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Identification
NameOxaliplatin
Accession NumberDB00526  (APRD00186)
Typesmall molecule
Groupsapproved, investigational
Description

Oxaliplatin is a platinum-based chemotherapy drug in the same family as cisplatin and carboplatin. It is typically administered in combination with fluorouracil and leucovorin in a combination known as Folfox for the treatment of colorectal cancer. Compared to cisplatin the two amine groups are replaced by cyclohexyldiamine for improved antitumour activity. The chlorine ligands are replaced by the oxalato bidentate derived from oxalic acid in order to improve water solubility. Oxaliplatin is marketed by Sanofi-Aventis under the trademark Eloxatin®.

Structure
Thumb
Synonyms
SynonymLanguageCode
Diaminocyclohexane OxalatoplatinumNot AvailableNot Available
L-OHPNot AvailableNot Available
OxalatoplatinNot AvailableNot Available
OxalatoplatinumNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
EloxatinSanofi-Aventis
Brand mixturesNot Available
Categories
CAS number61825-94-3
WeightAverage: 395.276
Monoisotopic: 395.044481331
Chemical FormulaC8H12N2O4Pt
InChI KeyDWAFYCQODLXJNR-BNTLRKBRSA-L
InChI
InChI=1S/C6H12N2.C2H2O4.Pt/c7-5-3-1-2-4-6(5)8;3-1(4)2(5)6;/h5-8H,1-4H2;(H,3,4)(H,5,6);/q-2;;+4/p-2/t5-,6-;;/m1../s1
IUPAC Name
(3aR,7aR)-octahydro-2',5'-dioxaspiro[cyclohexa[d]1,3-diaza-2-platinacyclopentane-2,1'-cyclopentane]-3',4'-dione
SMILES
O=C1O[Pt]2(N[C@@H]3CCCC[C@H]3N2)OC1=O
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassOrganonitrogen Compounds
ClassAmines
SubclassPolyamines
Direct parentPolyamines
Alternative parentsMetalloheterocyclic Compounds; Carboxylic Acids and Derivatives
SubstituentsNot Available
Classification descriptionThis compound belongs to the polyamines. These are compounds containing more than one amine group.
Pharmacology
IndicationUsed in combination with infusional 5-FU/LV, is indicated for the treatment of advanced carcinoma of the colon or rectum and for adjuvant treatment of stage III colon cancer patients who have undergone complete resection of the primary tumor.
PharmacodynamicsOxaliplatin selectively inhibits the synthesis of deoxyribonucleic acid (DNA). The guanine and cytosine content correlates with the degree of Oxaliplatin-induced cross-linking. At high concentrations of the drug, cellular RNA and protein synthesis are also suppressed.
Mechanism of actionOxaliplatin undergoes nonenzymatic conversion to active derivatives via displacement of the labile oxalate ligand. Several transient reactive species are formed, including monoaquo and diaquo DACH platinum, which covalently bind with macromolecules. After activation, oxaliplatin binds preferentially to the guanine and cytosine moieties of DNA, leading to cross-linking of DNA, thus inhibiting DNA synthesis and transcription. Cytotoxicity is cell-cycle nonspecific.
AbsorptionBioavailability is complete following intravenous administration. When a single 2-hour intravenous infusion of oxaliplatin at a dose of 85 mg/m^2 is given, the peak serum concentration was 0.814 mcg/mL.
Volume of distribution
  • 440 L [single 2-hour IV infusion at dose of 85 mg/m^2]
    At the end of a 2-hour infusion of oxaliplatin, approximately 15% of the administered platinum is present in the systemic circulation. The remaining 85% is rapidly distributed into tissues or eliminated in the urine.
Protein bindingPlasma protein binding of platinum (active metabolite) is irreversible and is greater than 90%, primarily to albumin and gamma-globulins. It is also irreversibly binds to erythrocytes.
Metabolism

Oxaliplatin undergoes nonenzymatic conversion in physiologic solutions to active derivatives via displacement of the labile oxalate ligand. Several transient reactive species are formed, including monoaquo and diaquo DACH platinum, which covalently bind with macromolecules. There is no evidence of cytochrome P450-mediated metabolism in vitro.

