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Identification
Name Erlotinib
Accession Number DB00530 (APRD00951)
Type small molecule
Groups approved
Description

Erlotinib hydrochloride (trade name Tarceva, Genentech/OSIP, originally coded as OSI-774) is a drug used to treat non-small cell lung cancer, pancreatic cancer and several other types of cancer.

Similar to gefitinib, erlotinib specifically targets the epidermal growth factor receptor (EGFR) tyrosine kinase. It binds in a reversible fashion to the adenosine triphosphate (ATP) binding site of the receptor. Erlotinib has recently been shown to be a potent inhibitor of JAK2V617F activity. JAK2V617F is a mutant of tyrosine kinase JAK2, is found in most patients with polycythemia vera (PV) and a substantial proportion of patients with idiopathic myelofibrosis or essential thrombocythemia. The study suggests that erlotinib may be used for treatment of JAK2V617F-positive PV and other myeloproliferative disorders.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
OSI-774
Salts Not Available
Brand names
Name Company
Tarceva
Brand mixtures Not Available
Categories
  • Protein Kinase Inhibitors
CAS number 183321-74-6
Weight Average: 393.4357
Monoisotopic: 393.168856239
Chemical Formula C22H23N3O4
InChI Key InChIKey=AAKJLRGGTJKAMG-UHFFFAOYSA-N
InChI
InChI=1S/C22H23N3O4/c1-4-16-6-5-7-17(12-16)25-22-18-13-20(28-10-8-26-2)21(29-11-9-27-3)14-19(18)23-15-24-22/h1,5-7,12-15H,8-11H2,2-3H3,(H,23,24,25)
Plain Text
IUPAC Name
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine
SMILES
COCCOC1=C(OCCOC)C=C2C(NC3=CC=CC(=C3)C#C)=NC=NC2=C1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Quinazolines
Substructures
  • Quinazolines
  • Alkynes
  • Aliphatic and Aryl Amines
  • Phenols and Derivatives
  • Ethers
  • Benzene and Derivatives
  • Pyrimidines and Derivatives
  • Catechols
  • Heterocyclic compounds
  • Aromatic compounds
  • Anisoles
  • Cyanamides
  • Phenyl Esters
  • Anilines
Pharmacology
Indication For the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen. Also for use, in combination with gemcitabine, as the first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer.
Pharmacodynamics Erlotinib is a Human Epidermal Growth Factor Receptor Type 1/Epidermal Growth Factor Receptor (HER1/EGFR) tyrosine kinase inhibitor.
Mechanism of action The mechanism of clinical antitumor action of erlotinib is not fully characterized. Erlotinib inhibits the intracellular phosphorylation of tyrosine kinase associated with the epidermal growth factor receptor (EGFR). Specificity of inhibition with regard to other tyrosine kinase receptors has not been fully characterized. EGFR is expressed on the cell surface of normal cells and cancer cells.
Absorption Erlotinib is about 60% absorbed after oral administration and its bioavailability is substantially increased by food to almost 100%.
Volume of distribution Not Available
Protein binding 93% protein bound to albumin and alpha-1 acid glycoprotein (AAG)
Metabolism
In vitro assays of cytochrome P450 metabolism showed that erlotinib is metabolized primarily by CYP3A4 and to a lesser extent by CYP1A2, and the extrahepatic isoform CYP1A1.
Route of elimination Not Available
Half life Median half-life of 36.2 hours.
Clearance Not Available
Toxicity Symptoms of overdose include diarrhea, rash, and liver transaminase elevation.
Affected organisms
  • Humans and other mammals
Pathways
Pathway Name SMPDB ID
Smp00472 Erlotinib Pathway SMP00472
Pharmacoeconomics
Manufacturers
  • Osi pharmaceuticals inc
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
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 6900221 2000-11-09 2020-11-09
United States 5747498 1998-11-08 2018-11-08
Canada 2514977 2010-06-22 2024-02-11
Canada 2216796 2003-09-02 2015-06-06
Properties
State solid
Experimental Properties
Property Value Source
water solubility Very slightly soluble (hydrochloride salt - maximal solubility of approximately 0.4 mg/mL occurs at a pH of approximately 2) Not Available
logP 2.7 Not Available
Predicted Properties
Property Value Source
water solubility 8.91e-03 g/l ALOGPS
logP 3.13 ALOGPS
logP 3.2 ChemAxon
logS -4.6 ALOGPS
pKa (strongest acidic) 16.14 ChemAxon
pKa (strongest basic) 4.59 ChemAxon
physiological charge 0 ChemAxon
hydrogen acceptor count 7 ChemAxon
hydrogen donor count 1 ChemAxon
polar surface area 74.73 ChemAxon
