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Identification
NameDoxorubicin
Accession NumberDB00997  (APRD00185)
TypeSmall Molecule
GroupsApproved, Investigational
Description

Doxorubicin is a cytotoxic anthracycline antibiotic isolated from cultures of Streptomyces peucetius var. caesius. Doxorubicin binds to nucleic acids, presumably by specific intercalation of the planar anthracycline nucleus with the DNA double helix.

Structure
Thumb
Synonyms
SynonymLanguageCode
(1S,3S)-3-Glycoloyl-3,5,12-trihydroxy-10-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl 3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosideNot AvailableNot Available
(8S-cis)-10-((3-amino-2,3,6-Trideoxy-alpha-L-lyxo-hexopyranosyl)oxy)-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-5,12-naphthacenedioneNot AvailableNot Available
14-hydroxydaunomycinNot AvailableNot Available
14-hydroxydaunorubicineNot AvailableNot Available
AdriamycinNot AvailableNot Available
DoxorubicinNot AvailableNot Available
DoxorubicineNot AvailableNot Available
DoxorubicinumNot AvailableNot Available
HydroxydaunorubicinNot AvailableNot Available
Salts
Name/CAS Structure Properties
Doxorubicin Hydrochloride
Thumb
  • InChI Key: MWWSFMDVAYGXBV-BADIEKLNSA-N
  • Monoisotopic Mass: 579.150738514
  • Average Mass: 579.98
DBSALT000060
Brand names
NameCompany
AdriablastinaPfizer
AdriamycinPfizer
AdriblastinActavis
CaelyxJanssen-Cilag
DoxilJanssen
MyocetCephalon
RubexNot Available
Brand mixturesNot Available
Categories
CAS number23214-92-8
WeightAverage: 543.5193
Monoisotopic: 543.174060775
Chemical FormulaC27H29NO11
InChI KeyAOJJSUZBOXZQNB-TZSSRYMLSA-N
InChI
InChI=1S/C27H29NO11/c1-10-22(31)13(28)6-17(38-10)39-15-8-27(36,16(30)9-29)7-12-19(15)26(35)21-20(24(12)33)23(32)11-4-3-5-14(37-2)18(11)25(21)34/h3-5,10,13,15,17,22,29,31,33,35-36H,6-9,28H2,1-2H3/t10-,13-,15-,17-,22+,27-/m0/s1
IUPAC Name
(8S,10S)-10-{[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy}-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxy-5,7,8,9,10,12-hexahydrotetracene-5,12-dione
SMILES
COC1=CC=CC2=C1C(=O)C1=C(O)C3=C(C[C@](O)(C[C@@H]3O[C@H]3C[C@H](N)[C@H](O)[C@H](C)O3)C(=O)CO)C(O)=C1C2=O
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassPhenylpropanoids and Polyketides
ClassAnthracyclines
SubclassNot Available
Direct parentAnthracyclines
Alternative parentsTetracenequinones; Anthraquinones; O-glycosyl Compounds; Tetralins; Amino Sugars; Anisoles; Hydroquinones; Alkyl Aryl Ethers; Oxanes; Tertiary Alcohols; Ketones; 1,2-Aminoalcohols; Secondary Alcohols; Polyols; Dialkyl Ethers; Polyamines; Enolates; Acetals; Enols; Primary Alcohols; Aldehydes; Monoalkylamines
Substituentstetracenequinone; 1,4-anthraquinone; 9,10-anthraquinone; anthracene; glycosyl compound; o-glycosyl compound; amino sugar; acene; tetralin; phenol ether; hydroquinone; anisole; alkyl aryl ether; phenol derivative; benzene; saccharide; oxane; tertiary alcohol; 1,2-aminoalcohol; ketone; secondary alcohol; polyol; enol; dialkyl ether; acetal; primary alcohol; ether; polyamine; enolate; amine; primary aliphatic amine; primary amine; aldehyde; carbonyl group; alcohol; organonitrogen compound
Classification descriptionThis compound belongs to the anthracyclines. These are polyketides containing a tetracenequinone ring structure with a sugar attached by glycosidic linkage.
Pharmacology
IndicationDoxorubicin is used to produce regression in disseminated neoplastic conditions like acute lymphoblastic leukemia, acute myeloblastic leukemia, Wilms’ tumor, neuroblastoma, soft tissue and bone sarcomas, breast carcinoma, ovarian carcinoma, transitional cell bladder carcinoma, thyroid carcinoma, gastric carcinoma, Hodgkin’s disease, malignant lymphoma and bronchogenic carcinoma in which the small cell histologic type is the most responsive compared to other cell types. Doxorubicin is also indicated for use as a component of adjuvant therapy in women with evidence of axillary lymph node involvement following resection of primary breast cancer.
PharmacodynamicsDoxorubicin is an antineoplastic in the anthracycline class. General properties of drugs in this class include: interaction with DNA in a variety of different ways including intercalation (squeezing between the base pairs), DNA strand breakage and inhibition with the enzyme topoisomerase II. Most of these compounds have been isolated from natural sources and antibiotics. However, they lack the specificity of the antimicrobial antibiotics and thus produce significant toxicity. The anthracyclines are among the most important antitumor drugs available. Doxorubicin is widely used for the treatment of several solid tumors while daunorubicin and idarubicin are used exclusively for the treatment of leukemia. Doxorubicin may also inhibit polymerase activity, affect regulation of gene expression, and produce free radical damage to DNA. Doxorubicin possesses an antitumor effect against a wide spectrum of tumors, either grafted or spontaneous. The anthracyclines are cell cycle-nonspecific.
Mechanism of actionDoxorubicin has antimitotic and cytotoxic activity through a number of proposed mechanisms of action: Doxorubicin forms complexes with DNA by intercalation between base pairs, and it inhibits topoisomerase II activity by stabilizing the DNA-topoisomerase II complex, preventing the religation portion of the ligation-religation reaction that topoisomerase II catalyzes.
AbsorptionNot Available
Volume of distribution

