Oxaliplatin

Identification

Summary

Oxaliplatin is a platinum based chemotherapy agent used to treat carcinoma of the colon or rectum or stage III colon cancer.

Generic Name
Oxaliplatin
DrugBank Accession Number
DB00526
Background

Oxaliplatin is a platinum-based chemotherapy drug in the same family as cisplatin and carboplatin. Compared to cisplatin the two amine groups are replaced by diamino cyclohexane (DACH) group to provide a greater antitumor effect.2 However, this leads to poorer water solubility, which was compensated by the addition of the chloride moieties.2 Due to this chemical moiety, oxaliplatin readily undergoes non-enzymatic biotransformation, thus complicating oxaliplatin's pharmacokinetics.3 Like most platinum-based compounds, oxaliplatin's mechanism of action is primarily through DNA damage through DNA crosslinking, particularly intrastrand and interstrand crosslinking.3 However, due to the structure of oxaliplatin, its adducts make the binding of mismatch repair protein to DNA harder compared to cisplatin or carboplatin's adducts, resulting in greater cytotoxic effects.3 The DACH moiety also prevents cross-resistance with cisplatin and carboplatin.2

Although oxaliplatin has been investigated as a monotherapy, it is typically administered in combination with fluorouracil and leucovorin, known as the FOLFOX regimen, for the treatment of colorectal cancer.1,2 This is an effective combination treatment both as a first-line treatment and in patients refractory to an initial fluorouracil and leucovorin combination. Ongoing trials have also shown promising results for oxaliplatin use in nonHodgkin’s lymphoma, breast cancer, mesothelioma, and non-small cell lung cancer.2

Oxaliplatin was approved by the FDA on January 9, 2004 and is currently marketed by Sanofi-Aventis under the trademark Eloxatin®.7

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 397.294
Monoisotopic: 397.060149
Chemical Formula
C8H14N2O4Pt
Synonyms
  • Diaminocyclohexane Oxalatoplatinum
  • L-OHP
  • Oxalatoplatin
  • Oxalatoplatinum
  • Oxaliplatin
  • oxaliplatine
  • oxaliplatino
  • oxaliplatinum
External IDs
  • JM-83
  • NSC-266046
  • RP-54780
  • SR-96669

Pharmacology

Indication

Oxaliplatin, in combination with infusional fluorouracil and leucovorin, is indicated for the treatment of advanced colorectal cancer and adjuvant treatment of stage III colon cancer in patients who have undergone complete resection of the primary tumor.4

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Used in combination to treatAdvanced colorectal cancerRegimen in combination with: Fluorouracil (DB00544), Leucovorin (DB00650)•••••••••••••••••••••
Used as adjunct in combination to treatStage iii colon cancerRegimen in combination with: Leucovorin (DB00650), Fluorouracil (DB00544)•••••••••••••••••••• ••••••••• •• ••• •••••••••• ••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

In vivo studies have shown antitumor activities of oxaliplatin against colon carcinoma. In combination with fluorouracil, oxaliplatin exhibits in vitro and in vivo antiproliferative activity greater than either compound alone in several tumor models (HT29 [colon], GR [mammary], and L1210 [leukemia]).4

Mechanism of action

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. Both inter and intrastrand Pt-DNA crosslinks are formed. Crosslinks are formed between the N7 positions of two adjacent guanines (GG), adjacent adenine-guanines (AG), and guanines separated by an intervening nucleotide (GNG). These crosslinks inhibit DNA replication and transcription. Cytotoxicity is cell-cycle nonspecific.4

TargetActionsOrganism
ADNA
adduct
cross-linking/alkylation
Humans
Absorption

The reactive oxaliplatin derivatives are present as a fraction of the unbound platinum in plasma ultrafiltrate. After a single 2-hour intravenous infusion of oxaliplatin at a dose of 85 mg/m2, pharmacokinetic parameters expressed as ultrafiltrable platinum was Cmax of 0.814 mcg/mL. Interpatient and intrapatient variability in ultrafiltrable platinum exposure (AUC0-48hr) assessed over 3 cycles was 23% and 6%, respectively.4

Volume of distribution

After a single 2-hour intravenous infusion of oxaliplatin at a dose of 85 mg/m2, the volume of distribution is 440 L.At the end of a 2-hour infusion, 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.4

