Identification

Name
Etoposide
Accession Number
DB00773
Description

A semisynthetic derivative of podophyllotoxin that exhibits antitumor activity. Etoposide inhibits DNA synthesis by forming a complex with topoisomerase II and DNA. This complex induces breaks in double stranded DNA and prevents repair by topoisomerase II binding. Accumulated breaks in DNA prevent entry into the mitotic phase of cell division, and lead to cell death. Etoposide acts primarily in the G2 and S phases of the cell cycle.

Type
Small Molecule
Groups
Approved
Structure
Thumb
Weight
Average: 588.5566
Monoisotopic: 588.18429111
Chemical Formula
C29H32O13
Synonyms
  • (−)-etoposide
  • 4-demethylepipodophyllotoxin β-D-ethylideneglucoside
  • 4'-Demethylepipodophyllotoxin 9-(4,6-O-(R)-ethylidene-beta-D-glucopyranoside)
  • 9-((4,6-O-Ethylidine-beta-D-glucopyranosyl)oxy)-5,8,8a,9-tetrahydro-5-(4-hydroxy-3,4-dimethyloxyphenyl)furo(3',4'':6,7)naptho-(2,3-d)-1,3-dioxol-6(5aH)-one
  • Etoposide
  • Etoposido
  • Etoposidum
  • trans-Etoposide
External IDs
  • NSC-141540
  • VP-16-213

Pharmacology

Indication

For use in combination with other chemotherapeutic agents in the treatment of refractory testicular tumors and as first line treatment in patients with small cell lung cancer. Also used to treat other malignancies such as lymphoma, non-lymphocytic leukemia, and glioblastoma multiforme.

Associated Conditions
Contraindications & Blackbox Warnings
Learn about our commercial Contraindications & Blackbox Warnings data.
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Pharmacodynamics

Etoposide is an antineoplastic agent and an epipodophyllotoxin (a semisynthetic derivative of the podophyllotoxins). It inhibits DNA topoisomerase II, thereby ultimately inhibiting DNA synthesis. Etoposide is cell cycle dependent and phase specific, affecting mainly the S and G2 phases. Two different dose-dependent responses are seen. At high concentrations (10 µg/mL or more), lysis of cells entering mitosis is observed. At low concentrations (0.3 to 10 µg/mL), cells are inhibited from entering prophase. It does not interfere with microtubular assembly. The predominant macromolecular effect of etoposide appears to be the induction of DNA strand breaks by an interaction with DNA-topoisomerase II or the formation of free radicals.

Mechanism of action

Etoposide inhibits DNA topoisomerase II, thereby inhibiting DNA re-ligation. This causes critical errors in DNA synthesis at the premitotic stage of cell division and can lead to apoptosis of the cancer cell. Etoposide is cell cycle dependent and phase specific, affecting mainly the S and G2 phases of cell division. Inhibition of the topoisomerase II alpha isoform results in the anti-tumour activity of etoposide. The drug is also capable of inhibiting the beta isoform but inhibition of this target is not associated with the anti-tumour activity. It is instead associated with the carcinogenic effect.

TargetActionsOrganism
ADNA topoisomerase 2-alpha
inhibitor
Humans
NDNA topoisomerase 2-beta
inhibitor
Humans
Absorption

Absorbed well, time to peak plasma concentration is 1-1.5 hrs. Mean bioavailability is 50% (range of 25% - 75%). Cmax and AUC values for orally administered etoposide capsules display intra- and inter-subject variability. There is no evidence of first-pass effect for etoposide.

Volume of distribution

The disposition of etoposide is a biphasic process with a distribution half-life of 1.5 hours. It does not cross into cerebrospinal fluid well. Volume of distribution, steady state = 18 - 29 L.

Protein binding

97% protein bound.

Metabolism

Primarily hepatic (through O-demethylation via the CYP450 3A4 isoenzyme pathway) with 40% excreted unchanged in the urine. Etoposide also undergoes glutathione and glucuronide conjugation which are catalyzed by GSTT1/GSTP1 and UGT1A1, respectively. Prostaglandin synthases are also responsible for the conversion of etoposide to O-demethylated metabolites (quinone).

Hover over products below to view reaction partners

Route of elimination

Etoposide is cleared by both renal and nonrenal processes, i.e., metabolism and biliary excretion. Glucuronide and/or sulfate conjugates of etoposide are also excreted in human urine. Biliary excretion of unchanged drug and/or metabolites is an important route of etoposide elimination as fecal recovery of radioactivity is 44% of the intravenous dose. 56% of the dose was in the urine, 45% of which was excreted as etoposide.