Route of eliminationThe major route of platinum elimination is renal excretion. At five days after a single 2-hour infusion of oxaliplatin, urinary elimination accounted for about 54% of the platinum eliminated, with fecal excretion accounting for only about 2%.
Half lifeThe decline of ultrafilterable platinum levels following oxaliplatin administartion is triphasic, with two distribution phases: t1/2α; 0.43 hours and t1/2β; 16.8 hours. This is followed by a long terminal elimination phase that lasts 391 hours (t1/2γ).
Clearance
  • 10 – 17 L/h [renal clearance]
ToxicityThere have been five cases of oxaliplatin overdose reported. One patient received two 130 mg/m2 doses of oxaliplatin (cumulative dose of 260 mg/m2) within a 24-hour period. The patient experienced Grade 4 thrombocytopenia (<25,000/mm3) without any bleeding, which resolved. Two other patients were mistakenly administered oxaliplatin instead of carboplatin. One patient received a total oxaliplatin dose of 500 mg and the other received 650 mg. The first patient experienced dyspnea, wheezing, paresthesia, profuse vomiting and chest pain on the day of administration. She developed respiratory failure and severe bradycardia, and subsequently did not respond to resuscitation efforts. The other patient also experienced dyspnea, wheezing, paresthesia, and vomiting. Most common adverse reactions (incidence ≥ 40%) were peripheral sensory neuropathy, neutropenia, thrombocytopenia, anemia, nausea, increase in transaminases and alkaline phosphatase, diarrhea, emesis, fatigue and stomatitis.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.8638
Blood Brain Barrier + 0.7667
Caco-2 permeable - 0.6453
P-glycoprotein substrate Substrate 0.5056
P-glycoprotein inhibitor I Non-inhibitor 0.9332
P-glycoprotein inhibitor II Non-inhibitor 1.0
Renal organic cation transporter Non-inhibitor 0.9289
CYP450 2C9 substrate Non-substrate 0.8846
CYP450 2D6 substrate Non-substrate 0.8094
CYP450 3A4 substrate Non-substrate 0.6064
CYP450 1A2 substrate Non-inhibitor 0.8403
CYP450 2C9 substrate Non-inhibitor 0.8686
CYP450 2D6 substrate Non-inhibitor 0.8997
CYP450 2C19 substrate Non-inhibitor 0.8189
CYP450 3A4 substrate Non-inhibitor 0.8337
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9872
Ames test Non AMES toxic 0.6034
Carcinogenicity Non-carcinogens 0.938
Biodegradation Not ready biodegradable 0.9796
Rat acute toxicity 2.3765 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.8879
hERG inhibition (predictor II) Non-inhibitor 0.938
Pharmacoeconomics
Manufacturers
  • Sanofi aventis us llc
  • App pharmaceuticals llc
  • Ebewe pharma ges mbh nfg kg
  • Fresenius kabi oncology plc
  • Hospira inc
  • Hospira worldwide pty
  • Sun pharma global inc
  • Teva parenteral medicines inc
Packagers
Dosage forms
FormRouteStrength
Injection, powder, for solutionIntravenous50 mg, 100 mg
Injection, solutionIntravenous50 mg/10 mL; 100 mg/20 mL; 200 mg/40 mL
Prices
Unit descriptionCostUnit
Oxaliplatin 100 mg vial1650.0USDvial
Oxaliplatin 50 mg vial825.0USDvial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States54203191997-02-092017-02-09
United States52909611993-01-122013-01-12
Canada21969222004-06-012015-08-07
Properties
Statesolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
water solubility1.24e+01 g/lALOGPS
logP0.04ALOGPS
logP1.73ChemAxon
logS-1.5ALOGPS
pKa (strongest basic)5.88ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count4ChemAxon
hydrogen donor count2ChemAxon
polar surface area76.66ChemAxon
rotatable bond count0ChemAxon
refractivity65.92ChemAxon
polarizability21.29ChemAxon
number of rings3ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Masazumi Eriguchi, “Liposome preparations containing oxaliplatin.” U.S. Patent US20040022842, issued February 05, 2004.

