Welcome to DrugBank 4.0! If you prefer, you can still go back to version 3.0.
Identification
NamePazopanib
Accession NumberDB06589
Typesmall molecule
Groupsapproved
Description

Pazopanib is a small molecule inhibitor of multiple protein tyrosine kinases with potential antineoplastic activity. It is developed by GlaxoSmithKline and was FDA approved on October 19, 2009.

Structure
Thumb
SynonymsNot Available
Salts
Name/CAS Structure Properties
Pazopanib Hydrochloride
Thumb
  • InChI Key: MQHIQUBXFFAOMK-UHFFFAOYSA-N
  • Monoisotopic Mass: 473.140071444
  • Average Mass: 473.979
DBSALT000135
Brand names
NameCompany
Votrient GlaxoSmithKline
Brand mixturesNot Available
CategoriesNot Available
CAS number444731-52-6
WeightAverage: 437.518
Monoisotopic: 437.163393705
Chemical FormulaC21H23N7O2S
InChI KeyInChIKey=CUIHSIWYWATEQL-UHFFFAOYSA-N
InChI
InChI=1S/C21H23N7O2S/c1-13-5-6-15(11-19(13)31(22,29)30)24-21-23-10-9-20(25-21)27(3)16-7-8-17-14(2)28(4)26-18(17)12-16/h5-12H,1-4H3,(H2,22,29,30)(H,23,24,25)
IUPAC Name
5-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]pyrimidin-2-yl}amino)-2-methylbenzene-1-sulfonamide
SMILES
CN(C1=CC2=NN(C)C(C)=C2C=C1)C1=CC=NC(NC2=CC=C(C)C(=C2)S(N)(=O)=O)=N1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassBenzene and Substituted Derivatives
SubclassBenzenesulfonamides
Direct parentAminobenzenesulfonamides
Alternative parentsIndazoles; Toluenes; Aminopyrimidines and Derivatives; Sulfonamides; Sulfonyls; Pyrazoles; Tertiary Amines; Polyamines; Secondary Amines
Substituentsindazole; benzopyrazole; aminopyrimidine; toluene; pyrimidine; sulfonic acid derivative; sulfonyl; azole; sulfonamide; pyrazole; tertiary amine; polyamine; secondary amine; amine; organonitrogen compound
Classification descriptionThis compound belongs to the aminobenzenesulfonamides. These are organic compounds containing a benzenesulfonamide moiety with an amine group attached to the benzene ring.
Pharmacology
IndicationTreatment of advanced renal cell cancer and advanced soft tissue sarcoma (in patients previously treated with chemotherapy)
PharmacodynamicsPazopanib is a synthetic indazolylpyrimidine and reaches steady state concentrations of >15 μg/ml. This concentration is high enough to observe maximal inhibition of VEGFR2 phosphorylation and some anti-tumour activity (concentration required to inhibit receptors is 0.01 - 0.084 μmol/L). A reduction in tumour blood flow, increased tumour apoptosis, inhibition of tumour growth, reduction in tumour interstitial fluid pressure, and hypoxia in cancer cells can be observed in patients receiving treatment.
Mechanism of actionPazopanib is a second-generation multitargeted tyrosine kinase inhibitor against vascular endothelial growth factor receptor-1, -2, and -3, platelet-derived growth factor receptor-alpha, platelet-derived growth factor receptor-beta, and c-kit. These receptor targets are part of the angiogenesis pathway that facilitates the formation of tumour blood vessel for tumour survival and growth.
AbsorptionAbsorption of pazopanib in cancer patients is slow and incomplete. In patients with solid tumour, over a dose range of 50-2000 mg, absorption is nonlinear. Significant accumulation of pazopanib can also be observed in patients receiving 800 mg once daily for 22 days. Crushing tablets may increase exposure (increase in Cmax and AUC, while Tmax decreases by 2 hours). Bioavailability, oral tablet 800 mg, cancer patient = 21%; Bioavailability may be low due to incomplete absorption from the gastrointestinal tract. The major circulating component of the drug in the systemic is pazopanib, and not its metabolites. Mean maximum plasma concentration= 58.1 µg/mL; Mean AUC= 1037 µg · h/mL;
Volume of distribution

Vd steady state, IV administration 5 mg, cancer patient = 11.1 L (range of 9.15 – 13.4)

Protein binding>99% protein bound, independent of concentrations over a range of 10-100 μg/mL.
Metabolism

Metabolized by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C8. Metabolites are less active than pazopanib (10 to 20-fold less active). Three of its metabolites can be observed in the systemic and account for <10% of plasma radioactivity.

