth factor-activated receptor activity
Specific Function
Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFC and VEGFD, and plays an essential role in adult lymphangiogenesis and in the development of the vascular network and the cardi...
Gene Name
FLT4
Uniprot ID
P35916
Uniprot Name
Vascular endothelial growth factor receptor 3
Molecular Weight
152755.94 Da
References
  1. Lathia C, Lettieri J, Cihon F, Gallentine M, Radtke M, Sundaresan P: Lack of effect of ketoconazole-mediated CYP3A inhibition on sorafenib clinical pharmacokinetics. Cancer Chemother Pharmacol. 2006 May;57(5):685-92. Epub 2005 Aug 25. [Article]
  2. Adnane L, Trail PA, Taylor I, Wilhelm SM: Sorafenib (BAY 43-9006, Nexavar), a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature. Methods Enzymol. 2006;407:597-612. [Article]
  3. Gridelli C, Maione P, Del Gaizo F, Colantuoni G, Guerriero C, Ferrara C, Nicolella D, Comunale D, De Vita A, Rossi A: Sorafenib and sunitinib in the treatment of advanced non-small cell lung cancer. Oncologist. 2007 Feb;12(2):191-200. [Article]
  4. Strumberg D: Preclinical and clinical development of the oral multikinase inhibitor sorafenib in cancer treatment. Drugs Today (Barc). 2005 Dec;41(12):773-84. [Article]
  5. Reddy GK, Bukowski RM: Sorafenib: recent update on activity as a single agent and in combination with interferon-alpha2 in patients with advanced-stage renal cell carcinoma. Clin Genitourin Cancer. 2006 Mar;4(4):246-8. [Article]
  6. Iyer R, Fetterly G, Lugade A, Thanavala Y: Sorafenib: a clinical and pharmacologic review. Expert Opin Pharmacother. 2010 Aug;11(11):1943-55. doi: 10.1517/14656566.2010.496453. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
Curator comments
It binds to VEGFR-2 with an IC50 of 570 ng/mL.
General Function
Vascular endothelial growth factor-activated receptor activity
Specific Function
Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFC and VEGFD. Plays an essential role in the regulation of angiogenesis, vascular development, vascular permeability, and ...
Gene Name
KDR
Uniprot ID
P35968
Uniprot Name
Vascular endothelial growth factor receptor 2
Molecular Weight
151525.555 Da
References
  1. Schoffski P, Dumez H, Clement P, Hoeben A, Prenen H, Wolter P, Joniau S, Roskams T, Van Poppel H: Emerging role of tyrosine kinase inhibitors in the treatment of advanced renal cell cancer: a review. Ann Oncol. 2006 Aug;17(8):1185-96. Epub 2006 Jan 17. [Article]
  2. Veronese ML, Mosenkis A, Flaherty KT, Gallagher M, Stevenson JP, Townsend RR, O'Dwyer PJ: Mechanisms of hypertension associated with BAY 43-9006. J Clin Oncol. 2006 Mar 20;24(9):1363-9. Epub 2006 Jan 30. [Article]
  3. Rini BI: Sorafenib. Expert Opin Pharmacother. 2006 Mar;7(4):453-61. [Article]
  4. Adnane L, Trail PA, Taylor I, Wilhelm SM: Sorafenib (BAY 43-9006, Nexavar), a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature. Methods Enzymol. 2006;407:597-612. [Article]
  5. Lacouture ME, Desai A, Soltani K, Petronic-Rosic V, Laumann AE, Ratain MJ, Stadler WM: Inflammation of actinic keratoses subsequent to therapy with sorafenib, a multitargeted tyrosine-kinase inhibitor. Clin Exp Dermatol. 2006 Nov;31(6):783-5. Epub 2006 Jul 4. [Article]
  6. Iyer R, Fetterly G, Lugade A, Thanavala Y: Sorafenib: a clinical and pharmacologic review. Expert Opin Pharmacother. 2010 Aug;11(11):1943-55. doi: 10.1517/14656566.2010.496453. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
Curator comments
It binds to VEGFR-1 with an IC50 of 165 ng/mL.
General Function
Vegf-b-activated receptor activity
Specific Function
Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFB and PGF, and plays an essential role in the development of embryonic vasculature, the regulation of angiogenesis, cell ...