Half-life

4-11 hours

Clearance
  • Total body clearance = 33 - 48 mL/min [IV administration, adults]
  • Mean renal clearance = 7 - 10 mL/min/m^2
Adverse Effects
Learn about our commercial Adverse Effects data.
Learn More
Toxicity

Side effects include alopecia, constipation, diarrhea, nausea and vomiting and secondary malignancies (leukemia).

Affected organisms
  • Humans and other mammals
Pathways
PathwayCategory
Etoposide Metabolism PathwayDrug metabolism
Etoposide Action PathwayDrug action
Pharmacogenomic Effects/ADRs
Not Available

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
AbametapirThe serum concentration of Etoposide can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Etoposide can be increased when combined with Abatacept.
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Etoposide.
AbemaciclibAbemaciclib may decrease the excretion rate of Etoposide which could result in a higher serum level.
AbirateroneThe serum concentration of Etoposide can be increased when it is combined with Abiraterone.
AcalabrutinibThe metabolism of Etoposide can be increased when combined with Acalabrutinib.
AcenocoumarolThe therapeutic efficacy of Acenocoumarol can be increased when used in combination with Etoposide.
AcetaminophenThe metabolism of Etoposide can be increased when combined with Acetaminophen.
AcetazolamideThe metabolism of Etoposide can be decreased when combined with Acetazolamide.
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Etoposide.
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 inhibits CYP3A4 metabolism, which may increase the serum concentration of etoposide.
  • Exercise caution with St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce serum levels of etoposide.

Products

Product Ingredients
IngredientUNIICASInChI Key
Etoposide phosphate528XYJ8L1N117091-64-2LIQODXNTTZAGID-OCBXBXKTSA-N
International/Other Brands
Etopofos (Bristol-Myers Squibb) / Lastet (Cancernova) / Nexvep (Bristol-Myers Squibb) / Vepesid K (Bristol-Myers Squibb) / Vépéside (Novartis)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
EposinLiquidIntravenousPharmachemie B.V.Not applicableNot applicableCanada
EtopophosInjection, powder, lyophilized, for solution100 mg/1IntravenousE.R. Squibb & Sons, L.L.C.2009-06-012021-04-30Us
EtopophosInjection, powder, lyophilized, for solution100 mg/1IntravenousH2-Pharma, LLC2009-06-01Not applicableUs
EtoposideInjection, solution20 mg/1mLIntravenousMylan Laboratories Limited2018-01-03Not applicableUs
EtoposideLiquid20 mgIntravenousPharmel IncNot applicableNot applicableCanada
EtoposideInjection20 mg/1mLIntravenousThyMoorgan GmbH Pharmazir & Co. K.G2017-10-23Not applicableUs
EtoposideInjection20 mg/1mLIntravenousThyMoorgan GmbH Pharmazir & Co. K.G2017-10-23Not applicableUs
EtoposideInjection20 mg/1mLIntravenousMylan Laboratories Limited2018-01-03Not applicableUs
EtoposideInjection20 mg/1mLIntravenousThyMoorgan GmbH Pharmazir & Co. K.G2017-10-23Not applicableUs
EtoposideInjection20 mg/1mLIntravenousMylan Laboratories Limited2018-01-03Not applicableUs
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
Dom-etoposideLiquidIntravenousDominion PharmacalNot applicableNot applicableCanada
EtoposideInjection20 mg/1mLIntravenousHikma Pharmaceuticals USA Inc.1996-05-01Not applicableUs
EtoposideInjection20 mg/1mLIntravenousHikma Pharmaceuticals USA Inc.1997-02-01Not applicableUs
EtoposideInjection20 mg/1mLIntravenousBedford Pharmaceuticals1997-02-012013-06-30Us
EtoposideInjection20 mg/1mLIntravenousAccord Healthcare Limited2015-03-03Not applicableUs
EtoposideInjection20 mg/1mLIntravenousBedford Pharmaceuticals2001-10-222013-01-31Us
EtoposideCapsule50 mg/1OralMylan Pharmaceuticals Inc.2001-10-22Not applicableUs
EtoposideInjection20 mg/1mLIntravenousHikma Pharmaceuticals USA Inc.1997-02-01Not applicableUs
EtoposideInjection20 mg/1mLIntravenousBedford Pharmaceuticals2001-10-222012-03-31Us
EtoposideInjection20 mg/1mLIntravenousBedford Pharmaceuticals1996-05-012013-06-30Us
Additional Data Available
  • Application Number
    Application Number