Route of eliminationPrimarily excreted via feces (82.2%) and to a negligible extent via urine (<4%) in cancer patients. Most of the administered dose is excreted unchanged. Approximately 10% of dose are oxidative metabolites and are mostly eliminated via the feces.
Half life35 hours. Oral absorption is not the rate limiting step of elimination from the plasma.
Clearance

CL, cancer patient, IV administration 5 mg = 4mL/min
Half of the absorbed dose is cleared via oxidative metabolism.

ToxicityNot Available
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 1.0
Blood Brain Barrier + 0.8788
Caco-2 permeable + 0.5
P-glycoprotein substrate Non-substrate 0.8307
P-glycoprotein inhibitor I Non-inhibitor 0.8126
P-glycoprotein inhibitor II Inhibitor 0.5
Renal organic cation transporter Non-inhibitor 0.8152
CYP450 2C9 substrate Non-substrate 0.7797
CYP450 2D6 substrate Non-substrate 0.8008
CYP450 3A4 substrate Non-substrate 0.6024
CYP450 1A2 substrate Non-inhibitor 0.5
CYP450 2C9 substrate Non-inhibitor 0.5065
CYP450 2D6 substrate Non-inhibitor 0.7779
CYP450 2C19 substrate Non-inhibitor 0.6811
CYP450 3A4 substrate Non-inhibitor 0.5385
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.5668
Ames test Non AMES toxic 0.6543
Carcinogenicity Non-carcinogens 0.8567
Biodegradation Not ready biodegradable 0.9935
Rat acute toxicity 2.3961 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9219
hERG inhibition (predictor II) Non-inhibitor 0.7129
Pharmacoeconomics
Manufacturers
  • Glaxosmithkline
PackagersNot Available
Dosage forms
FormRouteStrength
TabletOral200 mg
PricesNot Available
Patents
CountryPatent NumberApprovedExpires (estimated)
United States71055302009-10-192023-10-19
United States72622032009-10-192021-12-19
United States81148852009-10-192021-12-19
Properties
Statesolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
water solubility4.33e-02 g/lALOGPS
logP3.59ALOGPS
logP3.55ChemAxon
logS-4ALOGPS
pKa (strongest acidic)10.41ChemAxon
pKa (strongest basic)5.07ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count7ChemAxon
hydrogen donor count2ChemAxon
polar surface area119.03ChemAxon
rotatable bond count5ChemAxon
refractivity132.18ChemAxon
polarizability45.41ChemAxon
number of rings4ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterNoChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis ReferenceNot Available
General Reference
  1. Sonpavde G, Hutson TE, Sternberg CN: Pazopanib, a potent orally administered small-molecule multitargeted tyrosine kinase inhibitor for renal cell carcinoma. Expert Opin Investig Drugs. 2008 Feb;17(2):253-61. Pubmed
  2. Verweij J, Sleijfer S: Pazopanib , a new therapy for metastatic soft tissue sarcoma. Expert Opin Pharmacother. 2013 May;14(7):929-35. doi: 10.1517/14656566.2013.780030. Epub 2013 Mar 14. Pubmed
  3. Deng Y, Sychterz C, Suttle AB, Dar MM, Bershas D, Negash K, Qian Y, Chen EP, Gorycki PD, Ho MY: Bioavailability, metabolism and disposition of oral pazopanib in patients with advanced cancer. Xenobiotica. 2013 May;43(5):443-53. doi: 10.3109/00498254.2012.734642. Epub 2012 Nov 16. Pubmed
  4. Deeks ED: Pazopanib: in advanced soft tissue sarcoma. Drugs. 2012 Nov 12;72(16):2129-40. doi: 10.2165/11209950-000000000-00000. Pubmed
External Links
ResourceLink
KEGG DrugD05380
ChEBI71219
ChEMBLCHEMBL477772
RxListhttp://www.rxlist.com/votrient-drug.htm
Drugs.comhttp://www.drugs.com/cdi/pazopanib.html
WikipediaPazopanib
ATC CodesL01XE11
AHFS Codes
  • 10:00