rotatable bond count 10 ChemAxon
refractivity 107.79 ChemAxon
polarizability 43.48 ChemAxon
References
Synthesis Reference Not Available
General Reference
  1. Raymond E, Faivre S, Armand JP: Epidermal growth factor receptor tyrosine kinase as a target for anticancer therapy. Drugs. 2000;60 Suppl 1:15-23; discussion 41-2. Pubmed
  2. Li Z, Xu M, Xing S, Ho WT, Ishii T, Li Q, Fu X, Zhao ZJ: Erlotinib effectively inhibits JAK2V617F activity and polycythemia vera cell growth. J Biol Chem. 2007 Feb 9;282(6):3428-32. Epub 2006 Dec 18. Pubmed
  3. Dudek AZ, Kmak KL, Koopmeiners J, Keshtgarpour M: Skin rash and bronchoalveolar histology correlates with clinical benefit in patients treated with gefitinib as a therapy for previously treated advanced or metastatic non-small cell lung cancer. Lung Cancer. 2006 Jan;51(1):89-96. Epub 2005 Nov 14. Pubmed
  4. Jones HE, Goddard L, Gee JM, Hiscox S, Rubini M, Barrow D, Knowlden JM, Williams S, Wakeling AE, Nicholson RI: Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells. Endocr Relat Cancer. 2004 Dec;11(4):793-814. Pubmed
  5. Blum G, Gazit A, Levitzki A: Substrate competitive inhibitors of IGF-1 receptor kinase. Biochemistry. 2000 Dec 26;39(51):15705-12. Pubmed
External Links
Resource Link
PubChem Compound 176870 Link_out
PubChem Substance 46508021 Link_out
ChemSpider 154044 Link_out
BindingDB 5446 Link_out
ChEBI 114785 Link_out
ChEMBL 114785 Link_out
Therapeutic Targets Database DAP001010 Link_out
PharmGKB PA134687924 Link_out
HET AQ4 Link_out
Drug Product Database 2269023 Link_out
RxList http://www.rxlist.com/cgi/generic4/tarceva.htm Link_out
Drugs.com http://www.drugs.com/cdi/erlotinib.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Erlotinib Link_out
ATC Codes
  • L01XE03
AHFS Codes
  • 10:00.00
PDB Entries Not Available
FDA label show (999 KB)
MSDS Not Available
Interactions
Drug Interactions
Drug Interaction
Atazanavir This CYP3A4 inhibitor increases levels/toxicity of erlotinib
Clarithromycin This CYP3A4 inhibitor increases levels/toxicity of erlotinib
Erythromycin This CYP3A4 inhibitor increases levels/toxicity of erlotinib
Indinavir This CYP3A4 inhibitor increases levels/toxicity of erlotinib
Itraconazole Itraconazole may decrease the metabolism of erlotinib. Monitor for changes in the therapeutic and adverse effects of erlotinib if itraconazole is initiated, discontinued or dose changed.
Ketoconazole This CYP3A4 inhibitor increases levels/toxicity of erlotinib
Nefazodone This CYP3A4 inhibitor increases levels/toxicity of erlotinib
Nelfinavir This CYP3A4 inhibitor increases levels/toxicity of erlotinib
Rifabutin Decreased levels/effect of erlotinib
Rifampin Decreased levels/effect of erlotinib
Rifapentine Decreased levels/effect of erlotinib
Ritonavir This CYP3A4 inhibitor increases levels/toxicity of erlotinib
Saquinavir This CYP3A4 inhibitor increases levels/toxicity of erlotinib
St. John's Wort Decreased levels/effect of erlotinib
Telithromycin Telithromycin may reduce clearance of Erlotinib. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Erlotinib if Telithromycin 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.
Troleandomycin This CYP3A4 inhibitor increases levels/toxicity of erlotinib
Voriconazole Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of erlotinib by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of erlotinib if voriconazole is initiated, discontinued or dose changed.
Food Interactions
  • Take at least 1 hour before or 2 hours after any food.
  • Take with a glass of water.
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. Kim TE, Murren JR: Erlotinib OSI/Roche/Genentech. Curr Opin Investig Drugs. 2002 Sep;3(9):1385-95. Pubmed
  2. Laird AD, Cherrington JM: Small molecule tyrosine kinase inhibitors: clinical development of anticancer agents. Expert Opin Investig Drugs. 2003 Jan;12(1):51-64. Pubmed
  3. Delbaldo C, Faivre S, Raymond E: [Epidermal growth factor inhibitors] Rev Med Interne. 2003 Jun;24(6):372-83. Pubmed
  4. Bulgaru AM, Mani S, Goel S, Perez-Soler R: Erlotinib (Tarceva): a promising drug targeting epidermal growth factor receptor tyrosine kinase. Expert Rev Anticancer Ther. 2003 Jun;3(3):269-79. Pubmed
  5. Akita RW, Sliwkowski MX: Preclinical studies with Erlotinib (Tarceva). Semin Oncol. 2003 Jun;30(3 Suppl 7):15-24. Pubmed
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. Nuclear receptor subfamily 1 group I member 2