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

    Learn more
  • Product Code
    Product Code

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

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Categories

ATC Codes
L01CB01 — Etoposide
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as podophyllotoxins. These are tetralin lignans in which the benzene moiety of the tetralin skeleton is fused to a 1,3-dioxolane and the cyclohexane is fused to a butyrolactone (pyrrolidin-2-one).
Kingdom
Organic compounds
Super Class
Lignans, neolignans and related compounds
Class
Lignan lactones
Sub Class
Podophyllotoxins
Direct Parent
Podophyllotoxins
Alternative Parents
Aryltetralin lignans / Furanonaphthodioxoles / Tetralins / Pyranodioxins / Dimethoxybenzenes / Methoxyphenols / Benzodioxoles / Anisoles / Phenoxy compounds / Alkyl aryl ethers
show 14 more
Substituents
1,2-diol / 1-aryltetralin lignan / Acetal / Alcohol / Alkyl aryl ether / Anisole / Aromatic heteropolycyclic compound / Benzenoid / Benzodioxole / Carbonyl group
show 30 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
organic heterotetracyclic compound, beta-D-glucoside, furonaphthodioxole (CHEBI:4911)

Chemical Identifiers

UNII
6PLQ3CP4P3
CAS number
33419-42-0
InChI Key
VJJPUSNTGOMMGY-MRVIYFEKSA-N
InChI
InChI=1S/C29H32O13/c1-11-36-9-20-27(40-11)24(31)25(32)29(41-20)42-26-14-7-17-16(38-10-39-17)6-13(14)21(22-15(26)8-37-28(22)33)12-4-18(34-2)23(30)19(5-12)35-3/h4-7,11,15,20-22,24-27,29-32H,8-10H2,1-3H3/t11-,15+,20-,21-,22+,24-,25-,26-,27-,29+/m1/s1
IUPAC Name
(10R,11R,15R,16S)-16-{[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-methyl-hexahydro-2H-pyrano[3,2-d][1,3]dioxin-6-yl]oxy}-10-(4-hydroxy-3,5-dimethoxyphenyl)-4,6,13-trioxatetracyclo[7.7.0.0³,⁷.0¹¹,¹⁵]hexadeca-1,3(7),8-trien-12-one
SMILES
[H][C@]12COC(=O)[C@]1([H])[C@H](C1=CC(OC)=C(O)C(OC)=C1)C1=CC3=C(OCO3)C=C1[C@H]2O[C@@H]1O[C@]2([H])CO[C@@H](C)O[C@@]2([H])[C@H](O)[C@H]1O

References

Synthesis Reference
US3524844
General References
  1. Zhou Z, Zwelling LA, Ganapathi R, Kleinerman ES: Enhanced etoposide sensitivity following adenovirus-mediated human topoisomerase IIalpha gene transfer is independent of topoisomerase IIbeta. Br J Cancer. 2001 Sep 1;85(5):747-51. [PubMed:11531262]
  2. Azarova AM, Lyu YL, Lin CP, Tsai YC, Lau JY, Wang JC, Liu LF: Roles of DNA topoisomerase II isozymes in chemotherapy and secondary malignancies. Proc Natl Acad Sci U S A. 2007 Jun 26;104(26):11014-9. Epub 2007 Jun 19. [PubMed:17578914]
Human Metabolome Database
HMDB0014911
KEGG Drug
D00125
KEGG Compound
C01576
PubChem Compound
36462
PubChem Substance
46505434
ChemSpider
33510
BindingDB
50127140
RxNav
4179
ChEBI
4911
ChEMBL
CHEMBL44657
ZINC
ZINC000003938684
Therapeutic Targets Database
DAP000786
PharmGKB
PA449552
PDBe Ligand
EVP
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Etoposide
AHFS Codes
  • 10:00.00 — Antineoplastic Agents
PDB Entries
3qx3 / 4lb9 / 5cdn / 5cdp / 5gwk / 5zrf
FDA label
Download (206 KB)
MSDS
Download (24.1 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingTreatmentALK-negative Anaplastic Large Cell Lymphoma / Angioimmunoblastic T Cell Lymphoma / Angioimmunoblastic T-Cell Lymphoma / Enteropathy Associated T Cell Lymphoma / Enteropathy-Associated T-Cell Lymphoma / Hepatosplenic T Cell Lymphoma / Hepatosplenic T-Cell Lymphoma / Peripherial T Cell Lymphoma,Not Otherwise Specified / Subcutaneous Panniculitis Like T Cell Lymphoma1
4CompletedTreatmentAcute Lymphobkastic Leukemia1
4CompletedTreatmentAcute Lymphoblastic Leukaemias (ALL)1
4CompletedTreatmentRetinoblastoma1
4RecruitingTreatmentAcute Lymphoblastic Leukaemias (ALL)1
4RecruitingTreatmentALK-Positive Anaplastic Large Cell Lymphoma1
4RecruitingTreatmentCentral Nervous System Embryonal Tumors / Medulloblastomas1
4RecruitingTreatmentIntracranial Germ Cell Tumors1
4RecruitingTreatmentMantle Cell Lymphoma (MCL)1
4RecruitingTreatmentNasal and Nasal-type NK/T-cell Lymphoma1

