PharmGKB: The Pharmacogenomics Knowledge Base

Drug/Small Molecule:
gefitinib

2D structure

Overview

Generic Names: ZD-1839; ZD1839
IUPAC Name: N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine
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]

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.

ATC Therapeutic Category

  • L01XE:Protein kinase inhibitors

Pharmacology and Interactions

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.

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.

Food Interactions

Avoid fresh grapefruit and its juice during therapy as grapefruit may increase serum product levels. Take without regard to meals.

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.

Protein Binding

90% primarily to serum albumin and alpha 1-acid glycoproteins.

Absorption

Absorbed slowly after oral administration with mean bioavailability of 60%.

Half Life

48 hours

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.

Chemical Properties

Chemical Formula:

C22H24ClFN4O3

SMILES Code:

COc1cc2c(cc1OCCCN3CCOCC3)c(ncn2)Nc4ccc(c(c4)Cl)F

(Format: OpenEye Isomeric)

Molecular Weight ( average / monoisotopic )

446.902 / 446.1521

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.

Curated Information

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, Pathways
Phenotype data available Genotype Data Available Literature annotations available Not annotated
ABCG2
  •   
  • PD
  • PK
  • FA
  • GN
Publications, Pathways, 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
  • PD
  •   
  • FA
  •   
Publications, Pathways
No phenotype data No genotype data Literature annotations available Not annotated
AKT2
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data Literature annotations available Not annotated
AKT3
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data Literature annotations available Not annotated
APAF1
  • CO
  •   
  •   
  • FA
  •   
Publications
No phenotype data No genotype data No literature annotations Not annotated
BTC
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data Literature annotations available Not annotated
CAMK1
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data No literature annotations Not annotated
CAMK1G
  •   
  • PD
  •   
  •   
  •   
Pathways
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, Pathways
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP2C19
  •   
  •   
  • PK
  •   
  •   
Publications, Pathways
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP2C9
  •   
  •   
  • PK
  •   
  •   
Publications, Pathways
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP2D6
  •   
  •   
  • PK
  •   
  •   
Publications, Pathways, Variants
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP3A4
  •   
  •   
  • PK
  •   
  •   
Publications, Pathways
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP3A5
  •   
  •   
  • PK
  •   
  •   
Publications, Pathways
No phenotype data No genotype data Literature annotations available Not annotated
EGF
  • CO
  • PD
  •   
  •   
  • GN
Publications, Pathways
Phenotype data available Genotype Data Available Literature annotations available Not annotated
EGFR
  • CO
  • PD
  •   
  • FA
  • GN
Publications, Pathways, Variants
No phenotype data No genotype data No literature annotations Not annotated
ELK1
  •   
  • PD
  •   
  •   
  •   
Pathways
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, Pathways
Phenotype data available No genotype data Literature annotations available Not annotated
ERBB3
  •   
  • PD
  •   
  • FA
  •   
Publications, Pathways
No phenotype data No genotype data Literature annotations available Not annotated
ERBB4
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data Literature annotations available Not annotated
EREG
  •   
  • PD
  •   
  •   
  •   
Pathways
Phenotype data available No genotype data Literature annotations available Not annotated
FOS
  •   
  • PD
  •   
  •   
  •   
Pathways
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 No literature annotations Not annotated
GRB2
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data Literature annotations available Not annotated
HBEGF
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data Literature annotations available Not annotated
HRAS
  •   
  • PD
  •   
  •   
  •   
Pathways
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
JAK1
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data Literature annotations available Not annotated
KIT
  • CO
  •   
  •   
  • FA
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
KRAS
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data Literature annotations available Not annotated
MAP2K1
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data Literature annotations available Not annotated
MAP2K2
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data Genotype Data Available Literature annotations available Not annotated
MAP2K7
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data Literature annotations available Not annotated
MAP3K1
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data Literature annotations available Not annotated
MAPK1
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data Literature annotations available Not annotated
MAPK3
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data Genotype Data Available Literature annotations available Not annotated
MAPK8
  •   
  • PD
  •   
  •   
  •   
Pathways
Phenotype data available No genotype data Literature annotations available Not annotated
MET
  •   
  • PD
  •   
  • FA
  •   
Publications
No phenotype data No genotype data No literature annotations Not annotated
MRAS
  •   
  • PD
  •   
  •   
  •   
Pathways
Phenotype data available No genotype data Literature annotations available Not annotated
MYC
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data No literature annotations Not annotated
NFKB2
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data Literature annotations available Not annotated
NRAS
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data Literature annotations available Not annotated
NRG1
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data No literature annotations Not annotated
NRG2
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data Literature annotations available Not annotated
NRG3
  •   
  • PD
  •   
  •   
  •   
Pathways
Phenotype data available No genotype data Literature annotations available Not annotated
PDGFRB
  • CO
  •   
  •   
  • FA
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
PIK3CA
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data Literature annotations available Not annotated
PIK3CB
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data Literature annotations available Not annotated
PIK3CD
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data Literature annotations available Not annotated
PIK3CG
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data Literature annotations available Not annotated
PLCG1
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data Literature annotations available Not annotated
PLCG2
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data Literature annotations available Not annotated
PRKCA
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data No literature annotations Not annotated
PRKCG
  •   
  • PD
  •   
  •   
  •   
Pathways
Phenotype data available No genotype data Literature annotations available Not annotated
PTGS2
  • CO
  •   
  •   
  •   
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
RAF1
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data No literature annotations Not annotated
RRAS
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data No literature annotations Not annotated
SHC1
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data No literature annotations Not annotated
SHC2
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data No literature annotations Not annotated
SHC3
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data Literature annotations available Not annotated
SOS1
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data Literature annotations available Not annotated
SP1
  •   
  • PD
  •   
  •   
  •   
Pathways
Phenotype data available No genotype data Literature annotations available Not annotated
STAT1
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data Literature annotations available Not annotated
STAT2
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data Genotype Data Available Literature annotations available Not annotated
STAT3
  •   
  • PD
  •   
  •   
  •   
Pathways
Phenotype data available No genotype data Literature annotations available Not annotated
STAT4
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data Genotype Data Available Literature annotations available Not annotated
STAT5A
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data Genotype Data Available Literature annotations available Not annotated
STAT5B
  •   
  • PD
  •   
  •   
  •   
Pathways
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