Protein binding

In patients, plasma protein binding of platinum is irreversible and is greater than 90%. The main binding proteins are albumin and gamma-globulins.4

Platinum also binds irreversibly and accumulates (approximately 2-fold) in erythrocytes, where it appears to have no relevant activity. No platinum accumulation was observed in plasma ultrafiltrate following 85 mg/m2 every two weeks.4

Metabolism

Oxaliplatin undergoes rapid and extensive nonenzymatic biotransformation. There is no evidence of cytochrome P450-mediated metabolism in vitro. Up to 17 platinum-containing derivatives have been observed in plasma ultrafiltrate samples from patients, including several cytotoxic species (monochloro DACH platinum, dichloro DACH platinum, and monoaquo and diaquo DACH platinum) and a number of noncytotoxic, conjugated species.4

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Route of elimination

The major route of platinum elimination is renal excretion. At five days after a single 2-hour infusion of ELOXATIN, urinary elimination accounted for about 54% of the platinum eliminated, with fecal excretion accounting for only about 2%.4

Half-life

The decline of ultrafilterable platinum levels following oxaliplatin administration 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).4

Clearance

Platinum was cleared from plasma at a rate (10-17 L/h) that was similar to or exceeded the average human glomerular filtration rate (GFR; 7.5 L/h). The renal clearance of ultrafiltrable platinum is significantly correlated with GFR.4

Adverse Effects
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Toxicity

The maximum dose of oxaliplatin that has been administered in a single infusion is 825 mg. Several cases of overdoses have been reported with oxaliplatin. Adverse reactions observed following an overdosage were grade 4 thrombocytopenia (less than 25,000/mm3) without bleeding, anemia, sensory neuropathy (including paresthesia, dysesthesia, laryngospasm, and facial muscle spasms), gastrointestinal disorders (including nausea, vomiting, stomatitis, flatulence, abdomen enlarged and grade 4 intestinal obstruction), grade 4 dehydration, dyspnea, wheezing, chest pain, respiratory failure, severe bradycardia, and death. Closely monitor patients suspected of receiving an overdose, including for the adverse reactions described above, and administer appropriate supportive treatment.4

Based on its direct interaction with DNA, ELOXATIN can cause fetal harm when administered to a pregnant woman. The available human data do not establish the presence or absence of major birth defects or miscarriages related to the use of oxaliplatin. Reproductive toxicity studies demonstrated adverse effects on embryo-fetal development in rats at maternal doses that were below the recommended human dose based on body surface area. Advise a pregnant woman of the potential risk to a fetus.4

In the adjuvant treatment trial, 400 patients who received oxaliplatin with fluorouracil/leucovorin were greater than or equal to 65 years. The effect of oxaliplatin in patients greater than or equal to 65 years was not conclusive. Patients greater than or equal to 65 years receiving ELOXATIN experienced more diarrhea and grade 3-4 neutropenia (45% vs 39%) compared to patients less than 65 years.4

The AUC of unbound platinum in plasma ultrafiltrate was increased in patients with renal impairment. No dose reduction is recommended for patients with mild (creatinine clearance 50 to 79 mL/min) or moderate (creatinine clearance 30 to 49 mL/min) renal impairment, calculated by Cockcroft-Gault equation. Reduce the dose of oxaliplatin in patients with severe renal impairment (creatinine clearance less than 30 mL/min).4

Long-term animal studies have not been performed to evaluate the carcinogenic potential of oxaliplatin. Oxaliplatin was not mutagenic to bacteria (Ames test) but was mutagenic to mammalian cells in vitro (L5178Y mouse lymphoma assay). Oxaliplatin was clastogenic both in vitro (chromosome aberration in human lymphocytes) and in vivo (mouse bone marrow micronucleus assay).4

In a fertility study, male rats were given oxaliplatin at 0, 0.5, 1, or 2 mg/kg/day for five days every 21 days for a total of three cycles prior to mating with females that received two cycles of oxaliplatin on the same schedule. A dose of 2 mg/kg/day (less than one-seventh the recommended human dose on a body surface area basis) did not affect the pregnancy rate but resulted in 97% postimplantation loss (increased early resorptions, decreased live fetuses, decreased live births), and delayed growth (decreased fetal weight).4

