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Identification
NameEtoposide
Accession NumberDB00773  (APRD00239)
TypeSmall Molecule
GroupsApproved
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. [PubChem]

Structure
Thumb
Synonyms
(-)-Etoposide
4-Demethylepipodophyllotoxin beta-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
EPE
EPEG
Epipodophyllotoxin
Eposin
Etopophos
Etoposid
Etoposide
Etoposido
Etoposidum
Lastet
Toposar
trans-Etoposide
Vepesid
VP-16
External Identifiers
  • BMY 40481
  • VP-16
  • VP-16-213
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Dom-etoposideliquid20 mgintravenousDominion PharmacalNot applicableNot applicableCanada
Eposinliquid20 mgintravenousPharmachemie B.V.Not applicableNot applicableCanada
Etopophosinjection, powder, lyophilized, for solution100 mg/1intravenousE.R. Squibb & Sons, L.L.C.2009-06-01Not applicableUs
Etoposideliquid20 mgintravenousPharmel IncNot applicableNot applicableCanada
Etoposide - Liq IV 20mg/mlliquid20 mgintravenousBdh Inc.1997-01-281998-07-01Canada
Etoposide Injectionliquid20 mgintravenousFresenius Kabi Canada Ltd2014-10-20Not applicableCanada
Etoposide Injectionliquid20 mgintravenousTeva Canada Limited1994-12-31Not applicableCanada
Etoposide Injection USPsolution20 mgintravenousSandoz Canada Incorporated2013-09-04Not applicableCanada
Etoposide Injection, USPliquid20 mgintravenousMylan Pharmaceuticals Ulc2014-07-10Not applicableCanada
Etoposide Injection, USPsolution20 mgintravenousHospira Healthcare Corporation1999-12-28Not applicableCanada
PMS-etoposideliquid20 mgintravenousPharmascience IncNot applicableNot applicableCanada
Vepesidcapsule50 mgoralBristol Myers Squibb Canada1984-12-31Not applicableCanada
Vepesid Inj 20mg/mlliquid20 mgintravenousBristol Labs Division Of Bristol Myers Squibb1981-12-312007-10-30Canada
Approved Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Etoposidecapsule50 mg/1oralMylan Pharmaceuticals Inc.2001-10-22Not applicableUs
Etoposideinjection20 mg/mLintravenousBlue Point Laboratories2013-11-14Not applicableUs
Etoposideinjection, solution20 mg/mLintravenousAPP Pharmaceuticals, LLC2001-07-18Not applicableUs
Etoposideinjection20 mg/mLintravenousAccord Healthcare Inc.2013-08-01Not applicableUs
Etoposideinjection20 mg/mLintravenousAccord Healthcare Inc.2013-09-15Not applicableUs
Toposarinjection, solution, concentrate20 mg/mLintravenousTeva Parenteral Medicines, Inc.1997-05-01Not applicableUs
Toposarinjection, solution, concentrate20 mg/mLintravenousTeva Parenteral Medicines, Inc.1996-08-01Not applicableUs
Toposarinjection, solution, concentrate20 mg/mLintravenousTeva Parenteral Medicines, Inc.1996-08-01Not applicableUs
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
EtopofosBristol-Myers Squibb
LastetCancernova
NexvepBristol-Myers Squibb
Vepesid KBristol-Myers Squibb
VépésideNovartis
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Etoposide Phosphate
Thumb
  • InChI Key: LIQODXNTTZAGID-OCBXBXKTSA-N
  • Monoisotopic Mass: 668.15062152
  • Average Mass: 668.5365
DBSALT000070
Categories
UNII6PLQ3CP4P3
CAS number33419-42-0
WeightAverage: 588.5566
Monoisotopic: 588.18429111
Chemical FormulaC29H32O13
InChI KeyInChIKey=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])[[email protected]](C1=CC(OC)=C(O)C(OC)=C1)C1=CC3=C(OCO3)C=C1[[email protected]]2O[C@@H]1O[C@]2([H])CO[C@@H](C)O[C@@]2([H])[[email protected]](O)[[email protected]]1O
Taxonomy
DescriptionThis 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).
KingdomOrganic compounds
Super ClassLignans, neolignans and related compounds
ClassLignan lactones
Sub ClassPodophyllotoxins
Direct ParentPodophyllotoxins
Alternative Parents
Substituents
  • Podophyllotoxin
  • 1-aryltetralin lignan
  • M-dimethoxybenzene
  • Dimethoxybenzene
  • Tetralin
  • Pyranodioxin
  • Methoxyphenol
  • Benzodioxole
  • Methoxybenzene
  • Phenol ether
  • Anisole
  • Phenol
  • Alkyl aryl ether
  • Benzenoid
  • Oxane
  • Monosaccharide
  • Gamma butyrolactone
  • Monocyclic benzene moiety
  • Meta-dioxane
  • Oxolane
  • Secondary alcohol
  • Lactone
  • Carboxylic acid ester
  • 1,2-diol
  • Oxacycle
  • Organoheterocyclic compound
  • Monocarboxylic acid or derivatives
  • Ether
  • Carboxylic acid derivative
  • Acetal
  • Hydrocarbon derivative
  • Organooxygen compound
  • Carbonyl group
  • Alcohol
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Pharmacology
IndicationFor 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.
PharmacodynamicsEtoposide 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 actionEtoposide 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.
Related Articles
AbsorptionAbsorbed 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 binding97% 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).