Pharmacological action: yes
Actions: agonist

Orphan receptor; its natural ligand is probably pregnane. Binds to a response element in the CYP3A4 and ABCB1/MDR1 genes promoter. Activates its expression in response to a wide variety of endobiotics and xenobiotics

Organism class: human
UniProt ID: O75469 Link_out
Gene: NR1I2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Harmsen S, Meijerman I, Beijnen JH, Schellens JH: Nuclear receptor mediated induction of cytochrome P450 3A4 by anticancer drugs: a key role for the pregnane X receptor. Cancer Chemother Pharmacol. 2009 Jun;64(1):35-43. Epub 2008 Oct 7. Pubmed
  2. van Erp NP, Gelderblom H, Guchelaar HJ: Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009 Dec;35(8):692-706. Epub 2009 Sep 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. van Erp NP, Gelderblom H, Guchelaar HJ: Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009 Dec;35(8):692-706. Epub 2009 Sep 5. Pubmed
  2. Johnson JR, Cohen M, Sridhara R, Chen YF, Williams GM, Duan J, Gobburu J, Booth B, Benson K, Leighton J, Hsieh LS, Chidambaram N, Zimmerman P, Pazdur R: Approval summary for erlotinib for treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen. Clin Cancer Res. 2005 Sep 15;11(18):6414-21. Pubmed
  3. 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. Hamilton M, Wolf JL, Rusk J, Beard SE, Clark GM, Witt K, Cagnoni PJ: Effects of smoking on the pharmacokinetics of erlotinib. Clin Cancer Res. 2006 Apr 1;12(7 Pt 1):2166-71. Pubmed

2. Cytochrome P450 3A5

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 oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics

UniProt ID: P20815 Link_out
Gene: CYP3A5 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. van Erp NP, Gelderblom H, Guchelaar HJ: Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009 Dec;35(8):692-706. Epub 2009 Sep 5. Pubmed
  2. 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

3. Cytochrome P450 1A2

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 oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N3-demethylation. Also acts in the metabolism of aflatoxin B1 and acetaminophen