Pharmacoeconomics

Manufacturers
  • Mylan pharmaceuticals inc
  • Bristol myers squibb co
  • Accord healthcare inc usa
  • App pharmaceuticals llc
  • Bedford laboratories div ben venue laboratories inc
  • Hospira inc
  • Marsam pharmaceuticals llc
  • Pharmachemie bv
  • Pierre fabre medicament
  • Teva parenteral medicines inc
  • Watson laboratories inc
Packagers
  • APP Pharmaceuticals
  • Baxter International Inc.
  • Bedford Labs
  • Ben Venue Laboratories Inc.
  • Bristol-Myers Squibb Co.
  • Hospira Inc.
  • Mead Johnson and Co.
  • Mylan
  • Pfizer Inc.
  • Pharmachemie BV
  • Pharmacia Inc.
  • R.P. Scherer GmbH and Co. KG
  • RP Scherer Canada Inc.
  • Sicor Pharmaceuticals
  • Teva Pharmaceutical Industries Ltd.
  • UDL Laboratories
  • Wyeth Pharmaceuticals
Dosage Forms
FormRouteStrength
Injection, powder, lyophilized, for solutionIntravenous100 mg/1
CapsuleOral50 mg/1
InjectionIntravenous20 mg/1mL
Injection, solutionIntravenous20 mg/1mL
LiquidIntravenous20 mg
LiquidIntravenous
SolutionIntravenous
Injection, solution, concentrateIntravenous20 mg/1mL
CapsuleOral50 mg
Capsule, liquid filledOral50 mg/1
InjectionIntravenous1 g/50mL
InjectionIntravenous100 mg/5mL
InjectionIntravenous150 mg/7.5mL
InjectionIntravenous500 mg/25mL
Prices
Unit descriptionCostUnit
VePesid 20 50 mg capsule Box1273.41USD box
Etopophos 100 mg vial159.55USD vial
Etoposide 50 mg capsule47.64USD capsule
Etoposide 100 mg/5 ml vial28.89USD ml
Toposar 100 mg/5 ml vial2.25USD ml
Toposar 1000 mg/50 ml vial1.12USD ml
Toposar 500 mg/25 ml vial1.06USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)236-251 °CPhysProp
water solubilitySparingly soluble FDA label
logP0.60HANSCH,C ET AL. (1995)
Predicted Properties
PropertyValueSource
Water Solubility0.978 mg/mLALOGPS
logP0.73ALOGPS
logP1.16ChemAxon
logS-2.8ALOGPS
pKa (Strongest Acidic)9.33ChemAxon
pKa (Strongest Basic)-3.7ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count12ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area160.83 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity139.02 m3·mol-1ChemAxon
Polarizability58.77 Å3ChemAxon
Number of Rings7ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.836
Blood Brain Barrier-0.9609
Caco-2 permeable-0.5234
P-glycoprotein substrateSubstrate0.7019
P-glycoprotein inhibitor INon-inhibitor0.8005
P-glycoprotein inhibitor IINon-inhibitor0.8381
Renal organic cation transporterNon-inhibitor0.8412
CYP450 2C9 substrateNon-substrate0.8228
CYP450 2D6 substrateNon-substrate0.9116
CYP450 3A4 substrateSubstrate0.6134
CYP450 1A2 substrateNon-inhibitor0.9045
CYP450 2C9 inhibitorNon-inhibitor0.6884
CYP450 2D6 inhibitorNon-inhibitor0.8392
CYP450 2C19 inhibitorNon-inhibitor0.529
CYP450 3A4 inhibitorNon-inhibitor0.8309
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.5576
Ames testNon AMES toxic0.9132
CarcinogenicityNon-carcinogens0.9325
BiodegradationNot ready biodegradable0.9467
Rat acute toxicity2.9588 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9847
hERG inhibition (predictor II)Non-inhibitor0.8734
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
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-004r-0090420000-e5d6bcd633116e0553a0
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-004i-0190000000-ac64a57347a9295be5dc
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-004r-0590000000-e0e45774111103754c46
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-002r-0980000000-ccf595459b4b1988d77a
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-002r-0950000000-4d3313053107615d463a
1H NMR Spectrum1D NMRNot Applicable
13C NMR Spectrum1D NMRNot Applicable