The distributive half-life is 5 minutes, which suggests that doxorubicin is rapidly taken up by tissue.
Steady state volume of distribution = 809 to 1214 L/m2

Protein bindingDoxorubicin and its major metabolite, doxorubicinol, is 74-76% bound to plasma protein. The extent to binding is independent of plasma concentration up to 1.1 mcg/mL. Doxorubicin does not cross the blood brain barrier.
Metabolism

Doxorubicin is capable of undergoing 3 metabolic routes: one-electron reduction, two-electron reduction, and deglycosidation. However, approximately half of the dose is eliminated from the body unchanged. Two electron reduction yields doxorubicinol, a secondary alcohol. This pathway is considered the primary metabolic pathway. The one electron reduction is facilitated by several oxidoreductases to form a doxirubicin-semiquinone radical. These enzymes include mitochondrial and cystolic NADPH dehydrogenates, xanthine oxidase, and nitric oxide synthases. Deglycosidation is a minor metabolic pathway (1-2% of the dose undergoes this pathway). The resultant metabolites are deoxyaglycone or hydroxyaglycone formed via reduction or hydrolysis respectively. Enzymes that may be involved with this pathway include xanthine oxidase, NADPH-cytochrome P450 reductase, and cytosolic NADPH dehydrogenase.

SubstrateEnzymesProduct
Doxorubicin
DoxorubicinolDetails
Doxorubicin
Doxorubicin-semiquinoneDetails
Doxorubicin
Doxorubicinol deoxaglyconeDetails
Doxorubicin
Not Available
Doxorubicine hydroxyaglyconeDetails
Doxorubicine hydroxyaglycone
Not Available
Doxirubicinol hydroxyaglyconeDetails
Route of elimination40% of the dose appears in bile in 5 days. 5-12% of the drug and its metabolites appears in urine during the same time period. <3% of the dose recovered in urine was doxorubicinol.
Half lifeTerminal half life = 20 - 48 hours.
Clearance
  • 324-809 mL/min/m2 [by metabolism and biliary excretion]
  • 1088 mL/min/m2 [Men]
  • 433 mL/min/m2 [Women]
  • 1540 mL/min/m2 [children greater than 2 years of age receiving administration of 10 to 75 mg/m2 doses]
  • 813 mL/min/m2 [infants younger than 2 years of age receiving administration of 10 to 75 mg/m2 doses]
ToxicityLD50=21800 ug/kg (rat, subcutaneous)
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Doxorubicin Metabolism PathwayDrug metabolismSMP00650
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption - 0.8092
Blood Brain Barrier - 0.9951
Caco-2 permeable - 0.799
P-glycoprotein substrate Substrate 0.7861
P-glycoprotein inhibitor I Non-inhibitor 0.8782
P-glycoprotein inhibitor II Non-inhibitor 0.8382
Renal organic cation transporter Non-inhibitor 0.9053
CYP450 2C9 substrate Non-substrate 0.8042
CYP450 2D6 substrate Non-substrate 0.9116
CYP450 3A4 substrate Substrate 0.5888
CYP450 1A2 substrate Non-inhibitor 0.9045
CYP450 2C9 substrate Non-inhibitor 0.9209
CYP450 2D6 substrate Non-inhibitor 0.9231
CYP450 2C19 substrate Non-inhibitor 0.9025
CYP450 3A4 substrate Non-inhibitor 0.831
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.8911
Ames test AMES toxic 0.9198
Carcinogenicity Non-carcinogens 0.9534
Biodegradation Not ready biodegradable 0.9672
Rat acute toxicity 2.6644 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9752
hERG inhibition (predictor II) Non-inhibitor 0.7195
Pharmacoeconomics
Manufacturers
  • Ortho biotech products lp
  • Pharmacia and upjohn co
  • App pharmaceuticals llc
  • Bedford laboratories div ben venue laboratories inc
  • Pharmachemie bv
  • Teva parenteral medicines inc
  • Bristol myers squibb co
Packagers
Dosage forms
FormRouteStrength
Injection, powder, for solutionIntravenous10 mg, 20 mg, 50 mg
Injection, solutionIntravenous 2 mg/mL
Prices
Unit descriptionCostUnit
Doxorubicin 50 mg vial132.0USDvial
Doxil 2 mg/ml vial115.78USDml
Adriamycin 50 mg vial64.8USDvial
Doxorubicin 10 mg vial44.4USDvial
Adriamycin 20 mg vial26.4USDvial
Adriamycin 10 mg vial13.2USDvial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States50135561992-10-202009-10-20
Canada13387021998-11-122013-11-12
Canada13355651995-05-162012-05-16
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point229-231 °CPhysProp
water solubilitySolubleNot Available
logP1.27HANSCH,C ET AL. (1995)
Caco2 permeability-6.8ADME Research, USCD
Predicted Properties
PropertyValueSource
Water Solubility1.18ALOGPS
logP1.41ALOGPS
logP0.92ChemAxon
logS-2.7ALOGPS
pKa (Strongest Acidic)9.53ChemAxon
pKa (Strongest Basic)8.94ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count12ChemAxon
Hydrogen Donor Count6ChemAxon
Polar Surface Area206.07 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity134.59 m3·mol-1ChemAxon
Polarizability53.87 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Gian P. Vicario, Sergio Penco, Federico Arcamone, “Daunorubicin and doxorubicin labelled with .sup.14 C at the 14-position and processes for their preparation.” U.S. Patent US4211864, issued March, 1976.

