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Identification
Name Docetaxel
Accession Number DB01248 (APRD00932)
Type small molecule
Groups approved
Description

Docetaxel is a clinically well established anti-mitotic chemotherapy medication used mainly for the treatment of breast, ovarian, and non-small cell lung cancer. Docetaxel binds to microtubules reversibly with high affinity and has a maximum stoichiometry of 1 mole docetaxel per mole tubulin in microtubules.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
Docetaxel anhydrous
Docetaxel, Trihydrate
TXL
Salts Not Available
Brand names
Name Company
Taxotere
Brand mixtures Not Available
Categories
  • Antineoplastic Agents
  • Radiation-Sensitizing Agents
  • Antimalarials
  • Antineoplastic Agents, Phytogenic
CAS number 114977-28-5
Weight Average: 807.8792
Monoisotopic: 807.346605409
Chemical Formula C43H53NO14
InChI Key InChIKey=ZDZOTLJHXYCWBA-VCVYQWHSSA-N
InChI
InChI=1S/C43H53NO14/c1-22-26(55-37(51)32(48)30(24-15-11-9-12-16-24)44-38(52)58-39(3,4)5)20-43(53)35(56-36(50)25-17-13-10-14-18-25)33-41(8,34(49)31(47)29(22)40(43,6)7)27(46)19-28-42(33,21-54-28)57-23(2)45/h9-18,26-28,30-33,35,46-48,53H,19-21H2,1-8H3,(H,44,52)/t26-,27-,28+,30-,31+,32+,33-,35-,41+,42-,43+/m0/s1
Plain Text
IUPAC Name
(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetyloxy)-15-{[(2R,3S)-3-{[(tert-butoxy)carbonyl]amino}-2-hydroxy-3-phenylpropanoyl]oxy}-1,9,12-trihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0^{3,10}.0^{4,7}]heptadec-13-en-2-yl benzoate
SMILES
[H][C@@]12C[C@H](O)[C@@]3(C)C(=O)[C@H](O)C4=C(C)[C@H](C[C@@](O)([C@@H](OC(=O)C5=CC=CC=C5)[C@]3([H])[C@@]1(CO2)OC(C)=O)C4(C)C)OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C1=CC=CC=C1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Taxanes
Substructures
  • Taxanes
  • Carbonyl Compounds
  • Carboxylic Acids and Derivatives
  • Glycerol and Derivatives
  • Hydroxy Compounds
  • Alkanes and Alkenes
  • Benzyl Alcohols and Derivatives
  • Acetates
  • Benzoates
  • Carbamates and Derivatives
  • Short-chain Hydroxy Acids
  • Cyclobutane and Derivatives
  • Ethers
  • Benzene and Derivatives
  • Alcohols and Polyols
  • Heterocyclic compounds
  • Aromatic compounds
  • Benzoyl Derivatives
  • Cyclohexenes and Derivatives
  • Cyclooctane and Derivatives
  • Ketones
Pharmacology
Indication For the treatment of patients with locally advanced or metastatic breast cancer after failure of prior chemotherapy. Also used as a single agent in the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of prior platinum-based chemotherapy. Lastly, for use, in combination with prednisone, in the treatment of patients with androgen independent (hormone refractory) metastatic prostate cancer.
Pharmacodynamics Docetaxel is a taxoid antineoplastic agent. It promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions. In addition, docetaxel induces abnormal arrays or "bundles" of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.
Mechanism of action Docetaxel interferes with the normal function of microtubule growth. Whereas drugs like colchicine cause the depolymerization of microtubules in vivo, docetaxel arrests their function by having the opposite effect; it hyper-stabilizes their structure. This destroys the cell's ability to use its cytoskeleton in a flexible manner. Specifically, docetaxel binds to the β-subunit of tubulin. Tubulin is the "building block" of mictotubules, and the binding of docetaxel locks these building blocks in place. The resulting microtubule/docetaxel complex does not have the ability to disassemble. This adversely affects cell function because the shortening and lengthening of microtubules (termed dynamic instability) is necessary for their function as a transportation highway for the cell. Chromosomes, for example, rely upon this property of microtubules during mitosis. Further research has indicated that docetaxel induces programmed cell death (apoptosis) in cancer cells by binding to an apoptosis stopping protein called Bcl-2 (B-cell leukemia 2) and thus arresting its function.
Absorption Not Available
Volume of distribution
  • 113 L
Protein binding About 94% protein bound, mainly to a1-acid glycoprotein, albumin, and lipoproteins.
Metabolism Hepatic. In vitro drug interaction studies revealed that docetaxel is metabolized by the CYP3A4 isoenzyme (1 major, 3 minor metabolites).
Route of elimination Docetaxel was eliminated in both the urine and feces following oxidative metabolism of the tert-butyl ester group, but fecal excretion was the main elimination route. Within 7 days, urinary and fecal excretion accounted for approximately 6% and 75% of the administered radioactivity, respectively.