Targets

Details
1. DNA topoisomerase 2-alpha
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Ubiquitin binding
Specific Function
Control of topological states of DNA by transient breakage and subsequent rejoining of DNA strands. Topoisomerase II makes double-strand breaks. Essential during mitosis and meiosis for proper segr...
Gene Name
TOP2A
Uniprot ID
P11388
Uniprot Name
DNA topoisomerase 2-alpha
Molecular Weight
174383.88 Da
References
  1. de Lucio B, Manuel V, Barrera-Rodriguez R: Characterization of human NSCLC cell line with innate etoposide-resistance mediated by cytoplasmic localization of topoisomerase II alpha. Cancer Sci. 2005 Nov;96(11):774-83. [PubMed:16271071]
  2. Lopez-Lazaro M, Pastor N, Azrak SS, Ayuso MJ, Austin CA, Cortes F: Digitoxin inhibits the growth of cancer cell lines at concentrations commonly found in cardiac patients. J Nat Prod. 2005 Nov;68(11):1642-5. [PubMed:16309315]
  3. Moneypenny CG, Shao J, Song Y, Gallagher EP: MLL rearrangements are induced by low doses of etoposide in human fetal hematopoietic stem cells. Carcinogenesis. 2006 Apr;27(4):874-81. Epub 2005 Dec 24. [PubMed:16377807]
  4. Uesaka T, Shono T, Kuga D, Suzuki SO, Niiro H, Miyamoto K, Matsumoto K, Mizoguchi M, Ohta M, Iwaki T, Sasaki T: Enhanced expression of DNA topoisomerase II genes in human medulloblastoma and its possible association with etoposide sensitivity. J Neurooncol. 2007 Sep;84(2):119-29. Epub 2007 Mar 15. [PubMed:17361331]
  5. Winnicka K, Bielawski K, Bielawska A: Cardiac glycosides in cancer research and cancer therapy. Acta Pol Pharm. 2006 Mar-Apr;63(2):109-15. [PubMed:17514873]
  6. 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
No
Actions
Inhibitor
General Function
Protein kinase c binding
Specific Function
Control of topological states of DNA by transient breakage and subsequent rejoining of DNA strands. Topoisomerase II makes double-strand breaks.
Gene Name
TOP2B
Uniprot ID
Q02880
Uniprot Name
DNA topoisomerase 2-beta
Molecular Weight
183265.825 Da
References
  1. Azarova AM, Lyu YL, Lin CP, Tsai YC, Lau JY, Wang JC, Liu LF: Roles of DNA topoisomerase II isozymes in chemotherapy and secondary malignancies. Proc Natl Acad Sci U S A. 2007 Jun 26;104(26):11014-9. Epub 2007 Jun 19. [PubMed:17578914]

