PharmGKB: The Pharmacogenomics Knowledge Base

Drug/Small Molecule:
paclitaxel

2D structure

Overview

Generic Names: 7-Epipaclitaxel; 7-Epitaxol; 7-epi-Paclitaxel; 7-epi-Taxol
Trade Names: Epitaxol; LipoPac; Onxol; Paxceed; Paxene; Taxol; Taxol A; Vascular Wrap; Xorane
PharmGKB Accession Id: PA450761

Description

A cyclodecane isolated from the bark of the Pacific yew tree, TAXUS brevifolia. It stabilizes microtubules in their polymerized form leading to cell death. PubChem (source: Drug Bank)

Indication

Used in the treatment of Kaposi's sarcoma and cancer of the lung, ovarian, and breast. (source: Drug Bank)

ATC Therapeutic Category

  • L01CD:Taxanes

Pharmacology, Interactions, and Contraindications

Mechanism Of Action

Paclitaxel interferes with the normal function of microtubule growth. Whereas drugs like colchicine cause the depolymerization of microtubules in vivo, paclitaxel 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, paclitaxel binds to the β subunit of tubulin. Tubulin is the "building block" of mictotubules, and the binding of paclitaxel locks these building blocks in place. The resulting microtubule/paclitaxel 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 paclitaxel 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. (source: Drug Bank)

Pharmacology

Paclitaxel is a taxoid antineoplastic agent indicated as first-line and subsequent therapy for the treatment of advanced carcinoma of the ovary, and other various cancers including breast cancer. Paclitaxel is a novel antimicrotubule agent that 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, paclitaxel induces abnormal arrays or "bundles" of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis. (source: Drug Bank)

Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation

Hepatic. In vitro studies with human liver microsomes and tissue slices showed that paclitaxel was metabolized primarily to 6a-hydrox-ypaclitaxel by the cytochrome P450 isozyme CYP2C8; and to two minor metabolites, 3’-p-hydroxypaclitaxel and 6a, 3’-p-dihydroxypaclitaxel, by CYP3A4. (source: Drug Bank)

Protein Binding

89%-98% (source: Drug Bank)

Absorption

I.V injected (source: Drug Bank)

Toxicity

Rat (ipr) LD<sub>50</sub>=32530 µg/kg. Symptoms of overdose include bone marrow suppression, peripheral neurotoxicity, and mucositis. Overdoses in pediatric patients may be associated with acute ethanol toxicity. (source: Drug Bank)

Isomeric SMILES Code:

CC1=C2[C@H](C(=O)[C@@]3([C@H](C[C@@H]4[C@]([C@H]3[C@@H]([C@@](C2(C)C)(C[C@@H]1OC(=O)[C@@H]([C@H](c5ccccc5)NC(=O)c6ccccc6)O)O)OC(=O)c7ccccc7)(CO4)OC(=O)C)O)C)OC(=O)C (source: Drug Bank)

In-Depth Annotations (In-Depth Annotation)

  1. rs12721627 at chr7:99204029 in CYP3A, CYP3A4
    Part of CYP3A4*16B haplotype that has been shown to alter paclitaxel metabolite levels in Japanese(Asian) cancer patients; defining polymorphism for CYP3A4*16A.
    Variant Name:
    CYP3A4:T185S; CYP3A4:658 C>G; CYP3A4:185 Thr>Ser; CYP3A4*16A
    Related Drugs:
    paclitaxel
    Related Diseases:
    Neoplasms
    Evidence:
    http://www.pharmgkb.org/.../variant.jsp

Curated Annotations (Curated Annotation)

