Identification

Name
Lapatinib
Accession Number
DB01259
Description

Lapatinib is an anti-cancer drug developed by GlaxoSmithKline (GSK) as a treatment for solid tumours such as breast and lung cancer. It was approved by the FDA on March 13, 2007, for use in patients with advanced metastatic breast cancer in conjunction with the chemotherapy drug Capecitabine. Lapatinib is human epidermal growth factor receptor type 2 (HER2/ERBB2) and epidermal growth factor receptor (HER1/EGFR/ERBB1) tyrosine kinases inhibitor. It binds to the intracellular phosphorylation domain to prevent receptor autophosphorylation upon ligand binding.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 581.058
Monoisotopic: 580.134731942
Chemical Formula
C29H26ClFN4O4S
Synonyms
  • Lapatinib
  • N-(3-chloro-4-((3-fluorophenyl)methoxy)phenyl)-6-(5-(((2-(methylsulfonyl)ethyl)amino)methyl)-2-furanyl)-4-quinazolinamine
External IDs
  • GSK-572016
  • GW 572016
  • GW-572016X
  • GW572016

Pharmacology

Indication

Indicated in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress the human epidermal receptor type 2 (HER2) protein and who have received prior therapy including an anthracycline, a taxane, and trastuzuma.

Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Lapatinib is a small molecule and a member of the 4-anilinoquinazoline class of kinase inhibitors. An anti-cancer drug, lapatinib was developed by GlaxoSmithKline (GSK) as a treatment for solid tumours such as breast and lung cancer. It was approved by the FDA on March 13, 2007, for use in patients with advanced metastatic breast cancer in conjunction with the chemotherapy drug capecitabine.

Mechanism of action

Lapatinib is a 4-anilinoquinazoline kinase inhibitor of the intracellular tyrosine kinase domains of both epidermal growth factor receptor (HER1/EGFR/ERBB1) and human epidermal growth factor receptor type 2 (HER2/ERBB2)with a dissociation half-life of ≥300 minutes. Lapatinib inhibits ERBB-driven tumor cell growth in vitro and in various animal models. An additive effect was demonstrated in an in vitro study when lapatinib and 5-florouracil (the active metabolite of capecitabine) were used in combination in the 4 tumor cell lines tested. The growth inhibitory effects of lapatinib were evaluated in trastuzumab-conditioned cell lines. Lapatinib retained significant activity against breast cancer cell lines selected for long-term growth in trastuzumab-containing medium in vitro. These in vitro findings suggest non-cross-resistance between these two agents.

TargetActionsOrganism
AEpidermal growth factor receptor
antagonist
Humans
AReceptor tyrosine-protein kinase erbB-2
antagonist
Humans
Absorption

Absorption following oral administration of lapatinib is incomplete and variable.

Volume of distribution
Not Available
Protein binding

Highly bound (>99%) to albumin and alpha-1 acid glycoprotein

Metabolism

Lapatinib undergoes extensive metabolism, primarily by CYP3A4 and CYP3A5, with minor contributions from CYP2C19 and CYP2C8 to a variety of oxidated metabolites, none of which accounts for more than 14% of the dose recovered in the feces or 10% of lapatinib concentration in plasma.

Route of elimination

Lapatinib undergoes extensive metabolism, primarily by CYP3A4 and CYP3A5, with minor contributions from CYP2C19 and CYP2C8 to a variety of oxidated metabolites, none of which accounts for more than 14% of the dose recovered in the feces or 10% of lapatinib concentration in plasma.