Enzymes

Details
1. Cytochrome P450 3A4
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
Inducer
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. Kawashiro T, Yamashita K, Zhao XJ, Koyama E, Tani M, Chiba K, Ishizaki T: A study on the metabolism of etoposide and possible interactions with antitumor or supporting agents by human liver microsomes. J Pharmacol Exp Ther. 1998 Sep;286(3):1294-300. [PubMed:9732391]
  2. Schuetz E, Lan L, Yasuda K, Kim R, Kocarek TA, Schuetz J, Strom S: Development of a real-time in vivo transcription assay: application reveals pregnane X receptor-mediated induction of CYP3A4 by cancer chemotherapeutic agents. Mol Pharmacol. 2002 Sep;62(3):439-45. [PubMed:12181418]
  3. Zhuo X, Zheng N, Felix CA, Blair IA: Kinetics and regulation of cytochrome P450-mediated etoposide metabolism. Drug Metab Dispos. 2004 Sep;32(9):993-1000. [PubMed:15319341]
  4. Yang J, Bogni A, Schuetz EG, Ratain M, Dolan ME, McLeod H, Gong L, Thorn C, Relling MV, Klein TE, Altman RB: Etoposide pathway. Pharmacogenet Genomics. 2009 Jul;19(7):552-3. doi: 10.1097/FPC.0b013e32832e0e7f. [PubMed:19512958]
  5. Badowski ME, Burton B, Shaeer KM, Dicristofano J: Oral oncolytic and antiretroviral therapy administration: dose adjustments, drug interactions, and other considerations for clinical use. Drugs Context. 2019 Feb 13;8:212550. doi: 10.7573/dic.212550. eCollection 2019. [PubMed:30815023]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
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
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. Kawashiro T, Yamashita K, Zhao XJ, Koyama E, Tani M, Chiba K, Ishizaki T: A study on the metabolism of etoposide and possible interactions with antitumor or supporting agents by human liver microsomes. J Pharmacol Exp Ther. 1998 Sep;286(3):1294-300. [PubMed:9732391]
  2. Li X, Yun JK, Choi JS: Effects of morin on the pharmacokinetics of etoposide in rats. Biopharm Drug Dispos. 2007 Apr;28(3):151-6. doi: 10.1002/bdd.539. [PubMed:17315145]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic ...
Gene Name
CYP2E1
Uniprot ID
P05181
Uniprot Name
Cytochrome P450 2E1
Molecular Weight
56848.42 Da
References
  1. Kawashiro T, Yamashita K, Zhao XJ, Koyama E, Tani M, Chiba K, Ishizaki T: A study on the metabolism of etoposide and possible interactions with antitumor or supporting agents by human liver microsomes. J Pharmacol Exp Ther. 1998 Sep;286(3):1294-300. [PubMed:9732391]
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. Zhuo X, Zheng N, Felix CA, Blair IA: Kinetics and regulation of cytochrome P450-mediated etoposide metabolism. Drug Metab Dispos. 2004 Sep;32(9):993-1000. [PubMed:15319341]
  2. Yang J, Bogni A, Schuetz EG, Ratain M, Dolan ME, McLeod H, Gong L, Thorn C, Relling MV, Klein TE, Altman RB: Etoposide pathway. Pharmacogenet Genomics. 2009 Jul;19(7):552-3. doi: 10.1097/FPC.0b013e32832e0e7f. [PubMed:19512958]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
Gene Name
UGT1A1
Uniprot ID
P22309
Uniprot Name
UDP-glucuronosyltransferase 1-1
Molecular Weight
59590.91 Da
References
  1. Wen Z, Tallman MN, Ali SY, Smith PC: UDP-glucuronosyltransferase 1A1 is the principal enzyme responsible for etoposide glucuronidation in human liver and intestinal microsomes: structural characterization of phenolic and alcoholic glucuronides of etoposide and estimation of enzyme kinetics. Drug Metab Dispos. 2007 Mar;35(3):371-80. Epub 2006 Dec 6. [PubMed:17151191]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Glutathione transferase activity
Specific Function
Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. Acts on 1,2-epoxy-3-(4-nitrophenoxy)propane, phenethylisothiocyanate 4-nitrobenzyl chlorid...
Gene Name
GSTT1
Uniprot ID
P30711
Uniprot Name
Glutathione S-transferase theta-1
Molecular Weight
27334.755 Da
References
  1. Mans DR, Lafleur MV, Westmijze EJ, Horn IR, Bets D, Schuurhuis GJ, Lankelma J, Retel J: Reactions of glutathione with the catechol, the ortho-quinone and the semi-quinone free radical of etoposide. Consequences for DNA inactivation. Biochem Pharmacol. 1992 Apr 15;43(8):1761-8. [PubMed:1315544]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
S-nitrosoglutathione binding
Specific Function
Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. Regulates negatively CDK5 activity via p25/p35 translocation to prevent neurodegeneration.
Gene Name
GSTP1
Uniprot ID
P09211
Uniprot Name
Glutathione S-transferase P
Molecular Weight
23355.625 Da
References
  1. Mans DR, Lafleur MV, Westmijze EJ, Horn IR, Bets D, Schuurhuis GJ, Lankelma J, Retel J: Reactions of glutathione with the catechol, the ortho-quinone and the semi-quinone free radical of etoposide. Consequences for DNA inactivation. Biochem Pharmacol. 1992 Apr 15;43(8):1761-8. [PubMed:1315544]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Prostaglandin-endoperoxide synthase activity
