PharmGKB: The Pharmacogenomics Knowledge Base

Drug/Small Molecule:
gefitinib

2D structure

Overview

Generic Names: ZD-1839; ZD1839
Trade Names: Iressa; Irressat
PharmGKB Accession Id: PA131301952

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 (source: Drug Bank)

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. (source: Drug Bank)

ATC Therapeutic Category

  • L01XE:Protein kinase inhibitors

Pharmacology, Interactions, and Contraindications

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. (source: Drug Bank)

Pharmacology

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. (source: Drug Bank)

Food Interactions

Avoid fresh grapefruit and its juice during therapy as grapefruit may increase serum product levels.
Take without regard to meals. (source: Drug Bank)

Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation

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. (source: Drug Bank)

Protein Binding

90% primarily to serum albumin and alpha 1-acid glycoproteins. (source: Drug Bank)

Absorption

Absorbed slowly after oral administration with mean bioavailability of 60%. (source: Drug Bank)

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/m<sup>2</sup> (about 80 times the recommended clinical dose on a mg/m<sup>2</sup> basis) was lethal to rats. Half this dose caused no mortality in mice. Symptoms of overdose include diarrhea and skin rash. (source: Drug Bank)

Isomeric SMILES Code:

COc1cc2c(cc1OCCCN3CCOCC3)c(ncn2)Nc4ccc(c(c4)Cl)F (source: Drug Bank)

In-Depth Annotations (In-Depth Annotation)

  1. rs59421388 at chr22:40853554 in CYP2D6
    This variant is part of the reduced functioning haplotype CYP2D6*29, which is found at an estimated allele frequency of 20% in African Tanzanians.
    Variant Name:
    CYP2D6: 3183G>A; 3271G>A
    Related Drugs:
    citalopram, codeine, desipramine, fluoxetine, fluvoxamine, gefitinib, haloperidol, imipramine, morphine, tramadol
    Related Diseases:
    Cystic Fibrosis, Depression, Hypertension, Neoplasms, Pain, Parkinson Disease, Schizophrenia
    Evidence:
    http://www.pharmgkb.org/.../variant.jsp
  2. rs61736512 at chr22:40855078 in CYP2D6
    This variant is part of the reduced functioning haplotype CYP2D6*29, which is found at an estimated allele frequency of 20% in African Tanzanians.
    Variant Name:
    CYP2D6: 1659G>A; 1747G>A
    Related Drugs:
    citalopram, codeine, desipramine, fluoxetine, fluvoxamine, gefitinib, haloperidol, imipramine, morphine, tramadol
    Related Diseases:
    Cystic Fibrosis, Depression, Hypertension, Neoplasms, Pain, Parkinson Disease, Schizophrenia
    Evidence:
    http://www.pharmgkb.org/.../variant.jsp

Curated Annotations (Curated Annotation)

  1. rs2231142 at chr4:89271347 in ABCG2
    Lung cancer patients carrying the A allele of ABCG2:421C>A were at increased risk for diarrhea but not skin toxicity following oral gefitinib treatment.
    Variant Name:
    ABCG2:421C>A; ABCG2:Q141K; rs2231142
    Related Drugs:
    gefitinib
    Related Diseases:
    Carcinoma, Non-Small-Cell Lung, Diarrhea, Lung Neoplasms
    Evidence:
    PMID:17148776
  2. rs712829 at chr7:55054249 in EGFR
    The T allele of -216G/T was associated with improved progression free survival in gefitinib-treated non-small-cell lung cancer patients. It was also associated with significantly higher rates of stable disease/partial response and a significantly higher risk of treatment-related rash/diarrhea.
    Variant Name:
    EGFR:-216G>T
    Related Drugs:
    gefitinib
    Related Diseases:
    Carcinoma, Non-Small-Cell Lung
    Evidence:
    PMID:17375033
Variant names are different names that have been used in the literature and other resources to refer to the same variant.

The following genes are in curated knowledge about this drug.