  1. rs1056836 at chr2:38151707 in CYP1B1
    In clincal studies of breast cancer patients treated with paclitaxel, CYP1B1*3 was associated with progression-free survival, independent of paclitaxel clearance
    Variant Name:
    CYP1B1*3;CYP1B1:4326 C>G; CYP1B1:L432V
    Related Drugs:
    paclitaxel
    Related Diseases:
    Breast Neoplasms
    Evidence:
    PMID:19474787
  2. rs1045642 at chr7:86976581 in ABCB1
    Patients with this variant with metastatic breast cancer treated with palitaxel showed a significantly lower disease control rate and lower overall survival rate than the CC variant allele.
    Variant Name:
    ABCB1:3435 C>T
    Related Drugs:
    paclitaxel
    Related Diseases:
    Breast Neoplasms
    Evidence:
    PMID:18836089
  3. rs1045642 at chr7:86976581 in ABCB1
    Patients with both rs1045642 and rs2032582 variants have been associated with neutropenia from paclitaxel.
    Variant Name:
    ABCB1:3435 C>T
    Related Drugs:
    paclitaxel
    Related Diseases:
    Neutropenia
    Evidence:
    PMID:16950614
  4. rs2032582 at chr7:86998554 in ABCB1
    A study of 83 patients found that patients heterozygous for this variant in ABCB1 had a significantly higher clearance of paclitaxel than most other ABCB1 variants.
    Variant Name:
    ABCB1: G2677T/A; Ala893Ser/Thr
    Related Drugs:
    paclitaxel
    Related Diseases:
    Ovarian Neoplasms
    Evidence:
    PMID:19143748
  5. rs2032582 at chr7:86998554 in ABCB1
    This variant have been associated with response to palitaxel.
    Variant Name:
    ABCB1: 2677G>T/A
    Related Drugs:
    paclitaxel
    Evidence:
    PMID:16467099
  6. rs2032582 at chr7:86998554 in ABCB1
    Patients with epithelial ovarian cancer, with this variant, have been associated with response to taxane- and platinum-based therapy and gastrointestinal toxicity.
    Variant Name:
    ABCB1: 2677G>T/A
    Related Drugs:
    carboplatin, cisplatin, docetaxel, paclitaxel, taxanes
    Related Diseases:
    Ovarian Neoplasms
    Evidence:
    PMID:19203783
  7. rs2032582 at chr7:86998554 in ABCB1
    Patients with both rs1045642 and rs2032582 variants have been associated with neutropenia from paclitaxel.
    Variant Name:
    ABCB1: 2677G>T/A
    Related Drugs:
    paclitaxel
    Related Diseases:
    Neutropenia
    Evidence:
    PMID:16950614
  8. rs776746 at chr7:99108475 in CYP3A, CYP3A5
    Risk or phenotype-associated allele: A. Phenotype: This variant was associated with reduced risk for neurotoxicity with paclitaxel treatment. Study size: 132. Study population/ethnicity: Patients with Neoplasms receiving paclitaxel; Spain. Significance metric(s): HR = 0.55 (0.33-0.94); p = 0.027. Type of association: PK; TOX.
    Variant Name:
    rs776746 A>G; CYP3A5*3; Splicing defect
    Related Drugs:
    paclitaxel
    Related Diseases:
    Drug Toxicity, Neurotoxicity Syndromes
    Evidence:
    PMID:20212519
  9. rs3832694 at chr10:96786964 in CYP2C8
    The allelic variant is designated as CYP2C8*12 allele.
    Variant Name:
    CYP2C8: 1407delTTG; 461delV
    Related Drugs:
    paclitaxel
    Evidence:
    PMID:17558302
  10. rs10509681 at chr10:96788739 in CYP2C8
    The variant is part of the CYP2C8*3 allele. In in vitro studies, the recombinant expressed CYP2C8*3 exhibits markedly impaired metabolism of paclitaxel and arachidonic acid.
    Variant Name:
    CYP2C8: K399R; A1196G
    Related Drugs:
    paclitaxel
    Evidence:
    PMID:11668219
  11. rs1113129 at chr10:96801035 in CYP2C8
    Risk or phenotype-associated allele: C. Phenotype: This variant was associated with reduced risk for neurotoxicity with paclitaxel treatment. Study size: 132. Study population/ethnicity: Patients with Neoplasms receiving paclitaxel; Spain. Significance metric(s): HR = 0.59 (0.36-0.94); p = 0.026. Type of association: PK; TOX.
    Variant Name:
    rs1113129 G>C; CYP2C8-HapC; Haplotype low act
    Related Drugs:
    paclitaxel
    Related Diseases:
    Drug Toxicity, Neurotoxicity Syndromes
    Evidence:
    PMID:20212519
  12. rs11572103 at chr10:96808096 in CYP2C8
    The variant is part of the CYP2C8*2 allele. In an in vitro study, the CYP2C8*2 allele exhibited a two-fold lower clearance for paclitaxel than the wildtype.
    Variant Name:
    CYP2C8: I269F; A805T
    Related Drugs:
    paclitaxel
    Evidence:
    PMID:11668219
  13. rs1058930 at chr10:96808109 in CYP2C8
    Alleles positive for this variant are designated CYP2C8*4. In in vitro experiments, the paclitaxel 6 alpha-hydroxylase acivity associated with CYP2C8*4 appeared lower than the wildtpe but the difference was not significant.
    Variant Name:
    CYP2C8: I264M; C792G
    Related Drugs:
    paclitaxel
    Evidence:
    PMID:12429347
  14. rs11572080 at chr10:96817020 in CYP2C8
    The variant is part of the CYP2C8*3 allele. In in vitro studies, the recombinant expressed CYP2C8*3 exhibits markedly impaired metabolism of paclitaxel and arachidonic acid.
    Variant Name:
    CYP2C8: R139K; G416A
    Related Drugs:
    paclitaxel
    Evidence:
    PMID:11668219
  15. rs11572080 at chr10:96817020 in CYP2C8
    Risk or phenotype-associated allele: A. Phenotype: This variant was associated with increased risk for neurotoxicity with paclitaxel treatment. Study size: 132. Study population/ethnicity: Patients with Neoplasms receiving paclitaxel; Spain. Significance metric(s): HR = 1.54 (0.96-2.47); p = 0.072. Type of association: PK; TOX.
    Variant Name:
    rs11572080 G>A; CYP2C8*3; R139K
    Related Drugs:
    paclitaxel
    Related Diseases:
    Drug Toxicity, Neurotoxicity Syndromes
    Evidence:
    PMID:20212519