Gene Name
FLT1
Uniprot ID
P17948
Uniprot Name
Vascular endothelial growth factor receptor 1
Molecular Weight
150767.185 Da
References
  1. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, Cao Y, Shujath J, Gawlak S, Eveleigh D, Rowley B, Liu L, Adnane L, Lynch M, Auclair D, Taylor I, Gedrich R, Voznesensky A, Riedl B, Post LE, Bollag G, Trail PA: BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004 Oct 1;64(19):7099-109. [Article]
  2. Carlomagno F, Anaganti S, Guida T, Salvatore G, Troncone G, Wilhelm SM, Santoro M: BAY 43-9006 inhibition of oncogenic RET mutants. J Natl Cancer Inst. 2006 Mar 1;98(5):326-34. [Article]
  3. Wilhelm S, Carter C, Lynch M, Lowinger T, Dumas J, Smith RA, Schwartz B, Simantov R, Kelley S: Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov. 2006 Oct;5(10):835-44. [Article]
  4. Iyer R, Fetterly G, Lugade A, Thanavala Y: Sorafenib: a clinical and pharmacologic review. Expert Opin Pharmacother. 2010 Aug;11(11):1943-55. doi: 10.1517/14656566.2010.496453. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Vascular endothelial growth factor-activated receptor activity
Specific Function
Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine FLT3LG and regulates differentiation, proliferation and survival of hematopoietic progenitor cells and of dendritic cells...
Gene Name
FLT3
Uniprot ID
P36888
Uniprot Name
Receptor-type tyrosine-protein kinase FLT3
Molecular Weight
112902.51 Da
References
  1. Auclair D, Miller D, Yatsula V, Pickett W, Carter C, Chang Y, Zhang X, Wilkie D, Burd A, Shi H, Rocks S, Gedrich R, Abriola L, Vasavada H, Lynch M, Dumas J, Trail PA, Wilhelm SM: Antitumor activity of sorafenib in FLT3-driven leukemic cells. Leukemia. 2007 Mar;21(3):439-45. Epub 2007 Jan 4. [Article]
  2. Lierman E, Lahortiga I, Van Miegroet H, Mentens N, Marynen P, Cools J: The ability of sorafenib to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors. Haematologica. 2007 Jan;92(1):27-34. [Article]
  3. Iyer R, Fetterly G, Lugade A, Thanavala Y: Sorafenib: a clinical and pharmacologic review. Expert Opin Pharmacother. 2010 Aug;11(11):1943-55. doi: 10.1517/14656566.2010.496453. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Vascular endothelial growth factor binding
Specific Function
Tyrosine-protein kinase that acts as cell-surface receptor for homodimeric PDGFB and PDGFD and for heterodimers formed by PDGFA and PDGFB, and plays an essential role in the regulation of embryonic...
Gene Name
PDGFRB
Uniprot ID
P09619
Uniprot Name
Platelet-derived growth factor receptor beta
Molecular Weight
123966.895 Da
References
  1. Gollob JA: Sorafenib: scientific rationales for single-agent and combination therapy in clear-cell renal cell carcinoma. Clin Genitourin Cancer. 2005 Dec;4(3):167-74. [Article]
  2. Guida T, Anaganti S, Provitera L, Gedrich R, Sullivan E, Wilhelm SM, Santoro M, Carlomagno F: Sorafenib inhibits imatinib-resistant KIT and platelet-derived growth factor receptor beta gatekeeper mutants. Clin Cancer Res. 2007 Jun 1;13(11):3363-9. [Article]
  3. Unnithan J, Rini BI: The role of targeted therapy in metastatic renal cell carcinoma. ScientificWorldJournal. 2007 Mar 2;7:800-7. [Article]
  4. Iyer R, Fetterly G, Lugade A, Thanavala Y: Sorafenib: a clinical and pharmacologic review. Expert Opin Pharmacother. 2010 Aug;11(11):1943-55. doi: 10.1517/14656566.2010.496453. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Transmembrane receptor protein tyrosine kinase activity
Specific Function
Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine KITLG/SCF and plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell main...
