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Identification
NameVandetanib
Accession NumberDB05294
TypeSmall Molecule
GroupsApproved
Description

Vandetanib is an oral once-daily kinase inhibitor of tumour angiogenesis and tumour cell proliferation with the potential for use in a broad range of tumour types.

On April 6 2011, vandetanib was approved by the FDA to treat nonresectable, locally advanced, or metastatic medullary thyroid cancer in adult patients.

Structure
Thumb
Synonyms
4-BROMO-2-fluoro-N-[(4e)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4(1H)-ylidene]aniline
4-quinazolinamine, N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methyl-4-piperidinyl)methoxy]-
N-(4-Bromo-2-fluorophenyl)-6-methoxy-7-[(1-methyl-4-piperidinyl)methoxy]-4-quinazolinamine
N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine
Zactima
ZD 6474
ZD6474
External Identifiers
  • ZD-6474
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Caprelsatablet300 mgoralAstrazeneca Canada Inc2012-02-23Not applicableCanada
Caprelsatablet100 mgoralAstrazeneca Canada Inc2012-02-23Not applicableCanada
Caprelsatablet300 mg/1oralAstra Zeneca Pharmaceuticals Lp2011-07-25Not applicableUs
Caprelsatablet100 mg/1oralAstra Zeneca Pharmaceuticals Lp2011-07-25Not applicableUs
Vandetanibtablet100 mg/1oralAstra Zeneca Pharmaceuticals Lp2011-04-21Not applicableUs
Vandetanibtablet300 mg/1oralAstra Zeneca Pharmaceuticals Lp2011-04-21Not applicableUs
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
Zactima AstraZeneca
Zictifa AstraZeneca
Brand mixturesNot Available
SaltsNot Available
Categories
UNIIYO460OQ37K
CAS number443913-73-3
WeightAverage: 475.354
Monoisotopic: 474.106666884
Chemical FormulaC22H24BrFN4O2
InChI KeyInChIKey=UHTHHESEBZOYNR-UHFFFAOYSA-N
InChI
InChI=1S/C22H24BrFN4O2/c1-28-7-5-14(6-8-28)12-30-21-11-19-16(10-20(21)29-2)22(26-13-25-19)27-18-4-3-15(23)9-17(18)24/h3-4,9-11,13-14H,5-8,12H2,1-2H3,(H,25,26,27)
IUPAC Name
N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine
SMILES
COC1=C(OCC2CCN(C)CC2)C=C2N=CN=C(NC3=C(F)C=C(Br)C=C3)C2=C1
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as quinazolinamines. These are heterocyclic aromatic compounds containing a quianazoline moiety substituted by one or more amine groups.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassNaphthyridines
Sub ClassQuinazolines
Direct ParentQuinazolinamines
Alternative Parents
Substituents
  • Quinazolinamine
  • Anisole
  • Halobenzene
  • Fluorobenzene
  • Bromobenzene
  • Aminopyrimidine
  • Alkyl aryl ether
  • Imidolactam
  • Benzenoid
  • Pyrimidine
  • Piperidine
  • Monocyclic benzene moiety
  • Aryl halide
  • Aryl fluoride
  • Aryl bromide
  • Heteroaromatic compound
  • Tertiary aliphatic amine
  • Tertiary amine
  • Azacycle
  • Secondary amine
  • Ether
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Organofluoride
  • Organobromide
  • Organohalogen compound
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Pharmacology
IndicationVandetanib is currently approved as an alternative to local therapies for both unresectable and disseminated disease. Because Vandetanib can prolong the Q-T interval, it is contraindicated for use in patients with serious cardiac complications such as congenital long QT syndrome and uncompensated heart failure.
PharmacodynamicsMean IC50 of approximately 2.1 μg/mL.
Mechanism of actionZD-6474 is a potent and selective inhibitor of VEGFR (vascular endothelial growth factor receptor), EGFR (epidermal growth factor receptor) and RET (REarranged during Transfection) tyrosine kinases. VEGFR- and EGFR-dependent signalling are both clinically validated pathways in cancer, including non-small-cell lung cancer (NSCLC). RET activity is important in some types of thyroid cancer, and early data with vandetanib in medullary thyroid cancer has led to orphan-drug designation by the regulatory authorities in the USA and EU.
Related Articles
AbsorptionSlow- peak plasma concentrations reached at a median 6 hours. On multiple dosing, Vandetanib accumulates about 8 fold with steady state reached after around 3 months.
Volume of distribution

Vd of about 7450 L.