Testicular damage, characterized by degeneration, hypoplasia, and atrophy, was observed in dogs administered oxaliplatin at 0.75 mg/kg/day (approximately one-sixth of the recommended human dose on a body surface area basis) × 5 days every 28 days for three cycles. A no-effect level was not identified.4

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbataceptThe risk or severity of adverse effects can be increased when Oxaliplatin is combined with Abatacept.
AbciximabThe risk or severity of hemorrhage can be increased when Oxaliplatin is combined with Abciximab.
AbemaciclibAbemaciclib may decrease the excretion rate of Oxaliplatin which could result in a higher serum level.
AcebutololThe risk or severity of QTc prolongation can be increased when Oxaliplatin is combined with Acebutolol.
AceclofenacThe risk or severity of nephrotoxicity can be increased when Oxaliplatin is combined with Aceclofenac.
Food Interactions
No interactions found.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Act OxaliplatinSolution5 mg / mLIntravenousActavis Pharma Company2015-12-162018-07-09Canada flag
Act OxaliplatinPowder, for solution100 mg / vialIntravenousActavis Pharma CompanyNot applicableNot applicableCanada flag
Act OxaliplatinPowder, for solution50 mg / vialIntravenousActavis Pharma CompanyNot applicableNot applicableCanada flag
EloxatinSolution, concentrate200 mg/40mLIntravenoussanofi-aventis U.S. LLC2008-04-012008-04-01US flag
EloxatinPowder, for solution100 mg/1IntravenousSanofi Aventis2002-08-092009-04-30US flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
OxaliplatinInjection, solution5 mg/1mLIntravenousFosun Pharma USA Inc.2019-02-15Not applicableUS flag
OxaliplatinInjection, powder, lyophilized, for solution50 mg/10mLIntravenousSun Pharma Global Inc.2009-08-192016-12-21US flag
OxaliplatinInjection, solution5 mg/1mLIntravenousMeitheal Pharmaceuticals Inc.2024-01-11Not applicableUS flag
OxaliplatinInjection, solution100 mg/1mLIntravenousNextgen Pharmaceuticals LLC2020-07-01Not applicableUS flag
OxaliplatinInjection, solution, concentrate100 mg/20mLIntravenousSun Pharmaceutical Industries, Inc.2014-04-09Not applicableUS flag

Categories

ATC Codes
L01XA03 — Oxaliplatin
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as cyclohexylamines. These are organic compounds containing a cyclohexylamine moiety, which consist of a cyclohexane ring attached to an amine group.
Kingdom
Organic compounds
Super Class
Organic nitrogen compounds
Class
Organonitrogen compounds
Sub Class
Cyclohexylamines
Direct Parent
Cyclohexylamines
Alternative Parents
Dicarboxylic acids and derivatives / Organic transition metal salts / Carboxylic acids / Organopnictogen compounds / Organic oxides / Monoalkylamines / Hydrocarbon derivatives / Carbonyl compounds
Substituents
Aliphatic homomonocyclic compound / Amine / Carbonyl group / Carboxylic acid / Carboxylic acid derivative / Cyclohexylamine / Dicarboxylic acid or derivatives / Hydrocarbon derivative / Organic oxide / Organic oxygen compound
Molecular Framework
Not Available
External Descriptors
platinum coordination entity (CHEBI:31941)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
04ZR38536J
CAS number
61825-94-3
InChI Key
ZROHGHOFXNOHSO-BNTLRKBRSA-L
InChI
InChI=1S/C6H14N2.C2H2O4.Pt/c7-5-3-1-2-4-6(5)8;3-1(4)2(5)6;/h5-6H,1-4,7-8H2;(H,3,4)(H,5,6);/q;;+2/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
[H][N]1([H])[C@@H]2CCCC[C@H]2[N]([H])([H])[Pt]11OC(=O)C(=O)O1