Gene Name
KIT
Uniprot ID
P10721
Uniprot Name
Mast/stem cell growth factor receptor Kit
Molecular Weight
109863.655 Da
References
  1. Guida T, Anaganti S, Provitera L, Gedrich R, Sullivan E, Wilhelm SM, Santoro M, Carlomagno F: Sorafenib inhibits imatinib-resistant KIT and platelet-derived growth factor receptor beta gatekeeper mutants. Clin Cancer Res. 2007 Jun 1;13(11):3363-9. [Article]
  2. Koch CA, Gimm O, Vortmeyer AO, Al-Ali HK, Lamesch P, Ott R, Kluge R, Bierbach U, Tannapfel A: Does the expression of c-kit (CD117) in neuroendocrine tumors represent a target for therapy? Ann N Y Acad Sci. 2006 Aug;1073:517-26. [Article]
  3. Lierman E, Lahortiga I, Van Miegroet H, Mentens N, Marynen P, Cools J: The ability of sorafenib to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors. Haematologica. 2007 Jan;92(1):27-34. [Article]
  4. Cascone T, Gridelli C, Ciardiello F: Combined targeted therapies in non-small cell lung cancer: a winner strategy? Curr Opin Oncol. 2007 Mar;19(2):98-102. [Article]
  5. Liu L, Cao Y, Chen C, Zhang X, McNabola A, Wilkie D, Wilhelm S, Lynch M, Carter C: Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res. 2006 Dec 15;66(24):11851-8. [Article]
  6. Iyer R, Fetterly G, Lugade A, Thanavala Y: Sorafenib: a clinical and pharmacologic review. Expert Opin Pharmacother. 2010 Aug;11(11):1943-55. doi: 10.1517/14656566.2010.496453. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Protein tyrosine kinase activity
Specific Function
Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of embryonic development, cell proliferation, differentiation ...
Gene Name
FGFR1
Uniprot ID
P11362
Uniprot Name
Fibroblast growth factor receptor 1
Molecular Weight
91866.935 Da
References
  1. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, Cao Y, Shujath J, Gawlak S, Eveleigh D, Rowley B, Liu L, Adnane L, Lynch M, Auclair D, Taylor I, Gedrich R, Voznesensky A, Riedl B, Post LE, Bollag G, Trail PA: BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004 Oct 1;64(19):7099-109. [Article]
  2. Carlomagno F, Anaganti S, Guida T, Salvatore G, Troncone G, Wilhelm SM, Santoro M: BAY 43-9006 inhibition of oncogenic RET mutants. J Natl Cancer Inst. 2006 Mar 1;98(5):326-34. [Article]
  3. Wilhelm S, Carter C, Lynch M, Lowinger T, Dumas J, Smith RA, Schwartz B, Simantov R, Kelley S: Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov. 2006 Oct;5(10):835-44. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Transmembrane receptor protein tyrosine kinase activity
Specific Function
Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation upon binding with glial cell de...
Gene Name
RET
Uniprot ID
P07949
Uniprot Name
Proto-oncogene tyrosine-protein kinase receptor Ret
Molecular Weight
124317.465 Da
References
  1. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, Cao Y, Shujath J, Gawlak S, Eveleigh D, Rowley B, Liu L, Adnane L, Lynch M, Auclair D, Taylor I, Gedrich R, Voznesensky A, Riedl B, Post LE, Bollag G, Trail PA: BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004 Oct 1;64(19):7099-109. [Article]
  2. Carlomagno F, Anaganti S, Guida T, Salvatore G, Troncone G, Wilhelm SM, Santoro M: BAY 43-9006 inhibition of oncogenic RET mutants. J Natl Cancer Inst. 2006 Mar 1;98(5):326-34. [Article]
  3. Wilhelm S, Carter C, Lynch M, Lowinger T, Dumas J, Smith RA, Schwartz B, Simantov R, Kelley S: Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov. 2006 Oct;5(10):835-44. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
Curator comments
Sorafenib competitively inhibited CYP3A4 in vitro.