Half-life

Single-dose terminal half life: 14.2 hours Effective multiple-dose half life: 24 hours

Clearance
Not Available
Adverse Effects
Learn about our commercial Adverse Effects data.
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Toxicity

There has been a report of one patient who took 3,000 mg of lapatinib for 10 days. This patient had grade 3 diarrhea and vomiting on day 10.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Interacting Gene/EnzymeAllele nameGenotype(s)Defining Change(s)Type(s)DescriptionDetails
HLA class II histocompatibility antigen, DQ alpha 1 chainHLA-DQA1*02:01Not AvailableHLA-DQA1*02ADR Directly StudiedThe presence of this polymorphism in TNXB may indicate an increased risk of drug-induced ALT-elevations leading to hepatotoxicity when treated with lapatinib.Details
HLA class II histocompatibility antigen, DRB1-11 beta chainHLA-DRB1*07:01Not AvailableHLA-DRB1*07ADR Directly StudiedThe presence of this polymorphism in TNXB may indicate an increased risk of drug-induced ALT-elevations leading to hepatotoxicity when treated with lapatinib.Details
HLA class II histocompatibility antigen, DQ beta 1 chainHLA-DQB1*02:02Not AvailableHLA-DQB1*02ADR Directly StudiedThe presence of this polymorphism in TNXB may indicate an increased risk of drug-induced ALT-elevations leading to hepatotoxicity when treated with lapatinib.Details
Tenascin-X---(C;C) / (C;T)T > CADR Directly StudiedThe presence of this polymorphism in TNXB may indicate an increased risk of drug-induced ALT-elevations leading to hepatotoxicity when treated with lapatinib.Details

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbaloparatideThe therapeutic efficacy of Abaloparatide can be decreased when used in combination with Lapatinib.
AbametapirThe serum concentration of Lapatinib can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Lapatinib can be increased when combined with Abatacept.
AbirateroneThe metabolism of Lapatinib can be decreased when combined with Abiraterone.
AcalabrutinibThe metabolism of Lapatinib can be decreased when combined with Acalabrutinib.
AcebutololThe risk or severity of QTc prolongation can be increased when Lapatinib is combined with Acebutolol.
AcenocoumarolThe serum concentration of Acenocoumarol can be increased when it is combined with Lapatinib.
AcetaminophenThe serum concentration of Acetaminophen can be increased when it is combined with Lapatinib.
AcrivastineThe risk or severity of QTc prolongation can be increased when Lapatinib is combined with Acrivastine.
AdalimumabThe metabolism of Lapatinib can be increased when combined with Adalimumab.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
  • Avoid grapefruit products. Grapefruit may reduce the CYP3A4 metabolism of lapatinib, increasing its serum levels.
  • Take separate from meals. Take lapatinib at least 1 hour before or after eating, as lapatinib bioavailability is elevated by food.

Products

Product Ingredients
IngredientUNIICASInChI Key
Lapatinib ditosylateG873GX646R388082-78-8XNRVGTHNYCNCFF-UHFFFAOYSA-N
Product Images
International/Other Brands
Tycerb
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
TykerbTablet250 mgOralNovartis2009-06-05Not applicableCanada flag
TykerbTablet250 mg/1OralNovartis Pharmaceuticals Corporation2016-08-03Not applicableUS flag
TykerbTablet250 mg/1OralGlaxosmithkline Inc2007-03-162017-11-30US flag00173 0752 00 nlmimage10 8318c1b6
TyverbTablet, film coated250 mgOralNovartis Europharm Limited2008-06-10Not applicableEU flag
TyverbTablet, film coated250 mgOralNovartis Europharm Limited2008-06-10Not applicableEU flag
TyverbTablet, film coated250 mgOralNovartis Europharm Limited2008-06-10Not applicableEU flag
TyverbTablet, film coated250 mgOralNovartis Europharm Limited2008-06-10Not applicableEU flag
TyverbTablet, film coated250 mgOralNovartis Europharm Limited2008-06-10Not applicableEU flag
TyverbTablet, film coated250 mgOralNovartis Europharm Limited2008-06-10Not applicableEU flag
TyverbTablet, film coated250 mgOralNovartis Europharm Limited2008-06-10Not applicableEU flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
LapatinibTablet250 mg/1OralLupin Pharmaceuticals, Inc.2020-09-29Not applicableUS flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories

