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Identification
NameGefitinib
Accession NumberDB00317  (APRD00997, DB07998)
Typesmall molecule
Groupsapproved, investigational
Description

Gefitinib (originally coded ZD1839) is a drug used in the treatment of certain types of cancer. Acting in a similar manner to erlotinib (marketed as Tarceva), gefitinib selectively targets the mutant proteins in malignant cells. It is marketed by AstraZeneca under the trade name Iressa. [Wikipedia]

Structure
Thumb
Synonyms
SynonymLanguageCode
4-(3'-chloro-4'-Fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazolineNot AvailableNot Available
GefitinibNot AvailableNot Available
IressaNot AvailableNot Available
N-(3-chloro-4-Fluorophenyl)-7-methoxy-6-(3-(4-morpholinyl)propoxy)-4-quinazolinamineNot AvailableNot Available
ZD 1839Not AvailableNot Available
SaltsNot Available
Brand names
NameCompany
IressaAstraZeneca
Brand mixturesNot Available
CategoriesNot Available
CAS number184475-35-2
WeightAverage: 446.902
Monoisotopic: 446.152096566
Chemical FormulaC22H24ClFN4O3
InChI KeyXGALLCVXEZPNRQ-UHFFFAOYSA-N
InChI
InChI=1S/C22H24ClFN4O3/c1-29-20-13-19-16(12-21(20)31-8-2-5-28-6-9-30-10-7-28)22(26-14-25-19)27-15-3-4-18(24)17(23)11-15/h3-4,11-14H,2,5-10H2,1H3,(H,25,26,27)
IUPAC Name
N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(morpholin-4-yl)propoxy]quinazolin-4-amine
SMILES
COC1=C(OCCCN2CCOCC2)C=C2C(NC3=CC(Cl)=C(F)C=C3)=NC=NC2=C1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassNaphthyridines
SubclassQuinazolines
Direct parentQuinazolinamines
Alternative parentsAnisoles; Aminopyrimidines and Derivatives; Alkyl Aryl Ethers; Chlorobenzenes; Fluorobenzenes; Morpholines; Aryl Chlorides; Aryl Fluorides; Tertiary Amines; Polyamines; Secondary Amines; Organochlorides; Organofluorides
Substituentsanisole; phenol ether; fluorobenzene; aminopyrimidine; chlorobenzene; alkyl aryl ether; oxazinane; aryl halide; pyrimidine; benzene; aryl chloride; morpholine; aryl fluoride; tertiary amine; ether; secondary amine; polyamine; organochloride; organohalogen; organofluoride; amine; organonitrogen compound
Classification descriptionThis compound belongs to the quinazolinamines. These are heterocyclic aromatic compounds containing a quianazoline moiety substituted by one or more amine groups.
Pharmacology
IndicationFor the continued treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of either platinum-based or docetaxel chemotherapies.
PharmacodynamicsGefitinib inhibits the intracellular phosphorylation of numerous tyrosine kinases associated with transmembrane cell surface receptors, including the tyrosine kinases associated with the epidermal growth factor receptor (EGFR-TK). EGFR is expressed on the cell surface of many normal cells and cancer cells.
Mechanism of actionGefitinib inhibits the epidermal growth factor receptor (EGFR) tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme. Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited; and malignant cells are inhibited. Gefitinib is the first selective inhibitor of the EGFR tyrosine kinase which is also referred to as Her1 or ErbB-1. EGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers. Overexpression leads to inappropriate activation of the apoptotic Ras signal transduction cascade, eventually leading to uncontrolled cell proliferation.
AbsorptionAbsorbed slowly after oral administration with a mean bioavailability of 60%. Peak plasma levels occurs 3-7 hours post-administration. Food does not affect the bioavailability of gefitinib.
Volume of distribution
  • 1400 L [IV administration]
Protein binding90% primarily to serum albumin and alpha 1-acid glycoproteins (independent of drug concentrations).
Metabolism

Primarily hepatic via CYP3A4. Three sites of biotransformation have been identified: metabolism of the N-propoxymorpholino-group, demethylation of the methoxy-substituent on the quinazoline, and oxidative defluorination of the halogenated phenyl group.