PDB EntriesNot Available
FDA labelshow(593 KB)
MSDSshow(70.4 KB)
Interactions
Drug Interactions
Drug
ArtemetherAdditive QTc-prolongation may occur. Concomitant therapy should be avoided.
CarbamazepineAffects CYP3A4 metabolism therefore will decrease levels or effect of pazopanib. Consider alternate therapy.
CimetidineAffects CYP3A4 metabolism therefore will decrease levels or effect of pazopanib. Consider alternate therapy.
ClarithromycinClarithromycin is a strong inhibitor of CYP3A4 thus increasing exposure of pazopanib.
ConivaptanCYP3A4 Inhibitors (Strong) may increase the serum concentration of Pazopanib. Avoid concurrent use of pazopanib with strong inhibitors of CYP3A4 whenever possible. If it is not possible to avoid such a combination, reduce pazopanib dose to 400 mg. Further dose reductions may also be required.
ErythromycinAffects CYP3A4 metabolism therefore will decrease levels or effect of pazopanib. Consider alternate therapy.
EtravirinePazopanib, when used concomitantly with etravirine (a strong CYP3A4 inducer), may experience a decrease in serum concentration. It is recommended to avoid concurrent therapy.
IfosfamideIfosfamide decreases plasma levels of pazopanib.
IrinotecanIrinotecan is an uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) substrate and serum concentrations may increase if administered concurrently with pazopanib, an UGT1A1 inhibitor.
ItraconazoleAffects CYP3A4 metabolism therefore will decrease levels or effect of pazopanib. Consider alternate therapy.
IvacaftorInhibits p-glycoprotein and affects heptatic metabolism via CYP3A4 therefore increases levels of pazopanib. Consider alternate therapy.
KetoconazoleKetoconazole is a strong inhibitor of CYP3A4 thus increasing exposure of pazopanib by 120% in healthy subjects.
LapatinibLapatinib is a weak inhibitor of CYP3A4, BCRP, and p-glycoprotein and may increase exposure of pazopanib. AUC and Cmax increase by 50-60%.
LumefantrineAdditive QTc-prolongation may occur. Concomitant therapy should be avoided.
NefazodoneAffects CYP3A4 metabolism therefore will decrease levels or effect of pazopanib. Consider alternate therapy.
OndansetronAdditive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy is contraindicated.
PaclitaxelPazopanib increases exposure of paclitaxel
RifabutinAffects CYP3A4 metabolism therefore will decrease levels or effect of pazopanib. Consider alternate therapy.
RifampicinConcomitant therapy with a CYP3A4 inducer may decrease exposure of pazopanib.
RitonavirRitonavir is a strong inhibitor of CYP3A4 thus increasing exposure of pazopanib.
SaquinavirAffects CYP3A4 metabolism therefore will decrease levels or effect of pazopanib. Consider alternate therapy.
SimvastatinElevated liver enzyme levels may be observed with concomitant therapy with pazopanib. Monitor closely for adverse effects.
ToremifeneAdditive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy is contraindicated.
ZiprasidoneAdditive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy is contraindicated.
ZuclopenthixolAdditive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Zuclopenthixol acetateAdditive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Zuclopenthixol decanoateAdditive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Food Interactions
  • Avoid drinking grapefruit juice as it is a CYP 3A4 inhibitor and will increase exposure of pazopanib
  • Bioavailability increases with food. Take pazopanib on empty stomach.