References

Synthesis Reference

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

US20040022842
General References
  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. [Article]
  2. Graham J, Mushin M, Kirkpatrick P: Oxaliplatin. Nat Rev Drug Discov. 2004 Jan;3(1):11-2. [Article]
  3. Alcindor T, Beauger N: Oxaliplatin: a review in the era of molecularly targeted therapy. Curr Oncol. 2011 Jan;18(1):18-25. doi: 10.3747/co.v18i1.708. [Article]
  4. FDA Approved Drug Product: ELOXATIN (oxaliplatin) injection, for intravenous use (July 2023) [Link]
  5. FDA Approved Drug Products: ELOXATIN (oxaliplatin) injection, for intravenous use [Link]
  6. Oxaliplatin MSDS [Link]
  7. Sanofi-aventis receives FDA approval for new Eloxatin™ formulation [Link]
KEGG Drug
D01790
PubChem Compound
6857599
PubChem Substance
46509083
ChemSpider
8062727
RxNav
32592
ChEBI
31941
ChEMBL
CHEMBL414804
Therapeutic Targets Database
DAP000062
PharmGKB
PA131285527
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Oxaliplatin
FDA label
Download (2.35 MB)
MSDS
Download (38.4 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentColon Neoplasm1
4CompletedTreatmentColorectal Cancer4
4CompletedTreatmentColorectal Cancer / Cytokine-Induced Killer Cells / Postoperative Complications / Survival1
4CompletedTreatmentColorectal Neoplasms1
4CompletedTreatmentStage-Ⅱ Colorectal Cancer1