Half life Dose-dependent. Doses of 70 mg per square meter of body surface area (mg/m 2 ) or higher produce a triphasic elimination profile. With lower doses, assay limitations precluded detection of the terminal elimination phase. Alpha (distribution) 4 minutes. Beta 36 minutes. Gamma (terminal) 11.1 hours.
Clearance
  • 21 L/h/m2 [Cancer patients after IV administration of 20–115 mg/m2]
Toxicity Oral LD50 in rat is >2000 mg/kg. Anticipated complications of overdosage include: bone marrow suppression, peripheral neurotoxicity, and mucositis. In two reports of overdose, one patient received 150 mg/m2 and the other received 200 mg/m2 as 1-hour infusions. Both patients experienced severe neutropenia, mild asthenia, cutaneous reactions, and mild paresthesia, and recovered without incident.
Affected organisms
  • Humans and other mammals
Pathways
Pathway Name SMPDB ID
Smp00435 Docetaxel Pathway SMP00435
Pharmacoeconomics
Manufacturers
  • Sanofi aventis us llc
Packagers
Dosage forms
Form Route Strength
Solution Intravenous
Prices
Unit description Cost Unit
Taxotere 20 mg/0.5 ml vial 477.37 USD vial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Country Patent Number Approved Expires (estimated)
United States 5438072 1994-05-22 2014-05-22
United States 4814470 1993-05-14 2010-05-14
Canada 2150576 2005-06-21 2013-11-26
Canada 2149055 2003-01-07 2013-11-08
Properties
State solid
Experimental Properties
Property Value Source
melting point 232 °C PhysProp
water solubility Practically insoluble (0.025 mg/L) Not Available
logP 2.4 Not Available
Predicted Properties
Property Value Source
water solubility 1.27e-02 g/l ALOGPS
logP 2.59 ALOGPS
logP 2.92 ChemAxon
logS -4.8 ALOGPS
pKa (strongest acidic) 10.96 ChemAxon
pKa (strongest basic) -3 ChemAxon
physiological charge 0 ChemAxon
hydrogen acceptor count 10 ChemAxon
hydrogen donor count 5 ChemAxon
polar surface area 224.45 ChemAxon
rotatable bond count 13 ChemAxon
refractivity 203.9 ChemAxon
polarizability 82.06 ChemAxon
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Compound C11231 Link_out
PubChem Compound 148124 Link_out
PubChem Substance 46506766 Link_out
ChemSpider 130581 Link_out
ChEBI 4672 Link_out
ChEMBL 4672 Link_out
Therapeutic Targets Database DAP000590 Link_out
PharmGKB PA449383 Link_out
Drug Product Database 2177080 Link_out
RxList http://www.rxlist.com/cgi/generic3/docetaxel.htm Link_out
Drugs.com http://www.drugs.com/cdi/docetaxel.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Docetaxel Link_out
ATC Codes
  • L01CD02
AHFS Codes
  • 10:00.00
PDB Entries Not Available
FDA label show (140 KB)
MSDS show (100 KB)
Interactions
Drug Interactions
Drug Interaction
Aprepitant Aprepitant may change levels of the chemotherapy agent, docetaxel.
Carboplatin Platinum derivatives such as carboplatin may enhance the myelosuppressive effect of taxane derivatives such as docetaxel. Administer taxane derivative before platinum derivative when given as sequential infusions to limit toxicity. Administering the taxane derivative before the platinum derivative seems prudent.
Cisplatin Platinum derivatives such as cisplatin may enhance the myelosuppressive effect of taxane derivatives such as docetaxel. Administer taxane derivative before platinum derivative when given as sequential infusions to limit toxicity. Administer paclitaxel before cisplatin, when given as sequential infusions, to limit toxicity. Problems associated with other taxane/platinum combinations are possible, although unsubstantiated. Administering the taxane derivative before the platinum derivative seems prudent.
Erythromycin Erythromycin may increase the serum levels and toxicity of docetaxel.
Josamycin Josamycin may increase the serum levels and toxicity of docetaxel.
Ketoconazole Ketoconazole may increase the serum levels and toxicity of docetaxel.
Midazolam Midazolam may increase the serum levels and toxicity of docetaxel.
Orphenadrine Orphenadrine may increase the serum levels and toxicity of docetaxel.
Quinupristin This combination presents an increased risk of toxicity.
Telithromycin Telithromycin may reduce clearance of Docetaxel. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Docetaxel if Telithromycin is initiated, discontinued or dose changed.
Testosterone Testosterone may increase the serum levels and toxicity of docetaxel.
Testosterone Propionate Testosterone propionate may increase the serum levels and toxicity of docetaxel.
Trastuzumab Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
Valrubicin The taxane derivative, Docetaxel, may increase Valrubicin toxicity. Consider alternate therapy or monitor for toxic effects.
Voriconazole Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of docetaxel by decreasing its metabolism. Consider using a non-interacting antifungal or monitor for changes in the therapeutic and adverse effects of docetaxel if voriconazole is initiated, discontinued or dose changed.
Food Interactions Not Available
Targets