SubstrateEnzymesProduct
Etoposide
3'-demethyletoposideDetails
Etoposide
Etoposide glucuronideDetails
Etoposide
Etoposide catecholDetails
Etoposide catechol
Etoposide ortho-quinoneDetails
Route of eliminationEtoposide 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 life4-11 hours
Clearance
  • Total body clearance = 33 – 48 mL/min [IV administration, adults]
  • Mean renal clearance = 7 – 10 mL/min/m^2
ToxicitySide effects include alopecia, constipation, diarrhea, nausea and vomiting and secondary malignancies (leukemia).
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Etoposide Action PathwayDrug actionSMP00442
Etoposide Metabolism PathwayDrug metabolismSMP00601
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
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 )
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
Dosage forms
FormRouteStrength
Injection, powder, lyophilized, for solutionintravenous100 mg/1
Capsuleoral50 mg/1
Injectionintravenous20 mg/mL
Injection, solutionintravenous20 mg/mL
Liquidintravenous20 mg
Solutionintravenous20 mg
Injection, solution, concentrateintravenous20 mg/mL
Capsuleoral50 mg
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.
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point236-251 °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 FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
1D NMR1H NMR SpectrumNot Available
1D NMR13C NMR SpectrumNot Available
References
Synthesis Reference

DrugSyn.org

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 ]
External Links
ATC CodesL01CB01
AHFS Codes
  • 10:00.00
PDB EntriesNot Available
FDA labelDownload (206 KB)
MSDSDownload (24.1 KB)
Interactions
Drug Interactions
Drug
AcenocoumarolEtoposide may increase the anticoagulant activities of Acenocoumarol.
AprepitantThe serum concentration of Etoposide can be increased when it is combined with Aprepitant.
AtovaquoneThe serum concentration of Etoposide can be increased when it is combined with Atovaquone.
BexaroteneThe serum concentration of Etoposide can be decreased when it is combined with Bexarotene.
BosentanThe serum concentration of Etoposide can be decreased when it is combined with Bosentan.
CarbamazepineThe serum concentration of Etoposide can be decreased when it is combined with Carbamazepine.
ClozapineThe risk or severity of adverse effects can be increased when Etoposide is combined with Clozapine.
ConivaptanThe serum concentration of Etoposide can be increased when it is combined with Conivaptan.
CyclosporineThe metabolism of Etoposide can be decreased when combined with Cyclosporine.
DabrafenibThe serum concentration of Etoposide can be decreased when it is combined with Dabrafenib.
DasatinibThe serum concentration of Etoposide can be increased when it is combined with Dasatinib.
DeferasiroxThe serum concentration of Etoposide can be decreased when it is combined with Deferasirox.
DenosumabThe risk or severity of adverse effects can be increased when Denosumab is combined with Etoposide.
DicoumarolEtoposide may increase the anticoagulant activities of Dicoumarol.
EnzalutamideThe serum concentration of Etoposide can be decreased when it is combined with Enzalutamide.
FluconazoleThe metabolism of Etoposide can be decreased when combined with Fluconazole.
FosaprepitantThe serum concentration of Etoposide can be increased when it is combined with Fosaprepitant.
FosphenytoinThe serum concentration of Etoposide can be decreased when it is combined with Fosphenytoin.