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
  • APP Pharmaceuticals
  • Ben Venue Laboratories Inc.
  • Ebewe Pharma
  • Hospira Inc.
  • Sanofi-Aventis Inc.
  • Sun Pharmaceutical Industries Ltd.
  • Teva Pharmaceutical Industries Ltd.
Dosage Forms
FormRouteStrength
Solution, concentrateIntravenous5 mg
Solution100.000 mg
Injection, powder, for solution
Injection, powder, lyophilized, for solution
Injection, powder, for solution100 mg
Injection, powder, for solution50 mg
Injection, powder, lyophilized, for solutionIntravenous100 mg
Injection, solution, concentrateIntravenous
Powder, for solutionIntravenous100 mg/1
Powder, for solutionIntravenous5 MG/ML
Powder, for solutionIntravenous50 mg/1
SolutionIntravenous5 mg / mL
Solution, concentrateIntravenous200 mg/40mL
Solution, concentrateIntravenous50 mg
InjectionIntravenous200 mg/40ml
Solution, concentrateIntravenous100 mg
SolutionIntravenous100.000 mg
Injection, solution, concentrateIntravenous150 mg/30ml
SolutionIntravenous50 mg/10ml
SolutionParenteral50.000 mg
Injection, solutionIntravenous
SolutionIntravenous5 mg
InjectionIntravenous100 mg/20mL
InjectionIntravenous5 mg/1mL
InjectionIntravenous50 mg/10mL
Injection, powder, lyophilized, for solutionIntravenous100 mg/20mL
Injection, powder, lyophilized, for solutionIntravenous5 mg/1mL
Injection, powder, lyophilized, for solutionIntravenous50 mg/10mL
Injection, solutionIntravenous100 mg/20mL
Injection, solutionIntravenous100 mg/1mL
Injection, solutionIntravenous200 mg/40mL
Injection, solutionIntravenous5 mg/1mL
Injection, solutionIntravenous50 mg/10mL
Injection, solutionIntravenous50 mg/1mL
Injection, solution, concentrateIntravenous100 mg/20mL
Injection, solution, concentrateIntravenous5 mg/1mL
Injection, solution, concentrateIntravenous50 mg/10mL
Injection; injection, solution, concentrateIntravenous5 mg/ml
Powder, for solutionIntravenous100 mg/20mL
Powder, for solutionIntravenous50 mg/10mL
Injection, powder, for solutionParenteral
Powder, for solutionIntravenous100 mg / vial
Powder, for solutionIntravenous50 mg / vial
Injection, solution, concentrateIntravenous5 mg/ml
Injection, solutionIntravenous5 mg/ml
SolutionIntravenous200 mg
Injection, solution, concentrateIntravenous200 mg/40ml
Injection, powder, for solutionIntravenous
Powder100 mg/1vial
SolutionIntravenous5 mg/ml
Injection, powder, lyophilized, for solutionIntravenous5 mg/ml
Injection, powder, lyophilized, for solutionIntravenous10000000 mg
SolutionIntravenous100 mg
SolutionIntravenous50 mg
Powder, for solutionIntravenous
Injection, solution, concentrateIntravenous; Parenteral5 MG/ML
Injection, powder, for solutionIntravenous
Injection, powder, for solutionIntravenous50 mg
Injection, powder, lyophilized, for solutionParenteral50 mg
InjectionIntravenous100 MG
InjectionIntravenous50 MG
SolutionIntravenous50.000 mg
Injection, solutionIntravenous2 MG/ML
InjectionIntravenous5 mg/ml
Injection, powder, lyophilized, for solutionIntravenous200 mg
SolutionIntravenous100 mg/20ml
SolutionIntravenous200 mg/40ml
SolutionIntravenous50.00 mg
InjectionIntravenous
Injection, powder, lyophilized, for solutionIntravenous100.00 mg
Injection, powder, lyophilized, for solutionIntravenous50.00 mg
SolutionIntravenous100.00 mg
SolutionParenteral50.00 mg
Injection, powder, lyophilized, for solutionIntravenous50 mg
SolutionIntravenous2 mg/1ml
SolutionIntravenous5 mg/1ml
Powder50 mg/1vial
Injection, powder, for solution100 mg/1vial
Injection, powder, for solution50 mg/1vial
Injection, solutionIntravenous2 mg/1ml
Prices
Unit descriptionCostUnit
Oxaliplatin 100 mg vial1650.0USD vial
Oxaliplatin 50 mg vial825.0USD vial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US5290961No1994-03-012013-01-12US flag
CA2196922No2004-06-012015-08-07Canada flag
US5420319Yes1995-05-302017-02-09US flag
US5716988Yes1998-02-102016-02-07US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
boiling point (°C)100ºCL47311
water solubility6 mg/mLL47206
Predicted Properties
PropertyValueSource
Water Solubility27.5 mg/mLALOGPS
logP-0.47ALOGPS
logS-1.2ALOGPS
Physiological Charge0Chemaxon
Hydrogen Acceptor Count0Chemaxon
Hydrogen Donor Count0Chemaxon
Polar Surface Area85.82 Å2Chemaxon
Rotatable Bond Count0Chemaxon
Refractivity67.52 m3·mol-1Chemaxon
Polarizability21.9 Å3Chemaxon
Number of Rings3Chemaxon
Bioavailability1Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.8638
Blood Brain Barrier+0.7667
Caco-2 permeable-0.6453
P-glycoprotein substrateSubstrate0.5056
P-glycoprotein inhibitor INon-inhibitor0.9332
P-glycoprotein inhibitor IINon-inhibitor1.0
Renal organic cation transporterNon-inhibitor0.9289
CYP450 2C9 substrateNon-substrate0.8846
CYP450 2D6 substrateNon-substrate0.8094
CYP450 3A4 substrateNon-substrate0.6064
CYP450 1A2 substrateNon-inhibitor0.8403
CYP450 2C9 inhibitorNon-inhibitor0.8686
CYP450 2D6 inhibitorNon-inhibitor0.8997
CYP450 2C19 inhibitorNon-inhibitor0.8189
CYP450 3A4 inhibitorNon-inhibitor0.8337
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9872
Ames testNon AMES toxic0.6034
CarcinogenicityNon-carcinogens0.938
BiodegradationNot ready biodegradable0.9796
Rat acute toxicity2.3765 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8879
hERG inhibition (predictor II)Non-inhibitor0.938
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available
Chromatographic Properties
Collision Cross Sections (CCS)
Not Available