US4211864
General Reference
  1. Weiss RB: The anthracyclines: will we ever find a better doxorubicin? Semin Oncol. 1992 Dec;19(6):670-86. Pubmed
  2. Tan C, Tasaka H, Yu KP, Murphy ML, Karnofsky DA: Daunomycin, an antitumor antibiotic, in the treatment of neoplastic disease. Clinical evaluation with special reference to childhood leukemia. Cancer. 1967 Mar;20(3):333-53. Pubmed
  3. Arcamone F, Cassinelli G, Fantini G, Grein A, Orezzi P, Pol C, Spalla C: Adriamycin, 14-hydroxydaunomycin, a new antitumor antibiotic from S. peucetius var. caesius. Biotechnol Bioeng. 1969 Nov;11(6):1101-10. Pubmed
  4. Di Marco A, Gaetani M, Scarpinato B: Adriamycin (NSC-123,127): a new antibiotic with antitumor activity. Cancer Chemother Rep. 1969 Feb;53(1):33-7. Pubmed
  5. Lomovskaya N, Otten SL, Doi-Katayama Y, Fonstein L, Liu XC, Takatsu T, Inventi-Solari A, Filippini S, Torti F, Colombo AL, Hutchinson CR: Doxorubicin overproduction in Streptomyces peucetius: cloning and characterization of the dnrU ketoreductase and dnrV genes and the doxA cytochrome P-450 hydroxylase gene. J Bacteriol. 1999 Jan;181(1):305-18. Pubmed
  6. Mordente A, Meucci E, Silvestrini A, Martorana GE, Giardina B: New developments in anthracycline-induced cardiotoxicity. Curr Med Chem. 2009;16(13):1656-72. Pubmed
  7. Minotti G: Reactions of adriamycin with microsomal iron and lipids. Free Radic Res Commun. 1989;7(3-6):143-8. Pubmed
External Links
ResourceLink
KEGG DrugD03899
KEGG CompoundC01661
PubChem Compound31703
PubChem Substance46507641
ChemSpider29400
BindingDB22984
ChEBI28748
ChEMBLCHEMBL53463
Therapeutic Targets DatabaseDNC000163
PharmGKBPA449412
Drug Product Database2194465
RxListhttp://www.rxlist.com/cgi/generic2/doxor.htm
Drugs.comhttp://www.drugs.com/cdi/doxorubicin.html
WikipediaDoxorubicin
ATC CodesL01DB01
AHFS Codes
  • 10:00.00
PDB EntriesNot Available
FDA labelshow(105 KB)
MSDSshow(74.1 KB)
Interactions
Drug Interactions
Drug
Dabigatran etexilateP-Glycoprotein inducers such as doxorubicin may decrease the serum concentration of dabigatran etexilate. This combination should be avoided.
DigoxinThe antineoplasic agent decreases the effect of digoxin
TelithromycinTelithromycin may reduce clearance of Doxorubicin. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Doxorubicin if Telithromycin is initiated, discontinued or dose changed.
TerbinafineTerbinafine may reduce the metabolism and clearance of Doxorubicin. Consider alternate therapy or monitor for therapeutic/adverse effects of Doxorubicin if Terbinafine is initiated, discontinued or dose changed.
TrastuzumabTrastuzumab may increase the cardiotoxicity of Doxorubicin. Signs and symptoms of cardiac dysfunction should be monitored for frequently. Increased risk of heart failure. Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
VoriconazoleVoriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of doxorubicin by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of doxorubicin if voriconazole is initiated, discontinued or dose changed.
ZidovudineAdditive myelosuppression may occur. Doxorubicin may decrease the efficacy of zidovudine. Concomitant therapy should be avoided.
Food Interactions
  • Liberal fluid intake to increase urine output and help the excretion of uric acid.