1. Vascular endothelial growth factor receptor 1

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Vascular endothelial growth factor receptor 1 P17948 Details

References:

  1. Sonpavde G, Hutson TE: Pazopanib: a novel multitargeted tyrosine kinase inhibitor. Curr Oncol Rep. 2007 Mar;9(2):115-9. Pubmed

2. Vascular endothelial growth factor receptor 2

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Vascular endothelial growth factor receptor 2 P35968 Details

References:

  1. Sonpavde G, Hutson TE: Pazopanib: a novel multitargeted tyrosine kinase inhibitor. Curr Oncol Rep. 2007 Mar;9(2):115-9. Pubmed

3. Vascular endothelial growth factor receptor 3

Kind: protein

Organism: Human

Pharmacological action: yes

Components

Name UniProt ID Details
Vascular endothelial growth factor receptor 3 P35916 Details

References:

  1. Sonpavde G, Hutson TE: Pazopanib: a novel multitargeted tyrosine kinase inhibitor. Curr Oncol Rep. 2007 Mar;9(2):115-9. Pubmed

4. Platelet-derived growth factor receptor alpha

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Platelet-derived growth factor receptor alpha P16234 Details

References:

  1. Sonpavde G, Hutson TE: Pazopanib: a novel multitargeted tyrosine kinase inhibitor. Curr Oncol Rep. 2007 Mar;9(2):115-9. Pubmed

5. Platelet-derived growth factor receptor beta

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Platelet-derived growth factor receptor beta P09619 Details

References:

  1. Sonpavde G, Hutson TE: Pazopanib: a novel multitargeted tyrosine kinase inhibitor. Curr Oncol Rep. 2007 Mar;9(2):115-9. Pubmed

6. Mast/stem cell growth factor receptor Kit

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Mast/stem cell growth factor receptor Kit P10721 Details

References:

  1. Sonpavde G, Hutson TE: Pazopanib: a novel multitargeted tyrosine kinase inhibitor. Curr Oncol Rep. 2007 Mar;9(2):115-9. Pubmed

7. Fibroblast growth factor receptor 3

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Fibroblast growth factor receptor 3 P22607 Details

References:

  1. Deeks ED: Pazopanib: in advanced soft tissue sarcoma. Drugs. 2012 Nov 12;72(16):2129-40. doi: 10.2165/11209950-000000000-00000. Pubmed

8. Tyrosine-protein kinase ITK/TSK

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Tyrosine-protein kinase ITK/TSK Q08881 Details

References:

  1. Deeks ED: Pazopanib: in advanced soft tissue sarcoma. Drugs. 2012 Nov 12;72(16):2129-40. doi: 10.2165/11209950-000000000-00000. Pubmed

9. Fibroblast growth factor 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Fibroblast growth factor 1 P05230 Details

References:

  1. Deeks ED: Pazopanib: in advanced soft tissue sarcoma. Drugs. 2012 Nov 12;72(16):2129-40. doi: 10.2165/11209950-000000000-00000. Pubmed

10. SH2B adapter protein 3

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
SH2B adapter protein 3 Q9UQQ2 Details

References:

  1. Deeks ED: Pazopanib: in advanced soft tissue sarcoma. Drugs. 2012 Nov 12;72(16):2129-40. doi: 10.2165/11209950-000000000-00000. Pubmed

1. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. Keisner SV, Shah SR: Pazopanib: the newest tyrosine kinase inhibitor for the treatment of advanced or metastatic renal cell carcinoma. Drugs. 2011 Mar 5;71(4):443-54. doi: 10.2165/11588960-000000000-00000. Pubmed
  2. Goh BC, Reddy NJ, Dandamudi UB, Laubscher KH, Peckham T, Hodge JP, Suttle AB, Arumugham T, Xu Y, Xu CF, Lager J, Dar MM, Lewis LD: An evaluation of the drug interaction potential of pazopanib, an oral vascular endothelial growth factor receptor tyrosine kinase inhibitor, using a modified Cooperstown 5+1 cocktail in patients with advanced solid tumors. Clin Pharmacol Ther. 2010 Nov;88(5):652-9. Epub 2010 Sep 29. Pubmed
  3. Verweij J, Sleijfer S: Pazopanib , a new therapy for metastatic soft tissue sarcoma. Expert Opin Pharmacother. 2013 May;14(7):929-35. doi: 10.1517/14656566.2013.780030. Epub 2013 Mar 14. Pubmed