ATC Codes
L01XE07 — Lapatinib
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as quinazolinamines. These are heterocyclic aromatic compounds containing a quianazoline moiety substituted by one or more amine groups.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Diazanaphthalenes
Sub Class
Benzodiazines
Direct Parent
Quinazolinamines
Alternative Parents
Phenoxy compounds / Phenol ethers / Aniline and substituted anilines / Alkyl aryl ethers / Aminopyrimidines and derivatives / Aralkylamines / Chlorobenzenes / Fluorobenzenes / Aryl chlorides / Aryl fluorides
show 12 more
Substituents
Alkyl aryl ether / Amine / Aminopyrimidine / Aniline or substituted anilines / Aralkylamine / Aromatic heteropolycyclic compound / Aryl chloride / Aryl fluoride / Aryl halide / Azacycle
show 29 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
organofluorine compound, organochlorine compound, furans, quinazolines (CHEBI:49603)

Chemical Identifiers

UNII
0VUA21238F
CAS number
231277-92-2
InChI Key
BCFGMOOMADDAQU-UHFFFAOYSA-N
InChI
InChI=1S/C29H26ClFN4O4S/c1-40(36,37)12-11-32-16-23-7-10-27(39-23)20-5-8-26-24(14-20)29(34-18-33-26)35-22-6-9-28(25(30)15-22)38-17-19-3-2-4-21(31)13-19/h2-10,13-15,18,32H,11-12,16-17H2,1H3,(H,33,34,35)
IUPAC Name
N-{3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}-6-(5-{[(2-methanesulfonylethyl)amino]methyl}furan-2-yl)quinazolin-4-amine
SMILES
CS(=O)(=O)CCNCC1=CC=C(O1)C1=CC2=C(C=C1)N=CN=C2NC1=CC(Cl)=C(OCC2=CC(F)=CC=C2)C=C1

References

Synthesis Reference
US6727256
General References
  1. Nelson MH, Dolder CR: Lapatinib: a novel dual tyrosine kinase inhibitor with activity in solid tumors. Ann Pharmacother. 2006 Feb;40(2):261-9. Epub 2006 Jan 17. [PubMed:16418322]
  2. Burris HA 3rd: Dual kinase inhibition in the treatment of breast cancer: initial experience with the EGFR/ErbB-2 inhibitor lapatinib. Oncologist. 2004;9 Suppl 3:10-5. [PubMed:15163842]
  3. Burris HA 3rd, Hurwitz HI, Dees EC, Dowlati A, Blackwell KL, O'Neil B, Marcom PK, Ellis MJ, Overmoyer B, Jones SF, Harris JL, Smith DA, Koch KM, Stead A, Mangum S, Spector NL: Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas. J Clin Oncol. 2005 Aug 10;23(23):5305-13. Epub 2005 Jun 13. [PubMed:15955900]
  4. Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jagiello-Gruszfeld A, Crown J, Chan A, Kaufman B, Skarlos D, Campone M, Davidson N, Berger M, Oliva C, Rubin SD, Stein S, Cameron D: Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006 Dec 28;355(26):2733-43. [PubMed:17192538]
  5. Johnston SR, Leary A: Lapatinib: a novel EGFR/HER2 tyrosine kinase inhibitor for cancer. Drugs Today (Barc). 2006 Jul;42(7):441-53. [PubMed:16894399]
  6. Tevaarwerk AJ, Kolesar JM: Lapatinib: a small-molecule inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor-2 tyrosine kinases used in the treatment of breast cancer. Clin Ther. 2009;31 Pt 2:2332-48. doi: 10.1016/j.clinthera.2009.11.029. [PubMed:20110044]
  7. Medina PJ, Goodin S: Lapatinib: a dual inhibitor of human epidermal growth factor receptor tyrosine kinases. Clin Ther. 2008 Aug;30(8):1426-47. doi: 10.1016/j.clinthera.2008.08.008. [PubMed:18803986]
Human Metabolome Database
HMDB0015388
KEGG Drug
D04024
PubChem Compound
208908
PubChem Substance
46507141
ChemSpider
181006
BindingDB
5445
RxNav
480167
ChEBI
49603
ChEMBL
CHEMBL554
ZINC
ZINC000001550477
Therapeutic Targets Database
DCL000344
PharmGKB
PA152241907
PDBe Ligand
FMM
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Lapatinib
AHFS Codes
  • 10:00.00 — Antineoplastic Agents
PDB Entries
1xkk / 3bbt