Fusidic AcidThe serum concentration of Etoposide can be increased when it is combined with Fusidic Acid.
IdelalisibThe serum concentration of Etoposide can be increased when it is combined with Idelalisib.
IvacaftorThe serum concentration of Etoposide can be increased when it is combined with Ivacaftor.
LeflunomideThe risk or severity of adverse effects can be increased when Etoposide is combined with Leflunomide.
LuliconazoleThe serum concentration of Etoposide can be increased when it is combined with Luliconazole.
MetamizoleThe risk or severity of adverse effects can be increased when Metamizole is combined with Etoposide.
MifepristoneThe serum concentration of Etoposide can be increased when it is combined with Mifepristone.
MitotaneThe serum concentration of Etoposide can be decreased when it is combined with Mitotane.
NatalizumabThe risk or severity of adverse effects can be increased when Etoposide is combined with Natalizumab.
NelfinavirThe metabolism of Etoposide can be decreased when combined with Nelfinavir.
NetupitantThe serum concentration of Etoposide can be increased when it is combined with Netupitant.
PalbociclibThe serum concentration of Etoposide can be increased when it is combined with Palbociclib.
PhenobarbitalThe serum concentration of Etoposide can be decreased when it is combined with Phenobarbital.
PhenytoinThe serum concentration of Etoposide can be decreased when it is combined with Phenytoin.
PimecrolimusThe risk or severity of adverse effects can be increased when Pimecrolimus is combined with Etoposide.
PrimidoneThe serum concentration of Etoposide can be decreased when it is combined with Primidone.
RanolazineThe serum concentration of Etoposide can be increased when it is combined with Ranolazine.
RifabutinThe serum concentration of Etoposide can be decreased when it is combined with Rifabutin.
RifampicinThe serum concentration of Etoposide can be decreased when it is combined with Rifampicin.
RifapentineThe serum concentration of Etoposide can be decreased when it is combined with Rifapentine.
RoflumilastRoflumilast may increase the immunosuppressive activities of Etoposide.
SaquinavirThe serum concentration of Etoposide can be increased when it is combined with Saquinavir.
SiltuximabThe serum concentration of Etoposide can be decreased when it is combined with Siltuximab.
SimeprevirThe serum concentration of Etoposide can be increased when it is combined with Simeprevir.
Sipuleucel-TThe therapeutic efficacy of Sipuleucel-T can be decreased when used in combination with Etoposide.
St. John's WortThe serum concentration of Etoposide can be decreased when it is combined with St. John's Wort.
StiripentolThe serum concentration of Etoposide can be increased when it is combined with Stiripentol.
TacrolimusThe risk or severity of adverse effects can be increased when Tacrolimus is combined with Etoposide.
TesmilifeneThe serum concentration of Etoposide can be decreased when it is combined with Tesmilifene.
TocilizumabThe serum concentration of Etoposide can be decreased when it is combined with Tocilizumab.
TofacitinibEtoposide may increase the immunosuppressive activities of Tofacitinib.
TrastuzumabTrastuzumab may increase the neutropenic activities of Etoposide.
VerapamilThe serum concentration of Etoposide can be increased when it is combined with Verapamil.
WarfarinEtoposide may increase the anticoagulant activities of Warfarin.
Food Interactions
  • Grapefruit and grapefruit juice should be avoided throughout treatment as grapefruit can decrease serum levels of this product.