Targets

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Use our structured and evidence-based datasets to unlock new
insights and accelerate drug research.
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Use our structured and evidence-based datasets to unlock new insights and accelerate drug research.
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Kind
Nucleotide
Organism
Humans
Pharmacological action
Yes
Actions
Adduct
Cross-linking/alkylation
DNA is the molecule of heredity, as it is responsible for the genetic propagation of most inherited traits. It is a polynucleic acid that carries genetic information on cell growth, division, and function. DNA consists of two long strands of nucleotides twisted into a double helix and held together by hydrogen bonds. The sequence of nucleotides determines hereditary characteristics. Each strand serves as the template for subsequent DNA replication and as a template for mRNA production, leading to protein synthesis via ribosomes.
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. [Article]
  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. [Article]
  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 Nov 9;373(5):1123-40. Epub 2007 Aug 23. [Article]
  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. doi: 10.1021/bi100775t. [Article]
  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. doi: 10.1093/nar/gkp029. Epub 2009 Mar 2. [Article]
  6. Arango D, Wilson AJ, Shi Q, Corner GA, Aranes MJ, Nicholas C, Lesser M, Mariadason JM, Augenlicht LH: Molecular mechanisms of action and prediction of response to oxaliplatin in colorectal cancer cells. Br J Cancer. 2004 Nov 29;91(11):1931-46. doi: 10.1038/sj.bjc.6602215. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Glutathione transferase activity
Specific Function
Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. Acts on 1,2-epoxy-3-(4-nitrophenoxy)propane, phenethylisothiocyanate 4-nitrobenzyl chlorid...
Gene Name
GSTT1
Uniprot ID
P30711
Uniprot Name
Glutathione S-transferase theta-1
Molecular Weight
27334.755 Da
References
  1. Lecomte T, Landi B, Beaune P, Laurent-Puig P, Loriot MA: Glutathione S-transferase P1 polymorphism (Ile105Val) predicts cumulative neuropathy in patients receiving oxaliplatin-based chemotherapy. Clin Cancer Res. 2006 May 15;12(10):3050-6. doi: 10.1158/1078-0432.CCR-05-2076. [Article]
  2. Alcindor T, Beauger N: Oxaliplatin: a review in the era of molecularly targeted therapy. Curr Oncol. 2011 Jan;18(1):18-25. doi: 10.3747/co.v18i1.708. [Article]
  3. PharmGKB: Platinum Pathway, Pharmacokinetics/Pharmacodynamics [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Zinc ion binding
Specific Function
Metallothioneins have a high content of cysteine residues that bind various heavy metals; these proteins are transcriptionally regulated by both heavy metals and glucocorticoids.
Gene Name
MT1A
Uniprot ID
P04731
Uniprot Name
Metallothionein-1A
Molecular Weight
6120.19 Da
References
  1. PharmGKB: Platinum Pathway, Pharmacokinetics/Pharmacodynamics [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Zinc ion binding
Specific Function
Metallothioneins have a high content of cysteine residues that bind various heavy metals; these proteins are transcriptionally regulated by both heavy metals and glucocorticoids.
Gene Name
MT2A
Uniprot ID
P02795
Uniprot Name
Metallothionein-2
Molecular Weight
6042.05 Da
References
  1. Zhao Z, Zhang G, Li W: MT2A Promotes Oxaliplatin Resistance in Colorectal Cancer Cells. Cell Biochem Biophys. 2020 Dec;78(4):475-482. doi: 10.1007/s12013-020-00930-5. Epub 2020 Jul 7. [Article]
  2. PharmGKB: Platinum Pathway, Pharmacokinetics/Pharmacodynamics [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Peroxidase activity
Specific Function
Part of the host defense system of polymorphonuclear leukocytes. It is responsible for microbicidal activity against a wide range of organisms. In the stimulated PMN, MPO catalyzes the production o...
Gene Name
MPO
Uniprot ID
P05164
Uniprot Name
Myeloperoxidase
Molecular Weight
83867.71 Da
References
  1. Argyriou AA: Updates on Oxaliplatin-Induced Peripheral Neurotoxicity (OXAIPN). Toxics. 2015 May 29;3(2):187-197. doi: 10.3390/toxics3020187. [Article]