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentMalignancies1
3Active Not RecruitingTreatmentBreast Cancer3
3Active Not RecruitingTreatmentHER2 Positive Metastatic Breast Cancers1
3Active Not RecruitingTreatmentHER2-positive Advanced Breast Cancer1
3Active Not RecruitingTreatmentMale Breast Carcinoma / Stage IIA Breast Cancer AJCC v6 and v7 / Stage IIB Breast Cancer AJCC v6 and v7 / Stage IIIA Breast Cancer AJCC v7 / Stage IIIB Breast Cancer AJCC v7 / Stage IIIC Breast Cancer AJCC v71
3Active Not RecruitingTreatmentMetastatic Breast Cancer2
3Active Not RecruitingTreatmentNeoplasms, Breast3
3Active Not RecruitingTreatmentNeoplasms, Gastrointestinal Tract1
3CompletedTreatmentBreast Cancer3
3CompletedTreatmentEstrogen Receptor Positive / HER2 Positive Breast Carcinoma / HER2/Neu Negative / Progesterone Receptor Positive / Recurrent Breast Carcinoma / Stage IIIB Breast Cancer AJCC v7 / Stage IIIC Breast Cancer AJCC v7 / Stage IV Breast Cancer AJCC v6 and v71

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • GlaxoSmithKline Inc.
Dosage Forms
FormRouteStrength
TabletOral250 mg
TabletOral250 mg/1
Tablet, coatedOral250 mg
Tablet, film coatedOral
Tablet, film coated250 mg
Tablet
Tablet, film coatedOral250 mg
Prices
Unit descriptionCostUnit
Tykerb 250 mg tablet28.4USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
CA2413134No2010-05-112021-06-28Canada flag
CA2317589No2007-08-082019-01-08Canada flag
US6391874No2002-05-212017-07-11US flag
US6713485No2004-03-302020-09-29US flag
US6727256No2004-04-272019-01-08US flag
US6828320No2004-12-072017-07-11US flag
US8821927No2014-09-022029-09-18US flag
US8513262No2013-08-202019-01-08US flag
US7157466No2007-01-022021-11-19US flag
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

    Learn more

Properties

State
Solid
Experimental Properties
PropertyValueSource
logP5.4Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0223 mg/mLALOGPS
logP5.18ALOGPS
logP4.64ChemAxon
logS-4.4ALOGPS
pKa (Strongest Acidic)15.99ChemAxon
pKa (Strongest Basic)7.2ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area106.35 Å2ChemAxon
Rotatable Bond Count11ChemAxon
Refractivity152.42 m3·mol-1ChemAxon
Polarizability61.19 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.6201
Caco-2 permeable-0.5858
P-glycoprotein substrateSubstrate0.7403
P-glycoprotein inhibitor IInhibitor0.5414
P-glycoprotein inhibitor IINon-inhibitor0.7799
Renal organic cation transporterNon-inhibitor0.7442
CYP450 2C9 substrateNon-substrate0.6688
CYP450 2D6 substrateNon-substrate0.7644
CYP450 3A4 substrateSubstrate0.6619
CYP450 1A2 substrateInhibitor0.5386
CYP450 2C9 inhibitorNon-inhibitor0.5544
CYP450 2D6 inhibitorNon-inhibitor0.7861
CYP450 2C19 inhibitorInhibitor0.5274
CYP450 3A4 inhibitorInhibitor0.8065
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.9104
Ames testNon AMES toxic0.543
CarcinogenicityNon-carcinogens0.6788
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.5867 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Strong inhibitor0.537
hERG inhibition (predictor II)Inhibitor0.8417
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-00lr-0009070000-0d55ba750eaa2fb12020
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0ab9-0649800000-87742edfe3489dab4ac8