Targets

1. DNA

Kind: nucleotide

Organism: Human

Pharmacological action: yes

Actions: intercalation

Components

Name UniProt ID Details

References:

  1. Fornari FA, Randolph JK, Yalowich JC, Ritke MK, Gewirtz DA: Interference by doxorubicin with DNA unwinding in MCF-7 breast tumor cells. Mol Pharmacol. 1994 Apr;45(4):649-56. Pubmed
  2. Momparler RL, Karon M, Siegel SE, Avila F: Effect of adriamycin on DNA, RNA, and protein synthesis in cell-free systems and intact cells. Cancer Res. 1976 Aug;36(8):2891-5. Pubmed
  3. Frederick CA, Williams LD, Ughetto G, van der Marel GA, van Boom JH, Rich A, Wang AH: Structural comparison of anticancer drug-DNA complexes: adriamycin and daunomycin. Biochemistry. 1990 Mar 13;29(10):2538-49. Pubmed

2. DNA topoisomerase 2-alpha

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
DNA topoisomerase 2-alpha P11388 Details

References:

  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Rody A, Karn T, Gatje R, Ahr A, Solbach C, Kourtis K, Munnes M, Loibl S, Kissler S, Ruckhaberle E, Holtrich U, von Minckwitz G, Kaufmann M: Gene expression profiling of breast cancer patients treated with docetaxel, doxorubicin, and cyclophosphamide within the GEPARTRIO trial: HER-2, but not topoisomerase II alpha and microtubule-associated protein tau, is highly predictive of tumor response. Breast. 2007 Feb;16(1):86-93. Epub 2006 Sep 28. Pubmed
  3. Koehn H, Magan N, Isaacs RJ, Stowell KM: Differential regulation of DNA repair protein Rad51 in human tumour cell lines exposed to doxorubicin. Anticancer Drugs. 2007 Apr;18(4):419-25. Pubmed
  4. Hayashi S, Hatashita M, Matsumoto H, Shioura H, Kitai R, Kano E: Enhancement of radiosensitivity by topoisomerase II inhibitor, amrubicin and amrubicinol, in human lung adenocarcinoma A549 cells and kinetics of apoptosis and necrosis induction. Int J Mol Med. 2006 Nov;18(5):909-15. Pubmed
  5. Azarova AM, Lyu YL, Lin CP, Tsai YC, Lau JY, Wang JC, Liu LF: From the Cover: 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
  6. Menendez JA, Vellon L, Lupu R: DNA topoisomerase IIalpha (TOP2A) inhibitors up-regulate fatty acid synthase gene expression in SK-Br3 breast cancer cells: in vitro evidence for a ‘functional amplicon’ involving FAS, Her-2/neu and TOP2A genes. Int J Mol Med. 2006 Dec;18(6):1081-7. Pubmed

Enzymes

1. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

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. Epub 2009 Nov 24. Pubmed
  2. Lu H, Chen CS, Waxman DJ: Potentiation of methoxymorpholinyl doxorubicin antitumor activity by P450 3A4 gene transfer. Cancer Gene Ther. 2009 May;16(5):393-404. Epub 2008 Nov 14. Pubmed

2. Cytochrome P450 2D6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2D6 P10635 Details

References:

  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  2. 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. Epub 2009 Nov 24. Pubmed

3. Cytochrome P450 2B6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2B6 P20813 Details

References:

  1. Masek V, Anzenbacherova E, Etrych T, Strohalm J, Ulbrich K, Anzenbacher P: Interaction of HPMA copolymer-doxorubicin conjugates with human liver microsomal cytochromes P450. Comparison with free doxorubicin. Drug Metab Dispos. 2011 Jun 3. Pubmed

4. Cytochrome P450 1B1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 1B1 Q16678 Details

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. Epub 2009 Nov 24. Pubmed

5. Carbonyl reductase [NADPH] 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Carbonyl reductase [NADPH] 1 P16152 Details

References:

  1. Kassner N, Huse K, Martin HJ, Godtel-Armbrust U, Metzger A, Meineke I, Brockmoller J, Klein K, Zanger UM, Maser E, Wojnowski L: Carbonyl reductase 1 is a predominant doxorubicin reductase in the human liver. Drug Metab Dispos. 2008 Oct;36(10):2113-20. doi: 10.1124/dmd.108.022251. Epub 2008 Jul 17. Pubmed

6. Carbonyl reductase [NADPH] 3

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Carbonyl reductase [NADPH] 3 O75828 Details

References:

  1. Bains OS, Karkling MJ, Lubieniecka JM, Grigliatti TA, Reid RE, Riggs KW: Naturally occurring variants of human CBR3 alter anthracycline in vitro metabolism. J Pharmacol Exp Ther. 2010 Mar;332(3):755-63. doi: 10.1124/jpet.109.160614. Epub 2009 Dec 9. Pubmed

7. Alcohol dehydrogenase [NADP(+)]

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Alcohol dehydrogenase [NADP(+)] P14550 Details

References:

  1. Kassner N, Huse K, Martin HJ, Godtel-Armbrust U, Metzger A, Meineke I, Brockmoller J, Klein K, Zanger UM, Maser E, Wojnowski L: Carbonyl reductase 1 is a predominant doxorubicin reductase in the human liver. Drug Metab Dispos. 2008 Oct;36(10):2113-20. doi: 10.1124/dmd.108.022251. Epub 2008 Jul 17. Pubmed

8. Aldo-keto reductase family 1 member C3

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Aldo-keto reductase family 1 member C3 P42330 Details

References:

  1. Novotna R, Wsol V, Xiong G, Maser E: Inactivation of the anticancer drugs doxorubicin and oracin by aldo-keto reductase (AKR) 1C3. Toxicol Lett. 2008 Sep;181(1):1-6. doi: 10.1016/j.toxlet.2008.06.858. Epub 2008 Jun 21. Pubmed

9. NAD(P)H dehydrogenase [quinone] 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
NAD(P)H dehydrogenase [quinone] 1 P15559 Details

References:

  1. Pawlowska J, Tarasiuk J, Wolf CR, Paine MJ, Borowski E: Differential ability of cytostatics from anthraquinone group to generate free radicals in three enzymatic systems: NADH dehydrogenase, NADPH cytochrome P450 reductase, and xanthine oxidase. Oncol Res. 2003;13(5):245-52. Pubmed
  2. Niitsu N, Kasukabe T, Yokoyama A, Okabe-Kado J, Yamamoto-Yamaguchi Y, Umeda M, Honma Y: Anticancer derivative of butyric acid (Pivalyloxymethyl butyrate) specifically potentiates the cytotoxicity of doxorubicin and daunorubicin through the suppression of microsomal glycosidic activity. Mol Pharmacol. 2000 Jul;58(1):27-36. Pubmed

10. Xanthine dehydrogenase/oxidase

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Xanthine dehydrogenase/oxidase P47989 Details

References:

  1. Pawlowska J, Tarasiuk J, Wolf CR, Paine MJ, Borowski E: Differential ability of cytostatics from anthraquinone group to generate free radicals in three enzymatic systems: NADH dehydrogenase, NADPH cytochrome P450 reductase, and xanthine oxidase. Oncol Res. 2003;13(5):245-52. Pubmed
  2. Niitsu N, Kasukabe T, Yokoyama A, Okabe-Kado J, Yamamoto-Yamaguchi Y, Umeda M, Honma Y: Anticancer derivative of butyric acid (Pivalyloxymethyl butyrate) specifically potentiates the cytotoxicity of doxorubicin and daunorubicin through the suppression of microsomal glycosidic activity. Mol Pharmacol. 2000 Jul;58(1):27-36. Pubmed

11. Nitric oxide synthase, brain

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Nitric oxide synthase, brain P29475 Details

References:

  1. Vasquez-Vivar J, Martasek P, Hogg N, Masters BS, Pritchard KA Jr, Kalyanaraman B: Endothelial nitric oxide synthase-dependent superoxide generation from adriamycin. Biochemistry. 1997 Sep 23;36(38):11293-7. Pubmed
  2. Fogli S, Nieri P, Breschi MC: The role of nitric oxide in anthracycline toxicity and prospects for pharmacologic prevention of cardiac damage. FASEB J. 2004 Apr;18(6):664-75. Pubmed

12. Nitric oxide synthase, inducible

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Nitric oxide synthase, inducible P35228 Details

References:

  1. Vasquez-Vivar J, Martasek P, Hogg N, Masters BS, Pritchard KA Jr, Kalyanaraman B: Endothelial nitric oxide synthase-dependent superoxide generation from adriamycin. Biochemistry. 1997 Sep 23;36(38):11293-7. Pubmed
  2. Fogli S, Nieri P, Breschi MC: The role of nitric oxide in anthracycline toxicity and prospects for pharmacologic prevention of cardiac damage. FASEB J. 2004 Apr;18(6):664-75. Pubmed