Route of eliminationElimination is by metabolism (primarily CYP3A4) and excretion in feces. Excretion is predominantly via the feces (86%), with renal elimination of drug and metabolites accounting for less than 4% of the administered dose.
Half life48 hours [IV administration]
Clearance
  • 595 mL/min [IV administration]
ToxicityThe acute toxicity of gefitinib up to 500 mg in clinical studies has been low. In non-clinical studies, a single dose of 12,000 mg/m2 (about 80 times the recommended clinical dose on a mg/m2 basis) was lethal to rats. Half this dose caused no mortality in mice. Symptoms of overdose include diarrhea and skin rash.
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Gefitinib Action PathwayDrug actionSMP00473
SNP Mediated Effects
Interacting Gene/EnzymeSNP RS IDAllele nameDefining changeEffectReference(s)
Epidermal growth factor receptor
Gene symbol: EGFR
UniProt: P00533
Not AvailableG719A/C OR (L858R and L861Q)Not AvailableAssociated with enhanced activation of the EGFR tyrosine kinase in patients with non-small cell lung cancer (NSCLC) recieving tyrosine kinase inhibitor therapy.15118073
SNP Mediated Adverse Drug Reactions
Interacting Gene/EnzymeSNP RS IDAllele nameDefining changeAdverse ReactionReference(s)
ATP-binding cassette sub-family G member 2
Gene symbol: ABCG2
UniProt: Q9UNQ0
rs2231142 Not AvailableA AlleleDiarrhea17148776
ATP-binding cassette sub-family G member 2
Gene symbol: ABCG2
UniProt: Q9UNQ0
rs2231142 Not AvailableA alleleIn non-small lung cancer patients, those that are heterozygous (ABCG2 421C>A) have a higher risk of diarrhea.17148776
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9961
Blood Brain Barrier + 0.9759
Caco-2 permeable + 0.5934
P-glycoprotein substrate Substrate 0.693
P-glycoprotein inhibitor I Inhibitor 0.7361
P-glycoprotein inhibitor II Inhibitor 0.923
Renal organic cation transporter Inhibitor 0.5543
CYP450 2C9 substrate Non-substrate 0.7853
CYP450 2D6 substrate Non-substrate 0.6447
CYP450 3A4 substrate Substrate 0.6354
CYP450 1A2 substrate Inhibitor 0.7516
CYP450 2C9 substrate Non-inhibitor 0.6272
CYP450 2D6 substrate Non-inhibitor 0.6536
CYP450 2C19 substrate Inhibitor 0.644
CYP450 3A4 substrate Inhibitor 0.8206
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.9309
Ames test Non AMES toxic 0.5
Carcinogenicity Non-carcinogens 0.9218
Biodegradation Not ready biodegradable 1.0
Rat acute toxicity 2.5141 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Strong inhibitor 0.758
hERG inhibition (predictor II) Inhibitor 0.8019
Pharmacoeconomics
Manufacturers
  • Astrazeneca uk ltd
Packagers
Dosage forms
FormRouteStrength
TabletOral250 mg
Prices
Unit descriptionCostUnit
Tarceva 150 mg tablet163.98USDtablet
Tarceva 100 mg tablet144.98USDtablet
Iressa 250 mg tablet68.08USDtablet
Tarceva 25 mg tablet52.78USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States57705991997-05-052017-05-05
United States54571051993-01-192013-01-19
Canada22157322002-04-092016-04-23
Canada20869681998-06-232013-01-08
Properties
Statesolid
Experimental Properties
PropertyValueSource
water solubilitySparingly soluble (<pH4)Not Available
logP3.2Not Available
pKa5.4 and 7.2FDA label
Predicted Properties
PropertyValueSource
water solubility2.70e-02 g/lALOGPS
logP4.02ALOGPS
logP3.75ChemAxon
logS-4.2ALOGPS
pKa (strongest acidic)16.11ChemAxon
pKa (strongest basic)6.85ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count7ChemAxon
hydrogen donor count1ChemAxon
polar surface area68.74ChemAxon
rotatable bond count8ChemAxon
refractivity117.51ChemAxon
polarizability46.11ChemAxon
number of rings4ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleYesChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