Targets

Kind
Protein
Organism
Human
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 segregation of daughter chromosomes. May play a role in regulating the period length of ARNTL/BMAL1 transcriptional oscillation (By similarity).
Gene Name:
TOP2A
Uniprot ID:
P11388
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
Human
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
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

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrateinhibitorinducer
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 reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
  2. 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
Human
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 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 N...
Gene Name:
CYP1A2
Uniprot ID:
P05177
Molecular Weight:
58293.76 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
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 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...
Gene Name:
CYP2C8
Uniprot ID:
P10632
Molecular Weight:
55824.275 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
Kind
Protein
Organism
Human
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 or carcinogenic forms.
Gene Name:
CYP2E1
Uniprot ID:
P05181
Molecular Weight:
56848.42 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrateinducer
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 unrelated compounds, including steroids, fatty acids, and xenobiotics.
Gene Name:
CYP3A5
Uniprot ID:
P20815
Molecular Weight:
57108.065 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
Kind
Protein
Organism
Human
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 IX-alpha-C8 and IX-alpha-C12 monoconjugates and diconjugate. Is also able to catalyze the glucuronidation of 17beta-estradiol, 17alpha-ethinylestradiol, 1-hydroxypyrene, 4-methylumbelliferone, 1-naph...
Gene Name:
UGT1A1
Uniprot ID:
P22309
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
Human
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 chloride and 4-nitrophenethyl bromide. Displays glutathione peroxidase activity with cumene hydroperoxide.
Gene Name:
GSTT1
Uniprot ID:
P30711
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
Human
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
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
Human
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 brain, and in pathological conditions, such as in cancer. PTGS2 is responsible for production of inflammatory prostaglandins. Up-regulation of PTGS2 is also associated with increased cell adhesion, p...
Gene Name:
PTGS2
Uniprot ID:
P35354
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
Human
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 gastric epithelial cells, it is a key step in the generation of prostaglandins, such as prostaglandin E2 (PGE2), which plays an important role in cytoprotection. In platelets, it is involved in the gener...
Gene Name:
PTGS1
Uniprot ID:
P23219
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
Human
Pharmacological action
unknown
Actions
substrateinhibitor
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 hepatocytes (By similarity).
Gene Name:
ABCC3
Uniprot ID:
O15438
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
Human
Pharmacological action
unknown
Actions
substrateinhibitor
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) and N-ethylmaleimide S-glutathione (NEM-GS).Isoform 2: Inhibits TNF-alpha-mediated apoptosis through blocking one or more caspases.
Gene Name:
ABCC6
Uniprot ID:
O95255
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 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrateinhibitor
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
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
Human
Pharmacological action
unknown
Actions
substrateinhibitor
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, methotrexate, antiviral drugs and other xenobiotics. Confers resistance to anticancer drugs. Hydrolyzes ATP with low efficiency.
Gene Name:
ABCC1
Uniprot ID:
P33527
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
Human
Pharmacological action
unknown
Actions
substrateinhibitor
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
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
Human
Pharmacological action
unknown
Actions
substrateinhibitor
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
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
Human
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 from mitochondria to cytosol and from cytosol to extracellular space, and cellular export of hemin, and heme. Xenobiotic transporter that may play an important role in the exclusion of xenobiotics from t...
Gene Name:
ABCG2
Uniprot ID:
Q9UNQ0
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 ]
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Drug created on June 13, 2005 07:24 / Updated on October 08, 2013 14:23