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Gomo C, Coriat R, Faivre L, Mir O, Ropert S, Billemont B, Dauphin A, Tod M, Goldwasser F, Blanchet B: Pharmacokinetic interaction involving sorafenib and the calcium-channel blocker felodipine in a patient with hepatocellular carcinoma. Invest New Drugs. 2011 Dec;29(6):1511-4. doi: 10.1007/s10637-010-9514-3. Epub 2010 Aug 13. [Article]
  2. van Erp NP, Gelderblom H, Guchelaar HJ: Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009 Dec;35(8):692-706. doi: 10.1016/j.ctrv.2009.08.004. Epub 2009 Sep 5. [Article]
  3. Flaherty KT, Lathia C, Frye RF, Schuchter L, Redlinger M, Rosen M, O'Dwyer PJ: Interaction of sorafenib and cytochrome P450 isoenzymes in patients with advanced melanoma: a phase I/II pharmacokinetic interaction study. Cancer Chemother Pharmacol. 2011 Nov;68(5):1111-8. doi: 10.1007/s00280-011-1585-0. Epub 2011 Feb 25. [Article]
  4. Sugiyama M, Fujita K, Murayama N, Akiyama Y, Yamazaki H, Sasaki Y: Sorafenib and sunitinib, two anticancer drugs, inhibit CYP3A4-mediated and activate CY3A5-mediated midazolam 1'-hydroxylation. Drug Metab Dispos. 2011 May;39(5):757-62. doi: 10.1124/dmd.110.037853. Epub 2011 Jan 25. [Article]
  5. Flockhart Table of Drug Interactions [Link]
  6. FDA Approved Drug Products: NEXAVAR (sorafenib) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Sorafenib competitively inhibited CYP2C9 in vitro.
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Gong L, Giacomini MM, Giacomini C, Maitland ML, Altman RB, Klein TE: PharmGKB summary: sorafenib pathways. Pharmacogenet Genomics. 2017 Jun;27(6):240-246. doi: 10.1097/FPC.0000000000000279. [Article]
  2. Holstein A, Kovacs P, Beil W: Severe hypoglycemia due to possible interaction between glibenclamide and sorafenib in a patient with hepatocellular carcinoma. Curr Drug Saf. 2013 Apr;8(2):148-52. [Article]
  3. FDA Approved Drug Products: NEXAVAR (sorafenib) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
Curator comments
Sorafenib competitively inhibited CYP2C8 in vitro.
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. Flaherty KT, Lathia C, Frye RF, Schuchter L, Redlinger M, Rosen M, O'Dwyer PJ: Interaction of sorafenib and cytochrome P450 isoenzymes in patients with advanced melanoma: a phase I/II pharmacokinetic interaction study. Cancer Chemother Pharmacol. 2011 Nov;68(5):1111-8. doi: 10.1007/s00280-011-1585-0. Epub 2011 Feb 25. [Article]
  2. Flockhart Table of Drug Interactions [Link]
  3. FDA Approved Drug Products: NEXAVAR (sorafenib) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxygen binding
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
References
  1. Flockhart Table of Drug Interactions [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxygen binding
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP3A7
Uniprot ID
P24462
Uniprot Name
Cytochrome P450 3A7
Molecular Weight
57525.03 Da
References
  1. Flockhart Table of Drug Interactions [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Sorafenib competitively inhibited CYP2B6 in vitro.
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
References
  1. Flaherty KT, Lathia C, Frye RF, Schuchter L, Redlinger M, Rosen M, O'Dwyer PJ: Interaction of sorafenib and cytochrome P450 isoenzymes in patients with advanced melanoma: a phase I/II pharmacokinetic interaction study. Cancer Chemother Pharmacol. 2011 Nov;68(5):1111-8. doi: 10.1007/s00280-011-1585-0. Epub 2011 Feb 25. [Article]
  2. Flockhart Table of Drug Interactions [Link]
  3. FDA Approved Drug Products: NEXAVAR (sorafenib) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. Flaherty KT, Lathia C, Frye RF, Schuchter L, Redlinger M, Rosen M, O'Dwyer PJ: Interaction of sorafenib and cytochrome P450 isoenzymes in patients with advanced melanoma: a phase I/II pharmacokinetic interaction study. Cancer Chemother Pharmacol. 2011 Nov;68(5):1111-8. doi: 10.1007/s00280-011-1585-0. Epub 2011 Feb 25. [Article]
  2. Zimmerman EI, Roberts JL, Li L, Finkelstein D, Gibson A, Chaudhry AS, Schuetz EG, Rubnitz JE, Inaba H, Baker SD: Ontogeny and sorafenib metabolism. Clin Cancer Res. 2012 Oct 15;18(20):5788-95. doi: 10.1158/1078-0432.CCR-12-1967. Epub 2012 Aug 27. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Sorafenib competitively inhibited CYP2C19 in vitro.