Protein bindingProtein binding of about 90%.
Metabolism

Unchanged vandentanib and metabolites vandetanib N-oxide and N-desmethyl vandetanib were detected in plasma, urine and feces. N-desmethyl-vandetanib is primarily produced by CYP3A4, and vandetanib-N-oxide is primarily produced by flavin–containing monooxygenase enzymes FMO1 and FMO3.

SubstrateEnzymesProduct
Vandetanib
Not Available
N-desmethyl vandetanibDetails
Route of eliminationAbout 69% was recovered following 21 days after a single dose of vandentanib. 44% was found in feces and 25% in urine.
Half lifeMedian half life of 19 days.
ClearanceNot Available
ToxicityNot Available
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9961
Blood Brain Barrier+0.9596
Caco-2 permeable+0.611
P-glycoprotein substrateSubstrate0.7412
P-glycoprotein inhibitor IInhibitor0.7327
P-glycoprotein inhibitor IIInhibitor0.9501
Renal organic cation transporterInhibitor0.6556
CYP450 2C9 substrateNon-substrate0.8419
CYP450 2D6 substrateNon-substrate0.5827
CYP450 3A4 substrateSubstrate0.6006
CYP450 1A2 substrateInhibitor0.7333
CYP450 2C9 inhibitorNon-inhibitor0.7749
CYP450 2D6 inhibitorInhibitor0.5867
CYP450 2C19 inhibitorInhibitor0.5077
CYP450 3A4 inhibitorInhibitor0.5288
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.8009
Ames testAMES toxic0.5693
CarcinogenicityNon-carcinogens0.9322
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.5482 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.5
hERG inhibition (predictor II)Inhibitor0.8342
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Tabletoral100 mg
Tabletoral300 mg
Tabletoral100 mg/1
Tabletoral300 mg/1
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7173038 No2001-08-142021-08-14Us
US8067427 No2008-08-082028-08-08Us
US8642608 No2002-02-062022-02-06Us
USRE42353 No1997-09-232017-09-23Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
water solubility0.008 mg/mL at 25°C (77°F )FDA Label
Predicted Properties
PropertyValueSource
Water Solubility0.0102 mg/mLALOGPS
logP5.01ALOGPS
logP4.54ChemAxon
logS-4.7ALOGPS
pKa (Strongest Acidic)13.8ChemAxon
pKa (Strongest Basic)9.13ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area59.51 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity118.63 m3·mol-1ChemAxon
Polarizability47.1 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Download (103 KB)
SpectraNot Available
References
Synthesis ReferenceNot Available
General References
  1. Bates D: ZD-6474. AstraZeneca. Curr Opin Investig Drugs. 2003 Dec;4(12):1468-72. [PubMed:14763134 ]
  2. Ton GN, Banaszynski ME, Kolesar JM: Vandetanib: a novel targeted therapy for the treatment of metastatic or locally advanced medullary thyroid cancer. Am J Health Syst Pharm. 2013 May 15;70(10):849-55. doi: 10.2146/ajhp120253. [PubMed:23640345 ]
  3. Andriamanana I, Gana I, Duretz B, Hulin A: Simultaneous analysis of anticancer agents bortezomib, imatinib, nilotinib, dasatinib, erlotinib, lapatinib, sorafenib, sunitinib and vandetanib in human plasma using LC/MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci. 2013 May 1;926:83-91. doi: 10.1016/j.jchromb.2013.01.037. Epub 2013 Mar 16. [PubMed:23562906 ]
External Links
ATC CodesL01XE12
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelDownload (220 KB)
MSDSDownload (220 KB)
Interactions
Drug Interactions
Drug
AfatinibThe serum concentration of Afatinib can be increased when it is combined with Vandetanib.
BexaroteneThe serum concentration of Vandetanib can be decreased when it is combined with Bexarotene.
BosentanThe serum concentration of Vandetanib can be decreased when it is combined with Bosentan.
BosutinibThe serum concentration of Bosutinib can be increased when it is combined with Vandetanib.
Brentuximab vedotinThe serum concentration of Brentuximab vedotin can be increased when it is combined with Vandetanib.
CarbamazepineThe serum concentration of Vandetanib can be decreased when it is combined with Carbamazepine.
CitalopramCitalopram may increase the QTc-prolonging activities of Vandetanib.
ColchicineThe serum concentration of Colchicine can be increased when it is combined with Vandetanib.
Dabigatran etexilateThe serum concentration of the active metabolites of Dabigatran etexilate can be increased when Dabigatran etexilate is used in combination with Vandetanib.
DabrafenibThe serum concentration of Vandetanib can be decreased when it is combined with Dabrafenib.
DeferasiroxThe serum concentration of Vandetanib can be decreased when it is combined with Deferasirox.
DigoxinThe serum concentration of Digoxin can be increased when it is combined with Vandetanib.
DofetilideDofetilide may increase the QTc-prolonging activities of Vandetanib.
DoxorubicinThe serum concentration of Doxorubicin can be increased when it is combined with Vandetanib.
EdoxabanThe serum concentration of Edoxaban can be increased when it is combined with Vandetanib.
EnzalutamideThe serum concentration of Vandetanib can be decreased when it is combined with Enzalutamide.
EverolimusThe serum concentration of Everolimus can be increased when it is combined with Vandetanib.
FosphenytoinThe serum concentration of Vandetanib can be decreased when it is combined with Fosphenytoin.
GoserelinGoserelin may increase the QTc-prolonging activities of Vandetanib.
IvabradineIvabradine may increase the QTc-prolonging activities of Vandetanib.
LedipasvirThe serum concentration of Ledipasvir can be increased when it is combined with Vandetanib.
LeuprolideLeuprolide may increase the QTc-prolonging activities of Vandetanib.
MetforminThe serum concentration of Metformin can be increased when it is combined with Vandetanib.