13. Nitric oxide synthase, endothelial

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Nitric oxide synthase, endothelial P29474 Details

References:

  1. Vasquez-Vivar J, Martasek P, Hogg N, Masters BS, Pritchard KA Jr, Kalyanaraman B: Endothelial nitric oxide synthase-dependent superoxide generation from adriamycin. Biochemistry. 1997 Sep 23;36(38):11293-7. Pubmed
  2. Fogli S, Nieri P, Breschi MC: The role of nitric oxide in anthracycline toxicity and prospects for pharmacologic prevention of cardiac damage. FASEB J. 2004 Apr;18(6):664-75. Pubmed

14. NADH dehydrogenase [ubiquinone] iron-sulfur protein 2, mitochondrial

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
NADH dehydrogenase [ubiquinone] iron-sulfur protein 2, mitochondrial O75306 Details

References:

  1. Pawlowska J, Tarasiuk J, Wolf CR, Paine MJ, Borowski E: Differential ability of cytostatics from anthraquinone group to generate free radicals in three enzymatic systems: NADH dehydrogenase, NADPH cytochrome P450 reductase, and xanthine oxidase. Oncol Res. 2003;13(5):245-52. Pubmed
  2. Thornalley PJ, Bannister WH, Bannister JV: Reduction of oxygen by NADH/NADH dehydrogenase in the presence of adriamycin. Free Radic Res Commun. 1986;2(3):163-71. Pubmed
  3. Nohl H, Gille L, Staniek K: The exogenous NADH dehydrogenase of heart mitochondria is the key enzyme responsible for selective cardiotoxicity of anthracyclines. Z Naturforsch C. 1998 Mar-Apr;53(3-4):279-85. Pubmed 9618942

15. NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial O75489 Details

References:

  1. Pawlowska J, Tarasiuk J, Wolf CR, Paine MJ, Borowski E: Differential ability of cytostatics from anthraquinone group to generate free radicals in three enzymatic systems: NADH dehydrogenase, NADPH cytochrome P450 reductase, and xanthine oxidase. Oncol Res. 2003;13(5):245-52. Pubmed
  2. Thornalley PJ, Bannister WH, Bannister JV: Reduction of oxygen by NADH/NADH dehydrogenase in the presence of adriamycin. Free Radic Res Commun. 1986;2(3):163-71. Pubmed
  3. Nohl H, Gille L, Staniek K: The exogenous NADH dehydrogenase of heart mitochondria is the key enzyme responsible for selective cardiotoxicity of anthracyclines. Z Naturforsch C. 1998 Mar-Apr;53(3-4):279-85. Pubmed 9618942

16. NADH dehydrogenase [ubiquinone] iron-sulfur protein 7, mitochondrial

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
NADH dehydrogenase [ubiquinone] iron-sulfur protein 7, mitochondrial O75251 Details

References:

  1. Pawlowska J, Tarasiuk J, Wolf CR, Paine MJ, Borowski E: Differential ability of cytostatics from anthraquinone group to generate free radicals in three enzymatic systems: NADH dehydrogenase, NADPH cytochrome P450 reductase, and xanthine oxidase. Oncol Res. 2003;13(5):245-52. Pubmed
  2. Thornalley PJ, Bannister WH, Bannister JV: Reduction of oxygen by NADH/NADH dehydrogenase in the presence of adriamycin. Free Radic Res Commun. 1986;2(3):163-71. Pubmed
  3. Nohl H, Gille L, Staniek K: The exogenous NADH dehydrogenase of heart mitochondria is the key enzyme responsible for selective cardiotoxicity of anthracyclines. Z Naturforsch C. 1998 Mar-Apr;53(3-4):279-85. Pubmed 9618942

17. NADPH--cytochrome P450 reductase

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
NADPH--cytochrome P450 reductase P16435 Details

References:

  1. Gutierrez PL, Gee MV, Bachur NR: Kinetics of anthracycline antibiotic free radical formation and reductive glycosidase activity. Arch Biochem Biophys. 1983 May;223(1):68-75. Pubmed

Transporters

1. Multidrug resistance protein 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor inducer

Components

Name UniProt ID Details
Multidrug resistance protein 1 P08183 Details

References:

  1. Fardel O, Lecureur V, Daval S, Corlu A, Guillouzo A: Up-regulation of P-glycoprotein expression in rat liver cells by acute doxorubicin treatment. Eur J Biochem. 1997 May 15;246(1):186-92. Pubmed
  2. 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
  3. Takara K, Tanigawara Y, Komada F, Nishiguchi K, Sakaeda T, Okumura K: Cellular pharmacokinetic aspects of reversal effect of itraconazole on P-glycoprotein-mediated resistance of anticancer drugs. Biol Pharm Bull. 1999 Dec;22(12):1355-9. Pubmed
  4. Jutabha P, Wempe MF, Anzai N, Otomo J, Kadota T, Endou H: Xenopus laevis oocytes expressing human P-glycoprotein: probing trans- and cis-inhibitory effects on [3H]vinblastine and [3H]digoxin efflux. Pharmacol Res. 2010 Jan;61(1):76-84. Epub 2009 Jul 21. Pubmed
  5. Li D, Jang SH, Kim J, Wientjes MG, Au JL: Enhanced drug-induced apoptosis associated with P-glycoprotein overexpression is specific to antimicrotubule agents. Pharm Res. 2003 Jan;20(1):45-50. Pubmed
  6. 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
  7. Kim S, Kim SS, Bang YJ, Kim SJ, Lee BJ: In vitro activities of native and designed peptide antibiotics against drug sensitive and resistant tumor cell lines. Peptides. 2003 Jul;24(7):945-53. Pubmed
  8. Ambudkar SV, Lelong IH, Zhang J, Cardarelli CO, Gottesman MM, Pastan I: Partial purification and reconstitution of the human multidrug-resistance pump: characterization of the drug-stimulatable ATP hydrolysis. Proc Natl Acad Sci U S A. 1992 Sep 15;89(18):8472-6. Pubmed
  9. Kusunoki N, Takara K, Tanigawara Y, Yamauchi A, Ueda K, Komada F, Ku Y, Kuroda Y, Saitoh Y, Okumura K: Inhibitory effects of a cyclosporin derivative, SDZ PSC 833, on transport of doxorubicin and vinblastine via human P-glycoprotein. Jpn J Cancer Res. 1998 Nov;89(11):1220-8. Pubmed
  10. Li YC, Fung KP, Kwok TT, Lee CY, Suen YK, Kong SK: Mitochondria-targeting drug oligomycin blocked P-glycoprotein activity and triggered apoptosis in doxorubicin-resistant HepG2 cells. Chemotherapy. 2004 Jun;50(2):55-62. Pubmed
  11. Sieczkowski E, Lehner C, Ambros PF, Hohenegger M: Double impact on p-glycoprotein by statins enhances doxorubicin cytotoxicity in human neuroblastoma cells. Int J Cancer. 2010 May 1;126(9):2025-35. Pubmed
  12. Bray J, Sludden J, Griffin MJ, Cole M, Verrill M, Jamieson D, Boddy AV: Influence of pharmacogenetics on response and toxicity in breast cancer patients treated with doxorubicin and cyclophosphamide. Br J Cancer. 2010 Mar 16;102(6):1003-9. Epub 2010 Feb 23. Pubmed
  13. Tao LY, Liang YJ, Wang F, Chen LM, Yan YY, Dai CL, Fu LW: Cediranib (recentin, AZD2171) reverses ABCB1- and ABCC1-mediated multidrug resistance by inhibition of their transport function. Cancer Chemother Pharmacol. 2009 Oct;64(5):961-9. Epub 2009 Mar 3. Pubmed
  14. Woodahl EL, Crouthamel MH, Bui T, Shen DD, Ho RJ: MDR1 (ABCB1) G1199A (Ser400Asn) polymorphism alters transepithelial permeability and sensitivity to anticancer agents. Cancer Chemother Pharmacol. 2009 Jun;64(1):183-8. Epub 2009 Jan 4. Pubmed

2. Multidrug resistance-associated protein 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Multidrug resistance-associated protein 1 P33527 Details

References:

  1. Loe DW, Almquist KC, Cole SP, Deeley RG: ATP-dependent 17 beta-estradiol 17-(beta-D-glucuronide) transport by multidrug resistance protein (MRP). Inhibition by cholestatic steroids. J Biol Chem. 1996 Apr 19;271(16):9683-9. Pubmed
  2. 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
  3. Tribull TE, Bruner RH, Bain LJ: The multidrug resistance-associated protein 1 transports methoxychlor and protects the seminiferous epithelium from injury. Toxicol Lett. 2003 Apr 30;142(1-2):61-70. Pubmed
  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
  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
  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. Pubmed
  7. Tao LY, Liang YJ, Wang F, Chen LM, Yan YY, Dai CL, Fu LW: Cediranib (recentin, AZD2171) reverses ABCB1- and ABCC1-mediated multidrug resistance by inhibition of their transport function. Cancer Chemother Pharmacol. 2009 Oct;64(5):961-9. Epub 2009 Mar 3. Pubmed
  8. Zheng LS, Wang F, Li YH, Zhang X, Chen LM, Liang YJ, Dai CL, Yan YY, Tao LY, Mi YJ, Yang AK, To KK, Fu LW: Vandetanib (Zactima, ZD6474) antagonizes ABCC1- and ABCG2-mediated multidrug resistance by inhibition of their transport function. PLoS One. 2009;4(4):e5172. Epub 2009 Apr 23. Pubmed