  Gene Relationship Evidence
Phenotype data available Genotype Data Available Literature annotations available Has annotations
ABCB1
  •   
  • PD
  • PK
  • FA
  • GN
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
ABCG2
  •   
  • PD
  • PK
  • FA
  • GN
Publications, Variants
No phenotype data No genotype data Literature annotations available Not annotated
ABL1
  • CO
  •   
  •   
  • FA
  •   
Publications
Phenotype data available No genotype data Literature annotations available Not annotated
AKT1
  • CO
  •   
  •   
  • FA
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
APAF1
  • CO
  •   
  •   
  • FA
  •   
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
CCND1
  • CO
  •   
  •   
  •   
  • GN
Publications
No phenotype data Genotype Data Available Literature annotations available Not annotated
CYP1A1
  •   
  •   
  • PK
  •   
  •   
Publications
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP2C19
  •   
  •   
  • PK
  •   
  •   
Publications
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP2C9
  •   
  •   
  • PK
  •   
  •   
Publications
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP2D6
  •   
  •   
  • PK
  •   
  •   
Publications, Variants
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP3A4
  •   
  •   
  • PK
  •   
  •   
Publications
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP3A5
  •   
  •   
  • PK
  •   
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
EGF
  • CO
  •   
  •   
  •   
  • GN
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
EGFR
  • CO
  • PD
  •   
  • FA
  • GN
Publications, Variants
No phenotype data No genotype data Literature annotations available Not annotated
EMP1
  •   
  •   
  •   
  • FA
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
ERBB2
  •   
  • PD
  •   
  • FA
  •   
Publications
Phenotype data available No genotype data Literature annotations available Not annotated
ERBB3
  •   
  • PD
  •   
  • FA
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
FUS
  • CO
  •   
  •   
  • FA
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
GAB1
  •   
  • PD
  •   
  • FA
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
IL15
  • CO
  •   
  •   
  • FA
  •   
Publications
No phenotype data Genotype Data Available Literature annotations available Not annotated
IL8
  • CO
  •   
  •   
  •   
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
IL8RA
  • CO
  •   
  •   
  •   
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
KIT
  • CO
  •   
  •   
  • FA
  •   
Publications
Phenotype data available No genotype data Literature annotations available Not annotated
MET
  •   
  • PD
  •   
  • FA
  •   
Publications
Phenotype data available No genotype data Literature annotations available Not annotated
PDGFRB
  • CO
  •   
  •   
  • FA
  •   
Publications
Phenotype data available No genotype data Literature annotations available Has annotations
PTGS2
  • CO
  •   
  •   
  •   
  • GN
Publications
Phenotype data available Genotype Data Available Literature annotations available Has annotations
UGT1A1
  •   
  •   
  •   
  • FA
  •   
Publications
No phenotype data Genotype Data Available Literature annotations available Not annotated
UGT1A7
  •   
  •   
  •   
  • FA
  •   
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
UGT1A9
  •   
  •   
  •   
  • FA
  •   
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
UGT2B7
  •   
  •   
  •   
  • FA
  •   
Publications

A list of non-curated publications that mention this drug along with other genes is available.

Drug Targets

Gene Description
EGFR Uncurated Annotation (source: Drug Bank)

A list of non-curated publications that mention this drug along with other drugs is available.

Drug Interactions

Drug Description
acenocoumarol Uncurated Annotation Gefitinib increases the anticoagulant effect (source: Drug Bank)
amobarbital Uncurated Annotation This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects (source: Drug Bank)
butalbital Uncurated Annotation This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects (source: Drug Bank)
carbamazepine Uncurated Annotation This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects (source: Drug Bank)
clarithromycin Uncurated Annotation This CYP3A4 inhibitor increases levels/toxicity of gefitinib (source: Drug Bank)
dicumarol Uncurated Annotation Gefitinib increases the anticoagulant effect (source: Drug Bank)
erythromycin Uncurated Annotation This CYP3A4 inhibitor increases levels/toxicity of gefitinib (source: Drug Bank)
hexobarbital Uncurated Annotation This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects (source: Drug Bank)
itraconazole Uncurated Annotation This CYP3A4 inhibitor increases levels/toxicity of gefitinib (source: Drug Bank)
ketoconazole Uncurated Annotation This CYP3A4 inhibitor increases levels/toxicity of gefitinib (source: Drug Bank)
mephenytoin Uncurated Annotation This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects (source: Drug Bank)
methylphenobarbital Uncurated Annotation This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects (source: Drug Bank)
pentobarbital Uncurated Annotation This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects (source: Drug Bank)
phenobarbital Uncurated Annotation This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects (source: Drug Bank)
phenytoin Uncurated Annotation This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects (source: Drug Bank)
primidone Uncurated Annotation This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects (source: Drug Bank)
rifampin Uncurated Annotation Rifampin reduces levels and efficacy of gefitinib (source: Drug Bank)
ritonavir Uncurated Annotation This CYP3A4 inhibitor increases levels/toxicity of gefitinib (source: Drug Bank)
warfarin Uncurated Annotation Gefitinib increases the anticoagulant effect (source: Drug Bank)

Curated Information

The following diseases are in curated knowledge about this drug.

  Disease Relationship Evidence
No phenotype data No genotype data Literature annotations available Not annotated
Carcinoma, Non-Small-Cell Lung
  • CO
  • PD
  •   
  • FA
  • GN
Publications, Variants
No phenotype data No genotype data Literature annotations available Not annotated
Carcinoma, Small Cell
  • CO
  •   
  •   
  • FA
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Drug Toxicity
  • CO
  • PD
  •   
  •   
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Glioblastoma
  • CO
  •   
  •   
  • FA
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Lung Diseases, Interstitial
  • CO
  • PD
  •   
  •   
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Lung Neoplasms
  • CO
  • PD
  • PK
  • FA
  • GN
Publications, Variants
Phenotype data available Genotype Data Available Literature annotations available Not annotated
Neoplasms
  • CO
  • PD
  • PK
  • FA
  • GN
Publications, Variants
Phenotype data available Genotype Data Available Literature annotations available Not annotated
Pancreatic Neoplasms
  • CO
  •   
  •   
  • FA
  •   
Publications

Non-Curated Information

A list of non-curated publications that mention this drug along with other diseases is available.

Additional Datasets

These datasets are minimally curated and are sorted alphabetically by title.

  1. The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease

LinkOuts

Web Resource:
Wikipedia
DrugBank:
DB00317
KEGG Drug ID:
D01977
PubChem Compound ID:
123631
PubChem Substance ID:
7849039

Common Searches

Search PubMed
Search Medline Plus
Search PubChem
Search CTD

Non-Curated Publications

A list of non-curated publications that mention this drug is available.

PharmGKB integrates drug information from different sources: DrugBank, Open Eye Scientific Software.
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