MifepristoneMifepristone may increase the QTc-prolonging activities of Vandetanib.
MitotaneThe serum concentration of Vandetanib can be decreased when it is combined with Mitotane.
NaloxegolThe serum concentration of Naloxegol can be increased when it is combined with Vandetanib.
OctreotideOctreotide may increase the QTc-prolonging activities of Vandetanib.
PamidronateThe risk or severity of adverse effects can be increased when Vandetanib is combined with Pamidronate.
PazopanibThe serum concentration of Pazopanib can be increased when it is combined with Vandetanib.
PhenobarbitalThe serum concentration of Vandetanib can be decreased when it is combined with Phenobarbital.
PhenytoinThe serum concentration of Vandetanib can be decreased when it is combined with Phenytoin.
PrimidoneThe serum concentration of Vandetanib can be decreased when it is combined with Primidone.
PrucaloprideThe serum concentration of Prucalopride can be increased when it is combined with Vandetanib.
RifabutinThe serum concentration of Vandetanib can be decreased when it is combined with Rifabutin.
RifampicinThe serum concentration of Vandetanib can be decreased when it is combined with Rifampicin.
RifapentineThe serum concentration of Vandetanib can be decreased when it is combined with Rifapentine.
RifaximinThe serum concentration of Rifaximin can be increased when it is combined with Vandetanib.
SaquinavirThe serum concentration of Saquinavir can be increased when it is combined with Vandetanib.
SilodosinThe serum concentration of Silodosin can be increased when it is combined with Vandetanib.
SiltuximabThe serum concentration of Vandetanib can be decreased when it is combined with Siltuximab.
St. John's WortThe serum concentration of Vandetanib can be decreased when it is combined with St. John's Wort.
TocilizumabThe serum concentration of Vandetanib can be decreased when it is combined with Tocilizumab.
TopotecanThe serum concentration of Topotecan can be increased when it is combined with Vandetanib.
VerapamilThe serum concentration of Verapamil can be increased when it is combined with Vandetanib.
VincristineThe serum concentration of Vincristine can be increased when it is combined with Vandetanib.
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Vascular endothelial growth factor receptor binding
Specific Function:
Growth factor active in angiogenesis, vasculogenesis and endothelial cell growth. Induces endothelial cell proliferation, promotes cell migration, inhibits apoptosis and induces permeabilization of blood vessels. Binds to the FLT1/VEGFR1 and KDR/VEGFR2 receptors, heparan sulfate and heparin. NRP1/Neuropilin-1 binds isoforms VEGF-165 and VEGF-145. Isoform VEGF165B binds to KDR but does not activ...
Gene Name:
VEGFA
Uniprot ID:
P15692
Molecular Weight:
27042.205 Da
References
  1. Link [Link]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Ubiquitin protein ligase binding
Specific Function:
Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses. Known ligands include EGF, TGFA/TGF-alpha, amphiregulin, epigen/EPGN, BTC/betacellulin, epiregulin/EREG and HBEGF/heparin-binding EGF. Ligand binding triggers receptor homo- and/or heterodimerization and autophosphorylation on ke...
Gene Name:
EGFR
Uniprot ID:
P00533
Molecular Weight:
134276.185 Da
References
  1. Link [Link]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Receptor binding
Specific Function:
Non-receptor tyrosine-protein kinase implicated in the regulation of a variety of signaling pathways that control the differentiation and maintenance of normal epithelia, as well as tumor growth. Function seems to be context dependent and differ depending on cell type, as well as its intracellular localization. A number of potential nuclear and cytoplasmic substrates have been identified. These...
Gene Name:
PTK6
Uniprot ID:
Q13882
Molecular Weight:
51833.72 Da
References
  1. Link [Link]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Transmembrane receptor protein tyrosine kinase activity
Specific Function:
Tyrosine-protein kinase that acts as cell-surface receptor for ANGPT1, ANGPT2 and ANGPT4 and regulates angiogenesis, endothelial cell survival, proliferation, migration, adhesion and cell spreading, reorganization of the actin cytoskeleton, but also maintenance of vascular quiescence. Has anti-inflammatory effects by preventing the leakage of proinflammatory plasma proteins and leukocytes from ...
Gene Name:
TEK
Uniprot ID:
Q02763
Molecular Weight:
125829.005 Da
References
  1. Link [Link]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Nadp binding
Specific Function:
This protein is involved in the oxidative metabolism of a variety of xenobiotics such as drugs and pesticides. Form I catalyzes the N-oxygenation of secondary and tertiary amines.
Gene Name:
FMO1
Uniprot ID:
Q01740
Molecular Weight:
60310.285 Da
References
  1. Link [Link]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Trimethylamine monooxygenase activity
Specific Function:
Involved in the oxidative metabolism of a variety of xenobiotics such as drugs and pesticides. It N-oxygenates primary aliphatic alkylamines as well as secondary and tertiary amines. Plays an important role in the metabolism of trimethylamine (TMA), via the production of TMA N-oxide (TMAO). Is also able to perform S-oxidation when acting on sulfide compounds (PubMed:9224773).
Gene Name:
FMO3
Uniprot ID:
P31513
Molecular Weight:
60032.975 Da
References
  1. Link [Link]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
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 reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
References
  1. Link [Link]