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. Flaherty KT, Lathia C, Frye RF, Schuchter L, Redlinger M, Rosen M, O'Dwyer PJ: Interaction of sorafenib and cytochrome P450 isoenzymes in patients with advanced melanoma: a phase I/II pharmacokinetic interaction study. Cancer Chemother Pharmacol. 2011 Nov;68(5):1111-8. doi: 10.1007/s00280-011-1585-0. Epub 2011 Feb 25. [Article]
  2. FDA Approved Drug Products: NEXAVAR (sorafenib) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Sorafenib competitively inhibited CYP2D6 in vitro.
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. Flaherty KT, Lathia C, Frye RF, Schuchter L, Redlinger M, Rosen M, O'Dwyer PJ: Interaction of sorafenib and cytochrome P450 isoenzymes in patients with advanced melanoma: a phase I/II pharmacokinetic interaction study. Cancer Chemother Pharmacol. 2011 Nov;68(5):1111-8. doi: 10.1007/s00280-011-1585-0. Epub 2011 Feb 25. [Article]
  2. FDA Approved Drug Products: NEXAVAR (sorafenib) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Retinoic acid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform has specificity for phenols. Isoform 2 lacks trans...
Gene Name
UGT1A9
Uniprot ID
O60656
Uniprot Name
UDP-glucuronosyltransferase 1-9
Molecular Weight
59940.495 Da
References
  1. Gomo C, Coriat R, Faivre L, Mir O, Ropert S, Billemont B, Dauphin A, Tod M, Goldwasser F, Blanchet B: Pharmacokinetic interaction involving sorafenib and the calcium-channel blocker felodipine in a patient with hepatocellular carcinoma. Invest New Drugs. 2011 Dec;29(6):1511-4. doi: 10.1007/s10637-010-9514-3. Epub 2010 Aug 13. [Article]
  2. van Erp NP, Gelderblom H, Guchelaar HJ: Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009 Dec;35(8):692-706. doi: 10.1016/j.ctrv.2009.08.004. Epub 2009 Sep 5. [Article]
  3. Keating GM, Santoro A: Sorafenib: a review of its use in advanced hepatocellular carcinoma. Drugs. 2009;69(2):223-40. doi: 10.2165/00003495-200969020-00006. [Article]
  4. FDA Approved Drug Products: NEXAVAR (sorafenib) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
Gene Name
UGT1A1
Uniprot ID
P22309
Uniprot Name
UDP-glucuronosyltransferase 1-1
Molecular Weight
59590.91 Da
References
  1. FDA Approved Drug Products: NEXAVAR (sorafenib) tablets, for oral use [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. Hu S, Chen Z, Franke R, Orwick S, Zhao M, Rudek MA, Sparreboom A, Baker SD: Interaction of the multikinase inhibitors sorafenib and sunitinib with solute carriers and ATP-binding cassette transporters. Clin Cancer Res. 2009 Oct 1;15(19):6062-9. doi: 10.1158/1078-0432.CCR-09-0048. Epub 2009 Sep 22. [Article]
  2. Lagas JS, van Waterschoot RA, Sparidans RW, Wagenaar E, Beijnen JH, Schinkel AH: Breast cancer resistance protein and P-glycoprotein limit sorafenib brain accumulation. Mol Cancer Ther. 2010 Feb;9(2):319-26. doi: 10.1158/1535-7163.MCT-09-0663. Epub 2010 Jan 26. [Article]
  3. FDA Approved Drug Products: NEXAVAR (sorafenib) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
Curator comments
The literature seems to reflect that Sorafenib is either strictly a substrate or an inhibitor.