  2. PharmGKB: Platinum Pathway, Pharmacokinetics/Pharmacodynamics [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Zinc ion binding
Specific Function
Destroys radicals which are normally produced within the cells and which are toxic to biological systems.
Gene Name
SOD1
Uniprot ID
P00441
Uniprot Name
Superoxide dismutase [Cu-Zn]
Molecular Weight
15935.685 Da
References
  1. Plasencia C, Martinez-Balibrea E, Martinez-Cardus A, Quinn DI, Abad A, Neamati N: Expression analysis of genes involved in oxaliplatin response and development of oxaliplatin-resistant HT29 colon cancer cells. Int J Oncol. 2006 Jul;29(1):225-35. [Article]
  2. PharmGKB: Platinum Pathway, Pharmacokinetics/Pharmacodynamics [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
S-nitrosoglutathione binding
Specific Function
Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. Regulates negatively CDK5 activity via p25/p35 translocation to prevent neurodegeneration.
Gene Name
GSTP1
Uniprot ID
P09211
Uniprot Name
Glutathione S-transferase P
Molecular Weight
23355.625 Da
References
  1. Peng Z, Wang Q, Gao J, Ji Z, Yuan J, Tian Y, Shen L: Association between GSTP1 Ile105Val polymorphism and oxaliplatin-induced neuropathy: a systematic review and meta-analysis. Cancer Chemother Pharmacol. 2013 Aug;72(2):305-14. doi: 10.1007/s00280-013-2194-x. Epub 2013 May 22. [Article]
  2. Lecomte T, Landi B, Beaune P, Laurent-Puig P, Loriot MA: Glutathione S-transferase P1 polymorphism (Ile105Val) predicts cumulative neuropathy in patients receiving oxaliplatin-based chemotherapy. Clin Cancer Res. 2006 May 15;12(10):3050-6. doi: 10.1158/1078-0432.CCR-05-2076. [Article]
  3. Alcindor T, Beauger N: Oxaliplatin: a review in the era of molecularly targeted therapy. Curr Oncol. 2011 Jan;18(1):18-25. doi: 10.3747/co.v18i1.708. [Article]
  4. PharmGKB: Platinum Pathway, Pharmacokinetics/Pharmacodynamics [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Protein homodimerization activity
Specific Function
Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles.
Gene Name
GSTM1
Uniprot ID
P09488
Uniprot Name
Glutathione S-transferase Mu 1
Molecular Weight
25711.555 Da
References
  1. Lecomte T, Landi B, Beaune P, Laurent-Puig P, Loriot MA: Glutathione S-transferase P1 polymorphism (Ile105Val) predicts cumulative neuropathy in patients receiving oxaliplatin-based chemotherapy. Clin Cancer Res. 2006 May 15;12(10):3050-6. doi: 10.1158/1078-0432.CCR-05-2076. [Article]
  2. Gataa I, Emile G, Loriot MA, Goldwasser F, Alexandre J: Association between high antitumor activity of oxaliplatin and cyclophosphamide and constitutional GSTM1 homozygous deletion in an advanced ovarian cancer patient. Chemotherapy. 2013;59(4):290-3. doi: 10.1159/000357517. Epub 2014 Jan 24. [Article]
  3. Alcindor T, Beauger N: Oxaliplatin: a review in the era of molecularly targeted therapy. Curr Oncol. 2011 Jan;18(1):18-25. doi: 10.3747/co.v18i1.708. [Article]
  4. PharmGKB: Platinum Pathway, Pharmacokinetics/Pharmacodynamics [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Superoxide dismutase activity
Specific Function
The enzyme apparently serves as a quinone reductase in connection with conjugation reactions of hydroquinons involved in detoxification pathways as well as in biosynthetic processes such as the vit...
Gene Name
NQO1
Uniprot ID
P15559
Uniprot Name
NAD(P)H dehydrogenase [quinone] 1
Molecular Weight
30867.405 Da
References
  1. PharmGKB: Platinum Pathway, Pharmacokinetics/Pharmacodynamics [Link]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Binder
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Schueffl H, Theiner S, Hermann G, Mayr J, Fronik P, Groza D, van Schonhooven S, Galvez L, Sommerfeld NS, Schintlmeister A, Reipert S, Wagner M, Mader RM, Koellensperger G, Keppler BK, Berger W, Kowol CR, Legin A, Heffeter P: Albumin-targeting of an oxaliplatin-releasing platinum(iv) prodrug results in pronounced anticancer activity due to endocytotic drug uptake in vivo. Chem Sci. 2021 Aug 26;12(38):12587-12599. doi: 10.1039/d1sc03311e. eCollection 2021 Oct 6. [Article]