US20040022842
General Reference
  1. Pasetto LM, D’Andrea MR, Rossi E, Monfardini S: Oxaliplatin-related neurotoxicity: how and why? Crit Rev Oncol Hematol. 2006 Aug;59(2):159-68. Epub 2006 Jun 27. Pubmed
  2. Graham J, Mushin M, Kirkpatrick P: Oxaliplatin. Nat Rev Drug Discov. 2004 Jan;3(1):11-2. Pubmed
  3. FDA label
External Links
ResourceLink
KEGG DrugD01790
PubChem Compound6857599
PubChem Substance46509083
ChemSpider8062727
ChEBI31941
ChEMBLCHEMBL414804
Therapeutic Targets DatabaseDAP000062
PharmGKBPA131285527
RxListhttp://www.rxlist.com/cgi/generic/eloxatin.htm
Drugs.comhttp://www.drugs.com/cdi/oxaliplatin.html
WikipediaOxaliplatin
ATC CodesL01XA03
AHFS Codes
  • 10:00
PDB EntriesNot Available
FDA labelshow(2.35 MB)
MSDSshow(38.4 KB)
Interactions
Drug Interactions
Drug
BendamustineIncreases toxicity through pharmacodynamic synergism. Additive myelosuppression.
TopotecanAdministration of Topotecan after Oxaliplatin therapy may increase the risk of hematologic toxicity, such as neutropenia and/or thrombocytopenia. A dose adjustment may be required or the sequence of administration reversed.
TrastuzumabTrastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
Food InteractionsNot Available

Targets

1. DNA

Kind: nucleotide

Organism: Human

Pharmacological action: yes

Actions: cross-linking/alkylation

Components

Name UniProt ID Details

References:

  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Sharma S, Gong P, Temple B, Bhattacharyya D, Dokholyan NV, Chaney SG: Molecular Dynamic Simulations of Cisplatin- and Oxaliplatin-d(GG) Intrastand Cross-links Reveal Differences in their Conformational Dynamics. J Mol Biol. 2007 Aug 23;. Pubmed
  4. Zhu G, Chang P, Lippard SJ: Recognition of platinum-DNA damage by poly(ADP-ribose) polymerase-1. Biochemistry. 2010 Jul 27;49(29):6177-83. Pubmed
  5. Ramachandran S, Temple BR, Chaney SG, Dokholyan NV: Structural basis for the sequence-dependent effects of platinum-DNA adducts. Nucleic Acids Res. 2009 May;37(8):2434-48. Epub 2009 Mar 2. Pubmed

Enzymes

1. Cytochrome P450 1A1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 1A1 P04798 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. Cytochrome P450 1A2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 1A2 P05177 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

3. Cytochrome P450 1B1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

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
  2. Song IS, Savaraj N, Siddik ZH, Liu P, Wei Y, Wu CJ, Kuo MT: Role of human copper transporter Ctr1 in the transport of platinum-based antitumor agents in cisplatin-sensitive and cisplatin-resistant cells. Mol Cancer Ther. 2004 Dec;3(12):1543-9. Pubmed
  3. Song IS, Savaraj N, Siddik ZH, Liu P, Wei Y, Wu CJ, Kuo MT: Role of human copper transporter Ctr1 in the transport of platinum-based antitumor agents in cisplatin-sensitive and cisplatin-resistant cells. Mol Cancer Ther. 2004 Dec;3(12):1543-9. Pubmed