Non-Curated Information

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

Metabolizing Enzymes

Drug Targets

Non-Curated Information

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

Drug Interactions

acenocoumarol Gefitinib increases the anticoagulant effect
amobarbital This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
anisindione Gefitinib increases the anticoagulant effect
aprobarbital This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
butabarbital This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
butalbital This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
butethal This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
carbamazepine This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
clarithromycin This CYP3A4 inhibitor increases levels/toxicity of gefitinib
dicumarol Gefitinib increases the anticoagulant effect
dihydroquinidine barbiturate This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
erythromycin This CYP3A4 inhibitor increases levels/toxicity of gefitinib
ethotoin This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
fosphenytoin This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
heptabarbital This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
hexobarbital This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
itraconazole This CYP3A4 inhibitor increases levels/toxicity of gefitinib
ketoconazole This CYP3A4 inhibitor increases levels/toxicity of gefitinib
mephenytoin This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
methohexital This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
methylphenobarbital This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
pentobarbital This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
phenobarbital This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
phenytoin This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
primidone This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
quinidine barbiturate This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
rifampin Rifampin reduces levels and efficacy of gefitinib
ritonavir This CYP3A4 inhibitor increases levels/toxicity of gefitinib
secobarbital This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
st. john's wort This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
talbutal This CYP3A4 inducer may reduce gefitinib concentrations and pharmacological effects
warfarin Gefitinib increases the anticoagulant effect

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
Adenocarcinoma
  •   
  • PD
  •   
  •   
  •   
Pathways
Phenotype data available Genotype Data Available Literature annotations available Not annotated
Breast Neoplasms
  •   
  • PD
  •   
  •   
  •   
Pathways
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
Phenotype data available Genotype Data Available Literature annotations available Not annotated
Colonic Neoplasms
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data Literature annotations available Not annotated
Head and Neck Neoplasms
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data Literature annotations available Not annotated
Lung Neoplasms
  • CO
  • PD
  • PK
  • FA
  • GN
Publications, Pathways, Variants
Phenotype data available Genotype Data Available Literature annotations available Not annotated
Neoplasms
  • CO
  • PD
  • PK
  • FA
  • GN
Publications, Pathways, Variants
Phenotype data available Genotype Data Available Literature annotations available Not annotated
Pancreatic Neoplasms
  •   
  • PD
  •   
  •   
  •   
Pathways

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.
The PharmGKB is financially supported by the NIH/ NIGMS and is managed at Stanford University (U01GM61374).
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