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Ubiquitin protein ligase binding
Specific Function
Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses. Known ligands include EGF, TG...
Gene Name
EGFR
Uniprot ID
P00533
Uniprot Name
Epidermal growth factor receptor
Molecular Weight
134276.185 Da
References
  1. Xia W, Mullin RJ, Keith BR, Liu LH, Ma H, Rusnak DW, Owens G, Alligood KJ, Spector NL: Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways. Oncogene. 2002 Sep 12;21(41):6255-63. [PubMed:12214266]
  2. Grana TM, Sartor CI, Cox AD: Epidermal growth factor receptor autocrine signaling in RIE-1 cells transformed by the Ras oncogene enhances radiation resistance. Cancer Res. 2003 Nov 15;63(22):7807-14. [PubMed:14633707]
  3. Xia W, Liu LH, Ho P, Spector NL: Truncated ErbB2 receptor (p95ErbB2) is regulated by heregulin through heterodimer formation with ErbB3 yet remains sensitive to the dual EGFR/ErbB2 kinase inhibitor GW572016. Oncogene. 2004 Jan 22;23(3):646-53. [PubMed:14737100]
  4. Zhou H, Kim YS, Peletier A, McCall W, Earp HS, Sartor CI: Effects of the EGFR/HER2 kinase inhibitor GW572016 on EGFR- and HER2-overexpressing breast cancer cell line proliferation, radiosensitization, and resistance. Int J Radiat Oncol Biol Phys. 2004 Feb 1;58(2):344-52. [PubMed:14751502]
  5. Langer CJ: Emerging role of epidermal growth factor receptor inhibition in therapy for advanced malignancy: focus on NSCLC. Int J Radiat Oncol Biol Phys. 2004 Mar 1;58(3):991-1002. [PubMed:14967461]
  6. Burris HA 3rd: Dual kinase inhibition in the treatment of breast cancer: initial experience with the EGFR/ErbB-2 inhibitor lapatinib. Oncologist. 2004;9 Suppl 3:10-5. [PubMed:15163842]
  7. Wood ER, Truesdale AT, McDonald OB, Yuan D, Hassell A, Dickerson SH, Ellis B, Pennisi C, Horne E, Lackey K, Alligood KJ, Rusnak DW, Gilmer TM, Shewchuk L: A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res. 2004 Sep 15;64(18):6652-9. [PubMed:15374980]
  8. Vazquez-Martin A, Oliveras-Ferraros C, Cufi S, Del Barco S, Martin-Castillo B, Menendez JA: Lapatinib, a dual HER1/HER2 tyrosine kinase inhibitor, augments basal cleavage of HER2 extracellular domain (ECD) to inhibit HER2-driven cancer cell growth. J Cell Physiol. 2011 Jan;226(1):52-7. doi: 10.1002/jcp.22333. [PubMed:20658522]
  9. Johnston SR, Leary A: Lapatinib: a novel EGFR/HER2 tyrosine kinase inhibitor for cancer. Drugs Today (Barc). 2006 Jul;42(7):441-53. [PubMed:16894399]
  10. Tevaarwerk AJ, Kolesar JM: Lapatinib: a small-molecule inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor-2 tyrosine kinases used in the treatment of breast cancer. Clin Ther. 2009;31 Pt 2:2332-48. doi: 10.1016/j.clinthera.2009.11.029. [PubMed:20110044]
  11. Medina PJ, Goodin S: Lapatinib: a dual inhibitor of human epidermal growth factor receptor tyrosine kinases. Clin Ther. 2008 Aug;30(8):1426-47. doi: 10.1016/j.clinthera.2008.08.008. [PubMed:18803986]
  12. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Transmembrane signaling receptor activity