2. Cytochrome P450 2D6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2D6 P10635 Details

References:

  1. Keisner SV, Shah SR: Pazopanib: the newest tyrosine kinase inhibitor for the treatment of advanced or metastatic renal cell carcinoma. Drugs. 2011 Mar 5;71(4):443-54. doi: 10.2165/11588960-000000000-00000. Pubmed
  2. Goh BC, Reddy NJ, Dandamudi UB, Laubscher KH, Peckham T, Hodge JP, Suttle AB, Arumugham T, Xu Y, Xu CF, Lager J, Dar MM, Lewis LD: An evaluation of the drug interaction potential of pazopanib, an oral vascular endothelial growth factor receptor tyrosine kinase inhibitor, using a modified Cooperstown 5+1 cocktail in patients with advanced solid tumors. Clin Pharmacol Ther. 2010 Nov;88(5):652-9. Epub 2010 Sep 29. Pubmed

3. Cytochrome P450 2C8

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2C8 P10632 Details

References:

  1. Keisner SV, Shah SR: Pazopanib: the newest tyrosine kinase inhibitor for the treatment of advanced or metastatic renal cell carcinoma. Drugs. 2011 Mar 5;71(4):443-54. doi: 10.2165/11588960-000000000-00000. Pubmed
  2. Verweij J, Sleijfer S: Pazopanib , a new therapy for metastatic soft tissue sarcoma. Expert Opin Pharmacother. 2013 May;14(7):929-35. doi: 10.1517/14656566.2013.780030. Epub 2013 Mar 14. Pubmed

4. Cytochrome P450 1A2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 1A2 P05177 Details

References:

  1. Verweij J, Sleijfer S: Pazopanib , a new therapy for metastatic soft tissue sarcoma. Expert Opin Pharmacother. 2013 May;14(7):929-35. doi: 10.1517/14656566.2013.780030. Epub 2013 Mar 14. Pubmed

1. Multidrug resistance protein 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Multidrug resistance protein 1 P08183 Details

References:

  1. Deng Y, Sychterz C, Suttle AB, Dar MM, Bershas D, Negash K, Qian Y, Chen EP, Gorycki PD, Ho MY: Bioavailability, metabolism and disposition of oral pazopanib in patients with advanced cancer. Xenobiotica. 2013 May;43(5):443-53. doi: 10.3109/00498254.2012.734642. Epub 2012 Nov 16. Pubmed

2. ATP-binding cassette sub-family G member 2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
ATP-binding cassette sub-family G member 2 Q9UNQ0 Details

References:

  1. Deng Y, Sychterz C, Suttle AB, Dar MM, Bershas D, Negash K, Qian Y, Chen EP, Gorycki PD, Ho MY: Bioavailability, metabolism and disposition of oral pazopanib in patients with advanced cancer. Xenobiotica. 2013 May;43(5):443-53. doi: 10.3109/00498254.2012.734642. Epub 2012 Nov 16. Pubmed

3. Solute carrier organic anion transporter family member 1B1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Solute carrier organic anion transporter family member 1B1 Q9Y6L6 Details

References:

  1. Deeks ED: Pazopanib: in advanced soft tissue sarcoma. Drugs. 2012 Nov 12;72(16):2129-40. doi: 10.2165/11209950-000000000-00000. Pubmed

4. UDP-glucuronosyltransferase 1-1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
UDP-glucuronosyltransferase 1-1 P22309 Details

References:

  1. Deeks ED: Pazopanib: in advanced soft tissue sarcoma. Drugs. 2012 Nov 12;72(16):2129-40. doi: 10.2165/11209950-000000000-00000. Pubmed

Comments
Drug created on March 19, 2008 10:38 / Updated on September 16, 2013 18:04