DrugSyn.org

US5770599
General Reference
  1. Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, Singh B, Heelan R, Rusch V, Fulton L, Mardis E, Kupfer D, Wilson R, Kris M, Varmus H: EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A. 2004 Sep 7;101(36):13306-11. Epub 2004 Aug 25. Pubmed
  2. Sordella R, Bell DW, Haber DA, Settleman J: Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science. 2004 Aug 20;305(5687):1163-7. Epub 2004 Jul 29. Pubmed
  3. FDA label
External Links
ResourceLink
KEGG DrugD01977
PubChem Compound123631
PubChem Substance46508649
ChemSpider110217
BindingDB5447
ChEBI49668
ChEMBLCHEMBL939
Therapeutic Targets DatabaseDAP000657
PharmGKBPA131301952
HETIRE
Drug Product Database2248676
RxListhttp://www.rxlist.com/cgi/generic3/iressa.htm
Drugs.comhttp://www.drugs.com/cdi/gefitinib.html
WikipediaGefitinib
ATC CodesL01XE02
AHFS Codes
  • 10:00.00
PDB EntriesNot Available
FDA labelshow(80.5 KB)
MSDSshow(59.2 KB)
Interactions
Drug Interactions
Drug
AcenocoumarolGefitinib may increase the anticoagulant effect of acenocoumarol.
AmobarbitalThe CYP3A4 inducer, amobarbital, may decrease the serum concentration and therapeutic effects of gefitinib.
AnisindioneGefitinib may increase the anticoagulant effect of anisindione.
AprobarbitalThe CYP3A4 inducer, aprobarbital, may decrease the serum concentration and therapeutic effects of gefitinib.
ButabarbitalThe CYP3A4 inducer, butabarbital, may decrease the serum concentration and therapeutic effects of gefitinib.
ButalbitalThe CYP3A4 inducer, butalbital, may decrease the serum concentration and therapeutic effects of gefitinib.
ButethalThe CYP3A4 inducer, butethal, may decrease the serum concentration and therapeutic effects of gefitinib.
CarbamazepineThe CYP3A4 inducer, carbamazepine, may decrease the serum concentration and therapeutic effects of gefitinib.
ClarithromycinThis CYP3A4 inhibitor increases levels/toxicity of gefitinib
DicoumarolGefitinib may increase the anticoagulant effect of dicumarol.
Dihydroquinidine barbiturateThe CYP3A4 inducer, dihydroquinidine barbiturate, may decrease the serum concentration and therapeutic effects of gefitinib.
ErythromycinThis CYP3A4 inhibitor increases levels/toxicity of gefitinib
EthotoinThe CYP3A4 inducer, ethotoin, may decrease the serum concentration and therapeutic effects of gefitinib.
EtravirineGefitinib, when administered concomitantly with etravirine (a strong CYP3A4 inducer), may experience a decrease in serum concentration. It is recommended to increase gefitinib dosage, if clinically appropriate, and to monitor for gefitinib therapy for efficacy and toxicity.
FosphenytoinThe CYP3A4 inducer, fosphenytoin, may decrease the serum concentration and therapeutic effects of gefitinib.
HeptabarbitalThe CYP3A4 inducer, heptabarbital, may decrease the serum concentration and therapeutic effects of gefitinib.
HexobarbitalThe CYP3A4 inducer, hexobarbital, may decrease the serum concentration and therapeutic effects of gefitinib.
ItraconazoleItraconazole, a strong CYP3A4 inhibitor, may decrease the metabolism of gefitinib. Monitor for changes in the therapeutic and adverse effects of gefitinib if itraconazole is initiated, discontinued or dose changed.
KetoconazoleThis CYP3A4 inhibitor increases levels/toxicity of gefitinib
MephenytoinThe CYP3A4 inducer, mephenytoin, may decrease the serum concentration and therapeutic effects of gefitinib.
MethohexitalThe CYP3A4 inducer, methohexital, may decrease the serum concentration and therapeutic effects of gefitinib.
MethylphenobarbitalThe CYP3A4 inducer, methylphenobarbital, may decrease the serum concentration and therapeutic effects of gefitinib.
PentobarbitalThe CYP3A4 inducer, pentobarbital, may decrease the serum concentration and therapeutic effects of gefitinib.
PhenobarbitalThe CYP3A4 inducer, phenobarbital, may decrease the serum concentration and therapeutic effects of gefitinib.
PhenytoinThe CYP3A4 inducer, phenytoin, may decrease the serum concentration and therapeutic effects of gefitinib.
PrimidoneThe CYP3A4 inducer, primidone, may decrease the serum concentration and therapeutic effects of gefitinib.
Quinidine barbiturateThe CYP3A4 inducer, quinidine barbiturate, may decrease the serum concentration and therapeutic effects of gefitinib.
RifampicinRifampin reduces levels and efficacy of gefitinib
RitonavirThis CYP3A4 inhibitor increases levels/toxicity of gefitinib
SecobarbitalThe CYP3A4 inducer, secobarbital, may decrease the serum concentration and therapeutic effects of gefitinib.
St. John's WortThe CYP3A4 inducer, St. John's Wort, may decrease the serum concentration and therapeutic effects of gefitinib.
TalbutalThe CYP3A4 inducer, talbutal, may decrease the serum concentration and therapeutic effects of gefitinib.
TelithromycinTelithromycin may reduce clearance of Gefitinib. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Gefitinib if Telithromycin is initiated, discontinued or dose changed.
TopotecanThe BCRP/ABCG2 inhibitor, Gefitnib, may increase the bioavailability and serum concentration of oral Topotecan. Monitor for change in the therapeutic and adverse effects of Topotecan if Gefitinib is initiated, discontinued or dose changed.
TrastuzumabTrastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
VoriconazoleVoriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of gefitinib by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of gefitinib if voriconazole is initiated, discontinued or dose changed.
WarfarinGefitinib may increase the anticoagulant effect of warfarin.
Food Interactions
  • Avoid fresh grapefruit and its juice during therapy as grapefruit may increase serum product levels.
  • Take without regard to meals.