Specific Function
Protein tyrosine kinase that is part of several cell surface receptor complexes, but that apparently needs a coreceptor for ligand binding. Essential component of a neuregulin-receptor complex, alt...
Gene Name
ERBB2
Uniprot ID
P04626
Uniprot Name
Receptor tyrosine-protein kinase erbB-2
Molecular Weight
137909.27 Da
References
  1. Xia W, Liu LH, Ho P, Spector NL: Truncated ErbB2 receptor (p95ErbB2) is regulated by heregulin through heterodimer formation with ErbB3 yet remains sensitive to the dual EGFR/ErbB2 kinase inhibitor GW572016. Oncogene. 2004 Jan 22;23(3):646-53. [PubMed:14737100]
  2. Zhou H, Kim YS, Peletier A, McCall W, Earp HS, Sartor CI: Effects of the EGFR/HER2 kinase inhibitor GW572016 on EGFR- and HER2-overexpressing breast cancer cell line proliferation, radiosensitization, and resistance. Int J Radiat Oncol Biol Phys. 2004 Feb 1;58(2):344-52. [PubMed:14751502]
  3. Langer CJ: Emerging role of epidermal growth factor receptor inhibition in therapy for advanced malignancy: focus on NSCLC. Int J Radiat Oncol Biol Phys. 2004 Mar 1;58(3):991-1002. [PubMed:14967461]
  4. Burris HA 3rd: Dual kinase inhibition in the treatment of breast cancer: initial experience with the EGFR/ErbB-2 inhibitor lapatinib. Oncologist. 2004;9 Suppl 3:10-5. [PubMed:15163842]
  5. Wood ER, Truesdale AT, McDonald OB, Yuan D, Hassell A, Dickerson SH, Ellis B, Pennisi C, Horne E, Lackey K, Alligood KJ, Rusnak DW, Gilmer TM, Shewchuk L: A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res. 2004 Sep 15;64(18):6652-9. [PubMed:15374980]
  6. Grana TM, Sartor CI, Cox AD: Epidermal growth factor receptor autocrine signaling in RIE-1 cells transformed by the Ras oncogene enhances radiation resistance. Cancer Res. 2003 Nov 15;63(22):7807-14. [PubMed:14633707]
  7. Xia W, Mullin RJ, Keith BR, Liu LH, Ma H, Rusnak DW, Owens G, Alligood KJ, Spector NL: Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways. Oncogene. 2002 Sep 12;21(41):6255-63. [PubMed:12214266]
  8. Vazquez-Martin A, Oliveras-Ferraros C, Cufi S, Del Barco S, Martin-Castillo B, Menendez JA: Lapatinib, a dual HER1/HER2 tyrosine kinase inhibitor, augments basal cleavage of HER2 extracellular domain (ECD) to inhibit HER2-driven cancer cell growth. J Cell Physiol. 2011 Jan;226(1):52-7. doi: 10.1002/jcp.22333. [PubMed:20658522]
  9. Johnston SR, Leary A: Lapatinib: a novel EGFR/HER2 tyrosine kinase inhibitor for cancer. Drugs Today (Barc). 2006 Jul;42(7):441-53. [PubMed:16894399]
  10. Tevaarwerk AJ, Kolesar JM: Lapatinib: a small-molecule inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor-2 tyrosine kinases used in the treatment of breast cancer. Clin Ther. 2009;31 Pt 2:2332-48. doi: 10.1016/j.clinthera.2009.11.029. [PubMed:20110044]
  11. Medina PJ, Goodin S: Lapatinib: a dual inhibitor of human epidermal growth factor receptor tyrosine kinases. Clin Ther. 2008 Aug;30(8):1426-47. doi: 10.1016/j.clinthera.2008.08.008. [PubMed:18803986]
  12. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]