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
References
  1. Hu S, Chen Z, Franke R, Orwick S, Zhao M, Rudek MA, Sparreboom A, Baker SD: Interaction of the multikinase inhibitors sorafenib and sunitinib with solute carriers and ATP-binding cassette transporters. Clin Cancer Res. 2009 Oct 1;15(19):6062-9. doi: 10.1158/1078-0432.CCR-09-0048. Epub 2009 Sep 22. [Article]
  2. Lagas JS, van Waterschoot RA, Sparidans RW, Wagenaar E, Beijnen JH, Schinkel AH: Breast cancer resistance protein and P-glycoprotein limit sorafenib brain accumulation. Mol Cancer Ther. 2010 Feb;9(2):319-26. doi: 10.1158/1535-7163.MCT-09-0663. Epub 2010 Jan 26. [Article]
  3. Wei Y, Ma Y, Zhao Q, Ren Z, Li Y, Hou T, Peng H: New use for an old drug: inhibiting ABCG2 with sorafenib. Mol Cancer Ther. 2012 Aug;11(8):1693-702. doi: 10.1158/1535-7163.MCT-12-0215. Epub 2012 May 16. [Article]
  4. Huang WC, Hsieh YL, Hung CM, Chien PH, Chien YF, Chen LC, Tu CY, Chen CH, Hsu SC, Lin YM, Chen YJ: BCRP/ABCG2 inhibition sensitizes hepatocellular carcinoma cells to sorafenib. PLoS One. 2013 Dec 31;8(12):e83627. doi: 10.1371/journal.pone.0083627. eCollection 2013. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Atpase activity, coupled to transmembrane movement of substances
Specific Function
May be an organic anion pump relevant to cellular detoxification.
Gene Name
ABCC4
Uniprot ID
O15439
Uniprot Name
Multidrug resistance-associated protein 4
Molecular Weight
149525.33 Da
References
  1. Hu S, Chen Z, Franke R, Orwick S, Zhao M, Rudek MA, Sparreboom A, Baker SD: Interaction of the multikinase inhibitors sorafenib and sunitinib with solute carriers and ATP-binding cassette transporters. Clin Cancer Res. 2009 Oct 1;15(19):6062-9. doi: 10.1158/1078-0432.CCR-09-0048. Epub 2009 Sep 22. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Organic anion transmembrane transporter activity
Specific Function
Mediates hepatobiliary excretion of numerous organic anions. May function as a cellular cisplatin transporter.
Gene Name
ABCC2
Uniprot ID
Q92887
Uniprot Name
Canalicular multispecific organic anion transporter 1
Molecular Weight
174205.64 Da
References
  1. Hu S, Chen Z, Franke R, Orwick S, Zhao M, Rudek MA, Sparreboom A, Baker SD: Interaction of the multikinase inhibitors sorafenib and sunitinib with solute carriers and ATP-binding cassette transporters. Clin Cancer Res. 2009 Oct 1;15(19):6062-9. doi: 10.1158/1078-0432.CCR-09-0048. Epub 2009 Sep 22. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Transmembrane transporter activity
Specific Function
Can activate specifically hydrolysis of GTP bound to RAC1 and CDC42, but not RALA. Mediates ATP-dependent transport of S-(2,4-dinitrophenyl)-glutathione (DNP-SG) and doxorubicin (DOX) and is the ma...
Gene Name
RALBP1
Uniprot ID
Q15311
Uniprot Name
RalA-binding protein 1
Molecular Weight
76062.86 Da
References
  1. Singhal SS, Sehrawat A, Sahu M, Singhal P, Vatsyayan R, Rao Lelsani PC, Yadav S, Awasthi S: Rlip76 transports sunitinib and sorafenib and mediates drug resistance in kidney cancer. Int J Cancer. 2010 Mar 15;126(6):1327-38. doi: 10.1002/ijc.24767. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
Gene Name
SLCO1B1
Uniprot ID
Q9Y6L6
Uniprot Name
Solute carrier organic anion transporter family member 1B1
Molecular Weight
76447.99 Da
References
  1. Hu S, Mathijssen RH, de Bruijn P, Baker SD, Sparreboom A: Inhibition of OATP1B1 by tyrosine kinase inhibitors: in vitro-in vivo correlations. Br J Cancer. 2014 Feb 18;110(4):894-8. doi: 10.1038/bjc.2013.811. Epub 2014 Jan 7. [Article]

Drug created at June 13, 2005 13:24 / Updated at February 08, 2023 20:46