  2. FDA Approved Drug Product: ELOXATIN (oxaliplatin) injection, for intravenous use (July 2023) [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Quaternary ammonium group transmembrane transporter activity
Specific Function
Mediates tubular uptake of organic compounds from circulation. Mediates the influx of agmatine, dopamine, noradrenaline (norepinephrine), serotonin, choline, famotidine, ranitidine, histamin, creat...
Gene Name
SLC22A2
Uniprot ID
O15244
Uniprot Name
Solute carrier family 22 member 2
Molecular Weight
62579.99 Da
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. doi: 10.1111/j.1476-5381.2009.00569.x. Epub 2010 Jan 8. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Copper uptake transmembrane transporter activity
Specific Function
High-affinity, saturable copper transporter involved in dietary copper uptake.
Gene Name
SLC31A1
Uniprot ID
O15431
Uniprot Name
High affinity copper uptake protein 1
Molecular Weight
21090.545 Da
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. doi: 10.1124/mol.109.063172. Epub 2010 Feb 16. [Article]
  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. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Toxin transporter activity
Specific Function
Mediates potential-dependent transport of a variety of organic cations. May play a significant role in the disposition of cationic neurotoxins and neurotransmitters in the brain.
Gene Name
SLC22A3
Uniprot ID
O75751
Uniprot Name
Solute carrier family 22 member 3
Molecular Weight
61279.485 Da
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. doi: 10.1124/dmd.108.023168. Epub 2008 Aug 18. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
References
  1. 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. doi: 10.1016/j.tiv.2008.09.001. Epub 2008 Sep 9. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Organic anion transmembrane transporter activity
Specific Function
Mediates hepatobiliary excretion of numerous organic anions. May function as a cellular cisplatin transporter.
Gene Name
ABCC2
Uniprot ID
Q92887
Uniprot Name
Canalicular multispecific organic anion transporter 1
Molecular Weight
174205.64 Da
References
  1. Biswas R, Bugde P, He J, Merien F, Lu J, Liu DX, Myint K, Liu J, McKeage M, Li Y: Transport-Mediated Oxaliplatin Resistance Associated with Endogenous Overexpression of MRP2 in Caco-2 and PANC-1 Cells. Cancers (Basel). 2019 Sep 8;11(9):1330. doi: 10.3390/cancers11091330. [Article]
  2. PharmGKB: Platinum Pathway, Pharmacokinetics/Pharmacodynamics [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Copper-exporting atpase activity
Specific Function
Involved in the export of copper out of the cells, such as the efflux of hepatic copper into the bile.
Gene Name
ATP7B
Uniprot ID
P35670
Uniprot Name
Copper-transporting ATPase 2
Molecular Weight
157261.34 Da
References
  1. Martinez-Balibrea E, Martinez-Cardus A, Musulen E, Gines A, Manzano JL, Aranda E, Plasencia C, Neamati N, Abad A: Increased levels of copper efflux transporter ATP7B are associated with poor outcome in colorectal cancer patients receiving oxaliplatin-based chemotherapy. Int J Cancer. 2009 Jun 15;124(12):2905-10. doi: 10.1002/ijc.24273. [Article]
  2. PharmGKB: Platinum Pathway, Pharmacokinetics/Pharmacodynamics [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Superoxide dismutase copper chaperone activity
Specific Function
May supply copper to copper-requiring proteins within the secretory pathway, when localized in the trans-Golgi network. Under conditions of elevated extracellular copper, it relocalized to the plas...
Gene Name
ATP7A
Uniprot ID
Q04656
Uniprot Name
Copper-transporting ATPase 1
Molecular Weight
163372.275 Da
References
  1. Samimi G, Safaei R, Katano K, Holzer AK, Rochdi M, Tomioka M, Goodman M, Howell SB: Increased expression of the copper efflux transporter ATP7A mediates resistance to cisplatin, carboplatin, and oxaliplatin in ovarian cancer cells. Clin Cancer Res. 2004 Jul 15;10(14):4661-9. doi: 10.1158/1078-0432.CCR-04-0137. [Article]
  2. PharmGKB: Platinum Pathway, Pharmacokinetics/Pharmacodynamics [Link]

Drug created at June 13, 2005 13:24 / Updated at May 29, 2024 19:09