3. Canalicular multispecific organic anion transporter 2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Canalicular multispecific organic anion transporter 2 O15438 Details

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

4. Multidrug resistance-associated protein 6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Multidrug resistance-associated protein 6 O95255 Details

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
  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

5. ATP-binding cassette sub-family G member 2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
ATP-binding cassette sub-family G member 2 Q9UNQ0 Details

References:

  1. Suzuki M, Suzuki H, Sugimoto Y, Sugiyama Y: ABCG2 transports sulfated conjugates of steroids and xenobiotics. J Biol Chem. 2003 Jun 20;278(25):22644-9. Epub 2003 Apr 7. Pubmed
  2. 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
  3. Ozvegy C, Litman T, Szakacs G, Nagy Z, Bates S, Varadi A, Sarkadi B: Functional characterization of the human multidrug transporter, ABCG2, expressed in insect cells. Biochem Biophys Res Commun. 2001 Jul 6;285(1):111-7. Pubmed
  4. 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
  5. An Y, Ongkeko WM: ABCG2: the key to chemoresistance in cancer stem cells? Expert Opin Drug Metab Toxicol. 2009 Dec;5(12):1529-42. Pubmed
  6. Tiwari AK, Sodani K, Wang SR, Kuang YH, Ashby CR Jr, Chen X, Chen ZS: Nilotinib (AMN107, Tasigna) reverses multidrug resistance by inhibiting the activity of the ABCB1/Pgp and ABCG2/BCRP/MXR transporters. Biochem Pharmacol. 2009 Jul 15;78(2):153-61. Epub 2009 Apr 11. Pubmed
  7. Dai CL, Liang YJ, Wang YS, Tiwari AK, Yan YY, Wang F, Chen ZS, Tong XZ, Fu LW: Sensitization of ABCG2-overexpressing cells to conventional chemotherapeutic agent by sunitinib was associated with inhibiting the function of ABCG2. Cancer Lett. 2009 Jun 28;279(1):74-83. Epub 2009 Feb 18. Pubmed
  8. Zheng LS, Wang F, Li YH, Zhang X, Chen LM, Liang YJ, Dai CL, Yan YY, Tao LY, Mi YJ, Yang AK, To KK, Fu LW: Vandetanib (Zactima, ZD6474) antagonizes ABCC1- and ABCG2-mediated multidrug resistance by inhibition of their transport function. PLoS One. 2009;4(4):e5172. Epub 2009 Apr 23. Pubmed

6. Solute carrier family 22 member 16

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Solute carrier family 22 member 16 Q86VW1 Details

References:

  1. Bray J, Sludden J, Griffin MJ, Cole M, Verrill M, Jamieson D, Boddy AV: Influence of pharmacogenetics on response and toxicity in breast cancer patients treated with doxorubicin and cyclophosphamide. Br J Cancer. 2010 Mar 16;102(6):1003-9. Epub 2010 Feb 23. Pubmed

7. Multidrug resistance-associated protein 7

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Multidrug resistance-associated protein 7 Q5T3U5 Details

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

8. ATP-binding cassette sub-family B member 8, mitochondrial

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
ATP-binding cassette sub-family B member 8, mitochondrial Q9NUT2 Details

References:

  1. Elliott AM, Al-Hajj MA: ABCB8 mediates doxorubicin resistance in melanoma cells by protecting the mitochondrial genome. Mol Cancer Res. 2009 Jan;7(1):79-87. Pubmed

9. Bile salt export pump

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Bile salt export pump O95342 Details

References:

  1. Wang EJ, Casciano CN, Clement RP, Johnson WW: Fluorescent substrates of sister-P-glycoprotein (BSEP) evaluated as markers of active transport and inhibition: evidence for contingent unequal binding sites. Pharm Res. 2003 Apr;20(4):537-44. Pubmed

10. RalA-binding protein 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
RalA-binding protein 1 Q15311 Details

References:

  1. Singhal SS, Singhal J, Nair MP, Lacko AG, Awasthi YC, Awasthi S: Doxorubicin transport by RALBP1 and ABCG2 in lung and breast cancer. Int J Oncol. 2007 Mar;30(3):717-25. Pubmed

11. Canalicular multispecific organic anion transporter 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Canalicular multispecific organic anion transporter 1 Q92887 Details

References:

  1. Folmer Y, Schneider M, Blum HE, Hafkemeyer P: Reversal of drug resistance of hepatocellular carcinoma cells by adenoviral delivery of anti-ABCC2 antisense constructs. Cancer Gene Ther. 2007 Nov;14(11):875-84. Epub 2007 Aug 17. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:12