Enzymes

Details
1. Cytochrome P450 3A4
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
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 react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Medina PJ, Goodin S: Lapatinib: a dual inhibitor of human epidermal growth factor receptor tyrosine kinases. Clin Ther. 2008 Aug;30(8):1426-47. doi: 10.1016/j.clinthera.2008.08.008. [PubMed:18803986]
  2. van Erp NP, Gelderblom H, Guchelaar HJ: Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009 Dec;35(8):692-706. doi: 10.1016/j.ctrv.2009.08.004. Epub 2009 Sep 5. [PubMed:19733976]
  3. Teng WC, Oh JW, New LS, Wahlin MD, Nelson SD, Ho HK, Chan EC: Mechanism-based inactivation of cytochrome P450 3A4 by lapatinib. Mol Pharmacol. 2010 Oct;78(4):693-703. doi: 10.1124/mol.110.065839. Epub 2010 Jul 12. [PubMed:20624855]
  4. Tykerb (Lapatinib) FDA Label [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxygen binding
Specific Function
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 un...
Gene Name
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
References
  1. Medina PJ, Goodin S: Lapatinib: a dual inhibitor of human epidermal growth factor receptor tyrosine kinases. Clin Ther. 2008 Aug;30(8):1426-47. doi: 10.1016/j.clinthera.2008.08.008. [PubMed:18803986]
  2. van Erp NP, Gelderblom H, Guchelaar HJ: Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009 Dec;35(8):692-706. doi: 10.1016/j.ctrv.2009.08.004. Epub 2009 Sep 5. [PubMed:19733976]
  3. Tykerb (Lapatinib) FDA Label [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
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 un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. Teng WC, Oh JW, New LS, Wahlin MD, Nelson SD, Ho HK, Chan EC: Mechanism-based inactivation of cytochrome P450 3A4 by lapatinib. Mol Pharmacol. 2010 Oct;78(4):693-703. doi: 10.1124/mol.110.065839. Epub 2010 Jul 12. [PubMed:20624855]
  2. Get to know an Enzyme: CYP2C8 [Link]
  3. Tykerb (Lapatinib) FDA Label [Link]
  4. EMA label, Lapatinib [File]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. Medina PJ, Goodin S: Lapatinib: a dual inhibitor of human epidermal growth factor receptor tyrosine kinases. Clin Ther. 2008 Aug;30(8):1426-47. doi: 10.1016/j.clinthera.2008.08.008. [PubMed:18803986]
  2. van Erp NP, Gelderblom H, Guchelaar HJ: Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009 Dec;35(8):692-706. doi: 10.1016/j.ctrv.2009.08.004. Epub 2009 Sep 5. [PubMed:19733976]
  3. Nelson MH, Dolder CR: A review of lapatinib ditosylate in the treatment of refractory or advanced breast cancer. Ther Clin Risk Manag. 2007 Aug;3(4):665-73. [PubMed:18472989]
  4. Tykerb (Lapatinib) FDA Label [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. Dai CL, Tiwari AK, Wu CP, Su XD, Wang SR, Liu DG, Ashby CR Jr, Huang Y, Robey RW, Liang YJ, Chen LM, Shi CJ, Ambudkar SV, Chen ZS, Fu LW: Lapatinib (Tykerb, GW572016) reverses multidrug resistance in cancer cells by inhibiting the activity of ATP-binding cassette subfamily B member 1 and G member 2. Cancer Res. 2008 Oct 1;68(19):7905-14. doi: 10.1158/0008-5472.CAN-08-0499. [PubMed:18829547]
  2. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Tap2 binding
Specific Function
Involved in the transport of antigens from the cytoplasm to the endoplasmic reticulum for association with MHC class I molecules. Also acts as a molecular scaffold for the final stage of MHC class ...
Gene Name
TAP1
Uniprot ID
Q03518
Uniprot Name
Antigen peptide transporter 1
Molecular Weight
87216.855 Da
References
  1. Dai CL, Tiwari AK, Wu CP, Su XD, Wang SR, Liu DG, Ashby CR Jr, Huang Y, Robey RW, Liang YJ, Chen LM, Shi CJ, Ambudkar SV, Chen ZS, Fu LW: Lapatinib (Tykerb, GW572016) reverses multidrug resistance in cancer cells by inhibiting the activity of ATP-binding cassette subfamily B member 1 and G member 2. Cancer Res. 2008 Oct 1;68(19):7905-14. doi: 10.1158/0008-5472.CAN-08-0499. [PubMed:18829547]

Drug created on May 16, 2007 11:27 / Updated on October 25, 2020 09:16

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