Banner
Identification
Name Gefitinib
Accession Number DB00317 (APRD00997, DB07998)
Type small molecule
Groups approved
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
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms Not Available
Salts Not Available
Brand names
Name Company
Iressa
Irressat
Brand mixtures Not Available
Categories
  • Antineoplastic Agents
  • Protein Kinase Inhibitors
CAS number 184475-35-2
Weight Average: 446.902
Monoisotopic: 446.152096566
Chemical Formula C22H24ClFN4O3
InChI Key InChIKey=XGALLCVXEZPNRQ-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)
Plain Text
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
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Quinazolines
Substructures
  • Quinazolines
  • Aliphatic and Aryl Amines
  • Phenols and Derivatives
  • Ethers
  • Benzene and Derivatives
  • Aryl Halides
  • Halobenzenes
  • Pyrimidines and Derivatives
  • Catechols
  • Heterocyclic compounds
  • Aromatic compounds
  • Anisoles
  • Morpholines
  • Cyanamides
  • Phenyl Esters
  • Anilines
Pharmacology
Indication For the continued treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of either platinum-based or docetaxel chemotherapies.
Pharmacodynamics Gefitinib 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 action Gefitinib 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.
Absorption Absorbed slowly after oral administration with mean bioavailability of 60%.
Volume of distribution
  • 1400 L
Protein binding 90% primarily to serum albumin and alpha 1-acid glycoproteins.
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 elimination Elimination 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 life 48 hours
Clearance
  • 595 mL/min
Toxicity The 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
Pathway Name SMPDB ID
Smp00473 Gefitinib Pathway SMP00473
Pharmacoeconomics
Manufacturers
  • Astrazeneca uk ltd
Packagers
Dosage forms
Form Route Strength
Tablet Oral
Prices
Unit description Cost Unit
Tarceva 150 mg tablet 163.98 USD tablet
Tarceva 100 mg tablet 144.98 USD tablet
Iressa 250 mg tablet 68.08 USD tablet
Tarceva 25 mg tablet 52.78 USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Country Patent Number Approved Expires (estimated)
United States 5770599 1997-05-05 2017-05-05
United States 5457105 1993-01-19 2013-01-19
Canada 2215732 2002-04-09 2016-04-23
Canada 2086968 1998-06-23 2013-01-08
Properties
State solid
Experimental Properties
Property Value Source
water solubility Sparingly soluble (<pH4) Not Available
logP 3.2 Not Available
Predicted Properties
Property Value Source
water solubility 2.70e-02 g/l ALOGPS
logP 4.02 ALOGPS
logP 3.75 ChemAxon
logS -4.2 ALOGPS
pKa (strongest acidic) 16.11 ChemAxon
pKa (strongest basic) 6.85 ChemAxon
physiological charge 0 ChemAxon
hydrogen acceptor count 7 ChemAxon
hydrogen donor count 1 ChemAxon
polar surface area 68.74 ChemAxon
rotatable bond count 8 ChemAxon
refractivity 117.51 ChemAxon
polarizability 46.11 ChemAxon
References
Synthesis Reference Not Available
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
External Links
Resource Link
KEGG Drug D01977 Link_out
PubChem Compound 123631 Link_out
PubChem Substance 46508649 Link_out
ChemSpider 110217 Link_out
BindingDB 5447 Link_out
ChEBI 49668 Link_out
ChEMBL 49668 Link_out
Therapeutic Targets Database DAP000657 Link_out
PharmGKB PA131301952 Link_out
HET IRE Link_out
Drug Product Database 2248676 Link_out
RxList http://www.rxlist.com/cgi/generic3/iressa.htm Link_out
Drugs.com http://www.drugs.com/cdi/gefitinib.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Gefitinib Link_out
ATC Codes
  • L01XE02
AHFS Codes
  • 10:00.00
PDB Entries Not Available
FDA label show (80.5 KB)
MSDS show (59.2 KB)
Interactions
Drug Interactions
Drug Interaction
Acenocoumarol Gefitinib may increase the anticoagulant effect of acenocoumarol.
Amobarbital The CYP3A4 inducer, amobarbital, may decrease the serum concentration and therapeutic effects of gefitinib.
Anisindione Gefitinib may increase the anticoagulant effect of anisindione.
Aprobarbital The CYP3A4 inducer, aprobarbital, may decrease the serum concentration and therapeutic effects of gefitinib.
Butabarbital The CYP3A4 inducer, butabarbital, may decrease the serum concentration and therapeutic effects of gefitinib.
Butalbital The CYP3A4 inducer, butalbital, may decrease the serum concentration and therapeutic effects of gefitinib.