Specific Function
Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Constitutively expressed in some tissues in physiological conditions, such as the endothelium, kidney and...
Gene Name
PTGS2
Uniprot ID
P35354
Uniprot Name
Prostaglandin G/H synthase 2
Molecular Weight
68995.625 Da
References
  1. Haim N, Roman J, Nemec J, Sinha BK: Peroxidative free radical formation and O-demethylation of etoposide(VP-16) and teniposide(VM-26). Biochem Biophys Res Commun. 1986 Feb 26;135(1):215-20. [PubMed:3006680]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Prostaglandin-endoperoxide synthase activity
Specific Function
Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Involved in the constitutive production of prostanoids in particular in the stomach and platelets. In gas...
Gene Name
PTGS1
Uniprot ID
P23219
Uniprot Name
Prostaglandin G/H synthase 1
Molecular Weight
68685.82 Da
References
  1. Haim N, Roman J, Nemec J, Sinha BK: Peroxidative free radical formation and O-demethylation of etoposide(VP-16) and teniposide(VM-26). Biochem Biophys Res Commun. 1986 Feb 26;135(1):215-20. [PubMed:3006680]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Organic anion transmembrane transporter activity
Specific Function
May act as an inducible transporter in the biliary and intestinal excretion of organic anions. Acts as an alternative route for the export of bile acids and glucuronides from cholestatic hepatocyte...
Gene Name
ABCC3
Uniprot ID
O15438
Uniprot Name
Canalicular multispecific organic anion transporter 2
Molecular Weight
169341.14 Da
References
  1. Zeng H, Chen ZS, Belinsky MG, Rea PA, Kruh GD: Transport of methotrexate (MTX) and folates by multidrug resistance protein (MRP) 3 and MRP1: effect of polyglutamylation on MTX transport. Cancer Res. 2001 Oct 1;61(19):7225-32. [PubMed:11585759]
  2. Zehnpfennig B, Urbatsch IL, Galla HJ: Functional reconstitution of human ABCC3 into proteoliposomes reveals a transport mechanism with positive cooperativity. Biochemistry. 2009 May 26;48(20):4423-30. doi: 10.1021/bi9001908. [PubMed:19334674]
  3. Zelcer N, Saeki T, Reid G, Beijnen JH, Borst P: Characterization of drug transport by the human multidrug resistance protein 3 (ABCC3). J Biol Chem. 2001 Dec 7;276(49):46400-7. [PubMed:11581266]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Transporter activity
Specific Function
Isoform 1: May participate directly in the active transport of drugs into subcellular organelles or influence drug distribution indirectly. Transports glutathione conjugates as leukotriene-c4 (LTC4...
Gene Name
ABCC6
Uniprot ID
O95255
Uniprot Name
Multidrug resistance-associated protein 6
Molecular Weight
164904.81 Da
References
  1. Cai J, Daoud R, Alqawi O, Georges E, Pelletier J, Gros P: Nucleotide binding and nucleotide hydrolysis properties of the ABC transporter MRP6 (ABCC6). Biochemistry. 2002 Jun 25;41(25):8058-67. [PubMed:12069597]
  2. Belinsky MG, Chen ZS, Shchaveleva I, Zeng H, Kruh GD: Characterization of the drug resistance and transport properties of multidrug resistance protein 6 (MRP6, ABCC6). Cancer Res. 2002 Nov 1;62(21):6172-7. [PubMed:12414644]
Details
3. P-glycoprotein 1
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
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. Gao J, Murase O, Schowen RL, Aube J, Borchardt RT: A functional assay for quantitation of the apparent affinities of ligands of P-glycoprotein in Caco-2 cells. Pharm Res. 2001 Feb;18(2):171-6. [PubMed:11405287]
  2. Polli JW, Wring SA, Humphreys JE, Huang L, Morgan JB, Webster LO, Serabjit-Singh CS: Rational use of in vitro P-glycoprotein assays in drug discovery. J Pharmacol Exp Ther. 2001 Nov;299(2):620-8. [PubMed:11602674]
  3. Tang F, Horie K, Borchardt RT: Are MDCK cells transfected with the human MDR1 gene a good model of the human intestinal mucosa? Pharm Res. 2002 Jun;19(6):765-72. [PubMed:12134945]
  4. Schwab D, Fischer H, Tabatabaei A, Poli S, Huwyler J: Comparison of in vitro P-glycoprotein screening assays: recommendations for their use in drug discovery. J Med Chem. 2003 Apr 24;46(9):1716-25. [PubMed:12699389]
  5. Nagy H, Goda K, Fenyvesi F, Bacso Z, Szilasi M, Kappelmayer J, Lustyik G, Cianfriglia M, Szabo G Jr: Distinct groups of multidrug resistance modulating agents are distinguished by competition of P-glycoprotein-specific antibodies. Biochem Biophys Res Commun. 2004 Mar 19;315(4):942-9. [PubMed:14985103]
  6. Guo A, Marinaro W, Hu P, Sinko PJ: Delineating the contribution of secretory transporters in the efflux of etoposide using Madin-Darby canine kidney (MDCK) cells overexpressing P-glycoprotein (Pgp), multidrug resistance-associated protein (MRP1), and canalicular multispecific organic anion transporter (cMOAT). Drug Metab Dispos. 2002 Apr;30(4):457-63. [PubMed:11901101]