Targets

1. Epidermal growth factor receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
Epidermal growth factor receptor P00533 Details

References:

  1. Ciardiello F, Caputo R, Bianco R, Damiano V, Pomatico G, De Placido S, Bianco AR, Tortora G: Antitumor effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD-1839 (Iressa), an epidermal growth factor receptor-selective tyrosine kinase inhibitor. Clin Cancer Res. 2000 May;6(5):2053-63. Pubmed
  2. Albanell J, Codony-Servat J, Rojo F, Del Campo JM, Sauleda S, Anido J, Raspall G, Giralt J, Rosello J, Nicholson RI, Mendelsohn J, Baselga J: Activated extracellular signal-regulated kinases: association with epidermal growth factor receptor/transforming growth factor alpha expression in head and neck squamous carcinoma and inhibition by anti-epidermal growth factor receptor treatments. Cancer Res. 2001 Sep 1;61(17):6500-10. Pubmed
  3. Nicholson RI, Hutcheson IR, Harper ME, Knowlden JM, Barrow D, McClelland RA, Jones HE, Wakeling AE, Gee JM: Modulation of epidermal growth factor receptor in endocrine-resistant, oestrogen receptor-positive breast cancer. Endocr Relat Cancer. 2001 Sep;8(3):175-82. Pubmed
  4. Moasser MM, Basso A, Averbuch SD, Rosen N: The tyrosine kinase inhibitor ZD1839 (“Iressa”) inhibits HER2-driven signaling and suppresses the growth of HER2-overexpressing tumor cells. Cancer Res. 2001 Oct 1;61(19):7184-8. Pubmed
  5. Arteaga CL, Johnson DH: Tyrosine kinase inhibitors-ZD1839 (Iressa). Curr Opin Oncol. 2001 Nov;13(6):491-8. Pubmed
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