4. Cytochrome P450 2E1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2E1 P05181 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. Glutathione S-transferase theta-1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Glutathione S-transferase theta-1 P30711 Details

References:

  1. https://www.pharmgkb.org/pathway/PA150642262#

6. Metallothionein-1A

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Metallothionein-1A P04731 Details

References:

  1. https://www.pharmgkb.org/pathway/PA150642262#

7. Metallothionein-2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Metallothionein-2 P02795 Details

References:

  1. https://www.pharmgkb.org/pathway/PA150642262#

8. Myeloperoxidase

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Myeloperoxidase P05164 Details

References:

  1. https://www.pharmgkb.org/pathway/PA150642262#

9. Superoxide dismutase [Cu-Zn]

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Superoxide dismutase [Cu-Zn] P00441 Details

References:

  1. https://www.pharmgkb.org/pathway/PA150642262#

10. Glutathione S-transferase P

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Glutathione S-transferase P P09211 Details

References:

  1. https://www.pharmgkb.org/pathway/PA150642262#

11. Glutathione S-transferase Mu 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Glutathione S-transferase Mu 1 P09488 Details

References:

  1. https://www.pharmgkb.org/pathway/PA150642262#

12. 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. https://www.pharmgkb.org/pathway/PA150642262#

Transporters

1. Solute carrier family 22 member 2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Solute carrier family 22 member 2 O15244 Details

References:

  1. Burger H, Zoumaro-Djayoon A, Boersma AW, Helleman J, Berns EM, Mathijssen RH, Loos WJ, Wiemer EA: Differential transport of platinum compounds by the human organic cation transporter hOCT2 (hSLC22A2). Br J Pharmacol. 2010 Feb;159(4):898-908. Epub 2010 Jan 8. Pubmed

2. Solute carrier family 22 member 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Solute carrier family 22 member 1 O15245 Details

References:

  1. Ahlin G, Karlsson J, Pedersen JM, Gustavsson L, Larsson R, Matsson P, Norinder U, Bergstrom CA, Artursson P: Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1. J Med Chem. 2008 Oct 9;51(19):5932-42. Epub 2008 Sep 13. Pubmed

3. High affinity copper uptake protein 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
High affinity copper uptake protein 1 O15431 Details

References:

  1. Howell SB, Safaei R, Larson CA, Sailor MJ: Copper transporters and the cellular pharmacology of the platinum-containing cancer drugs. Mol Pharmacol. 2010 Jun;77(6):887-94. Epub 2010 Feb 16. Pubmed
  2. Song, I.S. et al. Role of human copper transporter Ctr1 in the transport of
    platinum-based antitumor agents in cisplatin-sensitive and cisplatin-resistant
    cells. Mol Cancer Ther 3, 1543-1549 (2004).Pubmed

4. Solute carrier family 22 member 3

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Solute carrier family 22 member 3 O75751 Details

References:

  1. Yokoo S, Masuda S, Yonezawa A, Terada T, Katsura T, Inui K: Significance of organic cation transporter 3 (SLC22A3) expression for the cytotoxic effect of oxaliplatin in colorectal cancer. Drug Metab Dispos. 2008 Nov;36(11):2299-306. Epub 2008 Aug 18. Pubmed

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

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

References:

  1. Ceckova M, Vackova Z, Radilova H, Libra A, Buncek M, Staud F: Effect of ABCG2 on cytotoxicity of platinum drugs: interference of EGFP. Toxicol In Vitro. 2008 Dec;22(8):1846-52. Epub 2008 Sep 9. Pubmed

6. 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. https://www.pharmgkb.org/pathway/PA150642262#

7. Copper-transporting ATPase 2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Copper-transporting ATPase 2 P35670 Details

References:

  1. https://www.pharmgkb.org/pathway/PA150642262#

8. Copper-transporting ATPase 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Copper-transporting ATPase 1 Q04656 Details

References:

  1. https://www.pharmgkb.org/pathway/PA150642262#

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:11