  7. Troutman MD, Thakker DR: Novel experimental parameters to quantify the modulation of absorptive and secretory transport of compounds by P-glycoprotein in cell culture models of intestinal epithelium. Pharm Res. 2003 Aug;20(8):1210-24. [PubMed:12948019]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Transporter activity
Specific Function
Mediates export of organic anions and drugs from the cytoplasm. Mediates ATP-dependent transport of glutathione and glutathione conjugates, leukotriene C4, estradiol-17-beta-o-glucuronide, methotre...
Gene Name
ABCC1
Uniprot ID
P33527
Uniprot Name
Multidrug resistance-associated protein 1
Molecular Weight
171589.5 Da
References
  1. Heijn M, Hooijberg JH, Scheffer GL, Szabo G, Westerhoff HV, Lankelma J: Anthracyclines modulate multidrug resistance protein (MRP) mediated organic anion transport. Biochim Biophys Acta. 1997 May 22;1326(1):12-22. [PubMed:9188796]
  2. Guo A, Marinaro W, Hu P, Sinko PJ: Delineating the contribution of secretory transporters in the efflux of etoposide using Madin-Darby canine kidney (MDCK) cells overexpressing P-glycoprotein (Pgp), multidrug resistance-associated protein (MRP1), and canalicular multispecific organic anion transporter (cMOAT). Drug Metab Dispos. 2002 Apr;30(4):457-63. [PubMed:11901101]
  3. Godinot N, Iversen PW, Tabas L, Xia X, Williams DC, Dantzig AH, Perry WL 3rd: Cloning and functional characterization of the multidrug resistance-associated protein (MRP1/ABCC1) from the cynomolgus monkey. Mol Cancer Ther. 2003 Mar;2(3):307-16. [PubMed:12657726]
  4. Nunoya K, Grant CE, Zhang D, Cole SP, Deeley RG: Molecular cloning and pharmacological characterization of rat multidrug resistance protein 1 (mrp1). Drug Metab Dispos. 2003 Aug;31(8):1016-26. [PubMed:12867490]
  5. Stride BD, Grant CE, Loe DW, Hipfner DR, Cole SP, Deeley RG: Pharmacological characterization of the murine and human orthologs of multidrug-resistance protein in transfected human embryonic kidney cells. Mol Pharmacol. 1997 Sep;52(3):344-53. [PubMed:9281595]
  6. Wong IL, Chan KF, Tsang KH, Lam CY, Zhao Y, Chan TH, Chow LM: Modulation of multidrug resistance protein 1 (MRP1/ABCC1)-mediated multidrug resistance by bivalent apigenin homodimers and their derivatives. J Med Chem. 2009 Sep 10;52(17):5311-22. doi: 10.1021/jm900194w. [PubMed:19725578]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Atpase activity, coupled to transmembrane movement of substances
Specific Function
ATP-dependent transporter probably involved in cellular detoxification through lipophilic anion extrusion.
Gene Name
ABCC10
Uniprot ID
Q5T3U5
Uniprot Name
Multidrug resistance-associated protein 7
Molecular Weight
161627.375 Da
References
  1. Chen ZS, Hopper-Borge E, Belinsky MG, Shchaveleva I, Kotova E, Kruh GD: Characterization of the transport properties of human multidrug resistance protein 7 (MRP7, ABCC10). Mol Pharmacol. 2003 Feb;63(2):351-8. [PubMed:12527806]
  2. Hopper-Borge E, Xu X, Shen T, Shi Z, Chen ZS, Kruh GD: Human multidrug resistance protein 7 (ABCC10) is a resistance factor for nucleoside analogues and epothilone B. Cancer Res. 2009 Jan 1;69(1):178-84. doi: 10.1158/0008-5472.CAN-08-1420. [PubMed:19118001]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Organic anion transmembrane transporter activity
Specific Function
Mediates hepatobiliary excretion of numerous organic anions. May function as a cellular cisplatin transporter.
Gene Name
ABCC2
Uniprot ID
Q92887
Uniprot Name
Canalicular multispecific organic anion transporter 1
Molecular Weight
174205.64 Da
References
  1. Tang F, Horie K, Borchardt RT: Are MDCK cells transfected with the human MRP2 gene a good model of the human intestinal mucosa? Pharm Res. 2002 Jun;19(6):773-9. [PubMed:12134946]
  2. Guo A, Marinaro W, Hu P, Sinko PJ: Delineating the contribution of secretory transporters in the efflux of etoposide using Madin-Darby canine kidney (MDCK) cells overexpressing P-glycoprotein (Pgp), multidrug resistance-associated protein (MRP1), and canalicular multispecific organic anion transporter (cMOAT). Drug Metab Dispos. 2002 Apr;30(4):457-63. [PubMed:11901101]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
References
  1. Wang X, Furukawa T, Nitanda T, Okamoto M, Sugimoto Y, Akiyama S, Baba M: Breast cancer resistance protein (BCRP/ABCG2) induces cellular resistance to HIV-1 nucleoside reverse transcriptase inhibitors. Mol Pharmacol. 2003 Jan;63(1):65-72. [PubMed:12488537]
  2. Allen JD, Van Dort SC, Buitelaar M, van Tellingen O, Schinkel AH: Mouse breast cancer resistance protein (Bcrp1/Abcg2) mediates etoposide resistance and transport, but etoposide oral availability is limited primarily by P-glycoprotein. Cancer Res. 2003 Mar 15;63(6):1339-44. [PubMed:12649196]

Drug created on June 13, 2005 07:24 / Updated on August 02, 2020 22:18

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