1. Tubulin beta-1 chain

Pharmacological action: yes
Actions: Binder

Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha-chain

Organism class: human
UniProt ID: Q9H4B7 Link_out
Gene: TUBB1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Gligorov J, Lotz JP: Preclinical pharmacology of the taxanes: implications of the differences. Oncologist. 2004;9 Suppl 2:3-8. Pubmed
  2. Matesanz R, Barasoain I, Yang CG, Wang L, Li X, de Ines C, Coderch C, Gago F, Barbero JJ, Andreu JM, Fang WS, Diaz JF: Optimization of taxane binding to microtubules: binding affinity dissection and incremental construction of a high-affinity analog of paclitaxel. Chem Biol. 2008 Jun;15(6):573-85. Pubmed
  3. Snyder JP, Nettles JH, Cornett B, Downing KH, Nogales E: The binding conformation of Taxol in beta-tubulin: a model based on electron crystallographic density. Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5312-6. Epub 2001 Apr 17. Pubmed
  4. Belani CP, Eckardt J: Development of docetaxel in advanced non-small-cell lung cancer. Lung Cancer. 2004 Dec;46 Suppl 2:S3-11. Pubmed

2. Apoptosis regulator Bcl-2

Pharmacological action: unknown

Suppresses apoptosis in a variety of cell systems including factor-dependent lymphohematopoietic and neural cells. Regulates cell death by controlling the mitochondrial membrane permeability. Appears to function in a feedback loop system with caspases. Inhibits caspase activity either by preventing the release of cytochrome c from the mitochondria and/or by binding to the apoptosis-activating factor (APAF-1)

Organism class: human
UniProt ID: P10415 Link_out
Gene: BCL2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Gligorov J, Lotz JP: Preclinical pharmacology of the taxanes: implications of the differences. Oncologist. 2004;9 Suppl 2:3-8. Pubmed
  2. Marshall J, Chen H, Yang D, Figueira M, Bouker KB, Ling Y, Lippman M, Frankel SR, Hayes DF: A phase I trial of a Bcl-2 antisense (G3139) and weekly docetaxel in patients with advanced breast cancer and other solid tumors. Ann Oncol. 2004 Aug;15(8):1274-83. Pubmed
  3. Inoue Y, Gika M, Abiko T, Oyama T, Saitoh Y, Yamazaki H, Nakamura M, Abe Y, Kawamura M, Kobayashi K: Bcl-2 overexpression enhances in vitro sensitivity against docetaxel in non-small cell lung cancer. Oncol Rep. 2005 Feb;13(2):259-64. Pubmed
  4. Petrylak DP: Chemotherapy for androgen-independent prostate cancer. World J Urol. 2005 Feb;23(1):10-3. Epub 2005 Feb 1. Pubmed
  5. Miyoshi Y, Uemura H, Kubota Y: [Treatment of androgen-independent hormone refractory prostate cancer using docetaxel] Nippon Rinsho. 2005 Feb;63(2):298-302. Pubmed
  6. Magi-Galluzzi C, Zhou M, Reuther AM, Dreicer R, Klein EA: Neoadjuvant docetaxel treatment for locally advanced prostate cancer: a clinicopathologic study. Cancer. 2007 Sep 15;110(6):1248-54. Pubmed
Enzymes

1. Cytochrome P450 3A4

Actions: substrate, inhibitor

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

2. Cytochrome P450 3A5

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics

UniProt ID: P20815 Link_out
Gene: CYP3A5 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.

3. Cytochrome P450 3A7

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics

UniProt ID: P24462 Link_out
Gene: CYP3A7 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.

4. Cytochrome P450 1B1

Actions: substrate, inhibitor, inducer

Participates in the metabolism of an as-yet-unknown biologically active molecule that is a participant in eye development

UniProt ID: Q16678 Link_out
Gene: CYP1B1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Transporters

1. Multidrug resistance protein 1

Actions: substrate

Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells

UniProt ID: P08183 Link_out
Gene: ABCB1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Wils P, Phung-Ba V, Warnery A, Lechardeur D, Raeissi S, Hidalgo IJ, Scherman D: Polarized transport of docetaxel and vinblastine mediated by P-glycoprotein in human intestinal epithelial cell monolayers. Biochem Pharmacol. 1994 Oct 7;48(7):1528-30. Pubmed
  2. Shirakawa K, Takara K, Tanigawara Y, Aoyama N, Kasuga M, Komada F, Sakaeda T, Okumura K: Interaction of docetaxel (“Taxotere”) with human P-glycoprotein. Jpn J Cancer Res. 1999 Dec;90(12):1380-6. Pubmed

2. Multidrug resistance-associated protein 7

Actions: substrate

ATP-dependent transporter probably involved in cellular detoxification through lipophilic anion extrusion

UniProt ID: Q5T3U5 Link_out
Gene: ABCC10 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Hopper-Borge E, Xu X, Shen T, Shi Z, Chen ZS, Kruh GD: Human multidrug resistance protein 7 (ABCC10) is a resistance factor for nucleoside analogues and epothilone B. Cancer Res. 2009 Jan 1;69(1):178-84. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:20