Butethal The CYP3A4 inducer, butethal, may decrease the serum concentration and therapeutic effects of gefitinib.
Carbamazepine The CYP3A4 inducer, carbamazepine, may decrease the serum concentration and therapeutic effects of gefitinib.
Clarithromycin This CYP3A4 inhibitor increases levels/toxicity of gefitinib
Dicumarol Gefitinib may increase the anticoagulant effect of dicumarol.
Dihydroquinidine barbiturate The CYP3A4 inducer, dihydroquinidine barbiturate, may decrease the serum concentration and therapeutic effects of gefitinib.
Erythromycin This CYP3A4 inhibitor increases levels/toxicity of gefitinib
Ethotoin The CYP3A4 inducer, ethotoin, may decrease the serum concentration and therapeutic effects of gefitinib.
Fosphenytoin The CYP3A4 inducer, fosphenytoin, may decrease the serum concentration and therapeutic effects of gefitinib.
Heptabarbital The CYP3A4 inducer, heptabarbital, may decrease the serum concentration and therapeutic effects of gefitinib.
Hexobarbital The CYP3A4 inducer, hexobarbital, may decrease the serum concentration and therapeutic effects of gefitinib.
Itraconazole Itraconazole, 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.
Ketoconazole This CYP3A4 inhibitor increases levels/toxicity of gefitinib
Mephenytoin The CYP3A4 inducer, mephenytoin, may decrease the serum concentration and therapeutic effects of gefitinib.
Methohexital The CYP3A4 inducer, methohexital, may decrease the serum concentration and therapeutic effects of gefitinib.
Methylphenobarbital The CYP3A4 inducer, methylphenobarbital, may decrease the serum concentration and therapeutic effects of gefitinib.
Pentobarbital The CYP3A4 inducer, pentobarbital, may decrease the serum concentration and therapeutic effects of gefitinib.
Phenobarbital The CYP3A4 inducer, phenobarbital, may decrease the serum concentration and therapeutic effects of gefitinib.
Phenytoin The CYP3A4 inducer, phenytoin, may decrease the serum concentration and therapeutic effects of gefitinib.
Primidone The CYP3A4 inducer, primidone, may decrease the serum concentration and therapeutic effects of gefitinib.
Quinidine barbiturate The CYP3A4 inducer, quinidine barbiturate, may decrease the serum concentration and therapeutic effects of gefitinib.
Rifampin Rifampin reduces levels and efficacy of gefitinib
Ritonavir This CYP3A4 inhibitor increases levels/toxicity of gefitinib
Secobarbital The CYP3A4 inducer, secobarbital, may decrease the serum concentration and therapeutic effects of gefitinib.
St. John's Wort The CYP3A4 inducer, St. John's Wort, may decrease the serum concentration and therapeutic effects of gefitinib.
Talbutal The CYP3A4 inducer, talbutal, may decrease the serum concentration and therapeutic effects of gefitinib.
Telithromycin Telithromycin 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.
Topotecan The 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.
Trastuzumab Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
Voriconazole Voriconazole, 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.
Warfarin Gefitinib 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

Pharmacological action: yes
Actions: antagonist

Isoform 2/truncated isoform may act as an antagonist

Organism class: human
UniProt ID: P00533 Link_out
Gene: EGFR Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

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 xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate, inhibitor

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 antidepressants

UniProt ID: P10635 Link_out
Gene: CYP2D6 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Transporters

1. Multidrug resistance protein 1

Actions: inhibitor

Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells

UniProt ID: P08183 Link_out
Gene: ABCB1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: inhibitor

Xenobiotic transporter that may play an important role in the exclusion of xenobiotics from the brain. May be involved in brain-to-blood efflux. Appears to play a major role in the multidrug resistance phenotype of several cancer cell lines. When overexpressed, the transfected cells become resistant to mitoxantrone, daunorubicin and doxorubicin, display diminished intracellular accumulation of daunorubicin, and manifest an ATP- dependent increase in the efflux of rhodamine 123

UniProt ID: Q9UNQ0 Link_out
Gene: ABCG2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Comments
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19