Enzymes

1. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

2. Cytochrome P450 2D6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2D6 P10635 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

3. Cytochrome P450 3A5

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
Cytochrome P450 3A5 P20815 Details

References:

  1. Li J, Zhao M, He P, Hidalgo M, Baker SD: Differential metabolism of gefitinib and erlotinib by human cytochrome P450 enzymes. Clin Cancer Res. 2007 Jun 15;13(12):3731-7. Pubmed

4. Cytochrome P450 1A1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Cytochrome P450 1A1 P04798 Details

References:

  1. Li J, Zhao M, He P, Hidalgo M, Baker SD: Differential metabolism of gefitinib and erlotinib by human cytochrome P450 enzymes. Clin Cancer Res. 2007 Jun 15;13(12):3731-7. Pubmed
  2. https://www.pharmgkb.org/pathway/PA152325160

5. Cytochrome P450 2C9

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2C9 P11712 Details

References:

  1. https://www.pharmgkb.org/pathway/PA152325160

6. Cytochrome P450 2C19

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2C19 P33261 Details

References:

  1. https://www.pharmgkb.org/pathway/PA152325160

Carriers

1. Serum albumin

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Serum albumin P02768 Details

References:

  1. FDA label

2. Alpha-1-acid glycoprotein 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Alpha-1-acid glycoprotein 1 P02763 Details

References:

  1. FDA label

Transporters

1. Multidrug resistance protein 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Multidrug resistance protein 1 P08183 Details

References:

  1. Shen J, Carcaboso AM, Hubbard KE, Tagen M, Wynn HG, Panetta JC, Waters CM, Elmeliegy MA, Stewart CF: Compartment-specific roles of ATP-binding cassette transporters define differential topotecan distribution in brain parenchyma and cerebrospinal fluid. Cancer Res. 2009 Jul 15;69(14):5885-92. Epub 2009 Jun 30. Pubmed

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

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

References:

  1. Ozvegy-Laczka C, Hegedus T, Varady G, Ujhelly O, Schuetz JD, Varadi A, Keri G, Orfi L, Nemet K, Sarkadi B: High-affinity interaction of tyrosine kinase inhibitors with the ABCG2 multidrug transporter. Mol Pharmacol. 2004 Jun;65(6):1485-95. Pubmed
  2. An Y, Ongkeko WM: ABCG2: the key to chemoresistance in cancer stem cells? Expert Opin Drug Metab Toxicol. 2009 Dec;5(12):1529-42. Pubmed
  3. Shen J, Carcaboso AM, Hubbard KE, Tagen M, Wynn HG, Panetta JC, Waters CM, Elmeliegy MA, Stewart CF: Compartment-specific roles of ATP-binding cassette transporters define differential topotecan distribution in brain parenchyma and cerebrospinal fluid. Cancer Res. 2009 Jul 15;69(14):5885-92. Epub 2009 Jun 30. Pubmed
  4. Noguchi K, Kawahara H, Kaji A, Katayama K, Mitsuhashi J, Sugimoto Y: Substrate-dependent bidirectional modulation of P-glycoprotein-mediated drug resistance by erlotinib. Cancer Sci. 2009 Sep;100(9):1701-7. Epub 2009 May 12. Pubmed
  5. Shi Z, Parmar S, Peng XX, Shen T, Robey RW, Bates SE, Fu LW, Shao Y, Chen YM, Zang F, Chen ZS: The epidermal growth factor tyrosine kinase inhibitor AG1478 and erlotinib reverse ABCG2-mediated drug resistance. Oncol Rep. 2009 Feb;21(2):483-9. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on October 08, 2013 14:23