UniProt ID: P05177 Link_out
Gene: CYP1A2
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. van Erp NP, Gelderblom H, Guchelaar HJ: Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009 Dec;35(8):692-706. Epub 2009 Sep 5. Pubmed
  2. Lu JF, Eppler SM, Wolf J, Hamilton M, Rakhit A, Bruno R, Lum BL: Clinical pharmacokinetics of erlotinib in patients with solid tumors and exposure-safety relationship in patients with non-small cell lung cancer. Clin Pharmacol Ther. 2006 Aug;80(2):136-45. Pubmed
  3. Johnson JR, Cohen M, Sridhara R, Chen YF, Williams GM, Duan J, Gobburu J, Booth B, Benson K, Leighton J, Hsieh LS, Chidambaram N, Zimmerman P, Pazdur R: Approval summary for erlotinib for treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen. Clin Cancer Res. 2005 Sep 15;11(18):6414-21. Pubmed
  4. 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
  5. Hamilton M, Wolf JL, Rusk J, Beard SE, Clark GM, Witt K, Cagnoni PJ: Effects of smoking on the pharmacokinetics of erlotinib. Clin Cancer Res. 2006 Apr 1;12(7 Pt 1):2166-71. Pubmed

4. Cytochrome P450 1A1

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 oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics

UniProt ID: P04798 Link_out
Gene: CYP1A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. van Erp NP, Gelderblom H, Guchelaar HJ: Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009 Dec;35(8):692-706. Epub 2009 Sep 5. Pubmed
  2. Johnson JR, Cohen M, Sridhara R, Chen YF, Williams GM, Duan J, Gobburu J, Booth B, Benson K, Leighton J, Hsieh LS, Chidambaram N, Zimmerman P, Pazdur R: Approval summary for erlotinib for treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen. Clin Cancer Res. 2005 Sep 15;11(18):6414-21. Pubmed
  3. 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

5. Cytochrome P450 2D6

Actions: substrate

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. van Erp NP, Gelderblom H, Guchelaar HJ: Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009 Dec;35(8):692-706. Epub 2009 Sep 5. Pubmed
  2. 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

6. Cytochrome P450 2C8

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 oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. In the epoxidation of arachidonic acid it generates only 14,15- and 11,12-cis-epoxyeicosatrienoic acids. It is the principal enzyme responsible for the metabolism the anti- cancer drug paclitaxel (taxol)

UniProt ID: P10632 Link_out
Gene: CYP2C8
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. van Erp NP, Gelderblom H, Guchelaar HJ: Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009 Dec;35(8):692-706. Epub 2009 Sep 5. Pubmed
  2. Hamilton M, Wolf JL, Rusk J, Beard SE, Clark GM, Witt K, Cagnoni PJ: Effects of smoking on the pharmacokinetics of erlotinib. Clin Cancer Res. 2006 Apr 1;12(7 Pt 1):2166-71. Pubmed

7. Cytochrome P450 1B1

Actions: substrate

Participates in the metabolism of an as-yet-unknown biologically active molecule that is a participant in eye development

UniProt ID: Q16678 Link_out
Gene: CYP1B1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. van Erp NP, Gelderblom H, Guchelaar HJ: Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009 Dec;35(8):692-706. Epub 2009 Sep 5. Pubmed
  2. 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
Transporters

1. 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. 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

2. Multidrug resistance protein 1

Actions: substrate

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. Marchetti S, de Vries NA, Buckle T, Bolijn MJ, van Eijndhoven MA, Beijnen JH, Mazzanti R, van Tellingen O, Schellens JH: Effect of the ATP-binding cassette drug transporters ABCB1, ABCG2, and ABCC2 on erlotinib hydrochloride (Tarceva) disposition in in vitro and in vivo pharmacokinetic studies employing Bcrp1-/-/Mdr1a/1b-/- (triple-knockout) and wild-type mice. Mol Cancer Ther. 2008 Aug;7(8):2280-7. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19