Carriers

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
binder
General Function:
Not Available
Specific Function:
Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in the body. Appears to function in modulating the activity of the immune system during the acute-phase reaction.
Gene Name:
ORM1
Uniprot ID:
P02763
Molecular Weight:
23511.38 Da
References
  1. Link [Link]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
binder
General Function:
Toxic substance binding
Specific Function:
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloidal osmotic pressure of blood. Major zinc transporter in plasma, typically binds about 80% of all plasma zinc.
Gene Name:
ALB
Uniprot ID:
P02768
Molecular Weight:
69365.94 Da
References
  1. Link [Link]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Transporter activity
Specific Function:
Mediates export of organic anions and drugs from the cytoplasm. Mediates ATP-dependent transport of glutathione and glutathione conjugates, leukotriene C4, estradiol-17-beta-o-glucuronide, methotrexate, antiviral drugs and other xenobiotics. Confers resistance to anticancer drugs. Hydrolyzes ATP with low efficiency.
Gene Name:
ABCC1
Uniprot ID:
P33527
Molecular Weight:
171589.5 Da
References
  1. Zheng LS, Wang F, Li YH, Zhang X, Chen LM, Liang YJ, Dai CL, Yan YY, Tao LY, Mi YJ, Yang AK, To KK, Fu LW: Vandetanib (Zactima, ZD6474) antagonizes ABCC1- and ABCG2-mediated multidrug resistance by inhibition of their transport function. PLoS One. 2009;4(4):e5172. doi: 10.1371/journal.pone.0005172. Epub 2009 Apr 23. [PubMed:19390592 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
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 from mitochondria to cytosol and from cytosol to extracellular space, and cellular export of hemin, and heme. Xenobiotic transporter that may play an important role in the exclusion of xenobiotics from t...
Gene Name:
ABCG2
Uniprot ID:
Q9UNQ0
Molecular Weight:
72313.47 Da
References
  1. Zheng LS, Wang F, Li YH, Zhang X, Chen LM, Liang YJ, Dai CL, Yan YY, Tao LY, Mi YJ, Yang AK, To KK, Fu LW: Vandetanib (Zactima, ZD6474) antagonizes ABCC1- and ABCG2-mediated multidrug resistance by inhibition of their transport function. PLoS One. 2009;4(4):e5172. doi: 10.1371/journal.pone.0005172. Epub 2009 Apr 23. [PubMed:19390592 ]
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Drug created on November 18, 2007 11:23 / Updated on May 26, 2016 02:10