Non-Curated Annotations (Non-Curated Annotation)

  1. rs28364274 at chr7:86971587 in ABCB1
    (i) Decreased intracellular calcein levels (increased function), (ii) increased intracellular BODIPy-FL- paclitaxel levels (decreased function), in transfected cells
    Variant Name:
    ABCB1: V1251I
    Related Drugs:
    calcein, paclitaxel
    Evidence:
    PMID:19940846
  2. rs2032582 at chr7:86998554 in ABCB1
    Increased intracellular BODIPy-FL- paclitaxel levels (decreased function) in transfected cells
    Variant Name:
    ABCB1: A893S
    Related Drugs:
    paclitaxel
    Evidence:
    PMID:19940846
Variant names are different names that have been used in the literature and other resources to refer to the same variant. Non-curated variant information is accumulated solely by computational methods and has not been verified by the scientific staff at PharmGKB.

The following genes are in curated knowledge about this drug.

  Gene Relationship Evidence
Phenotype data available Genotype Data Available Literature annotations available Has annotations
ABCB1
  • CO
  •   
  • PK
  • FA
  • GN
Publications, Variants
Phenotype data available Genotype Data Available Literature annotations available Not annotated
ABCC1
  • CO
  •   
  • PK
  • FA
  • GN
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
ABCC2
  • CO
  •   
  • PK
  • FA
  • GN
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
ABCG2
  • CO
  •   
  • PK
  • FA
  • GN
Publications
Phenotype data available No genotype data Literature annotations available Not annotated
BCL2
  • CO
  • PD
  •   
  • FA
  •   
Publications
Phenotype data available No genotype data Literature annotations available Not annotated
CDKN1A
  • CO
  •   
  •   
  •   
  • GN
Publications
No phenotype data Genotype Data Available Literature annotations available Not annotated
CYP1A2
  •   
  •   
  • PK
  •   
  • GN
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
CYP1B1
  • CO
  •   
  • PK
  •   
  • GN
Publications, Variants
No phenotype data Genotype Data Available Literature annotations available Has annotations
CYP2A6
  •   
  •   
  • PK
  •   
  • GN
Publications
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP2B6
  •   
  •   
  • PK
  •   
  • GN
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
CYP2C8
  • CO
  • PD
  • PK
  • FA
  • GN
Publications, Variants
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP2D6
  •   
  •   
  • PK
  •   
  • GN
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
CYP3A
  •   
  •   
  •   
  •   
  •   
Variants
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP3A4
  • CO
  • PD
  • PK
  • FA
  • GN
Publications, Variants
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP3A5
  • CO
  •   
  • PK
  • FA
  • GN
Publications, Variants
Phenotype data available Genotype Data Available Literature annotations available Has annotations
DPYD
  • CO
  • PD
  • PK
  •   
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
ERBB2
  • CO
  •   
  •   
  • FA
  • GN
Publications
Phenotype data available No genotype data Literature annotations available Not annotated
ERCC4
  • CO
  •   
  •   
  • FA
  •   
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
GSTM1
  • CO
  • PD
  • PK
  •   
  • GN
Publications
Phenotype data available Genotype Data Available Literature annotations available Has annotations
GSTP1
  •   
  • PD
  •   
  • FA
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
MAPT
  • CO
  •   
  •   
  •   
  • GN
Publications
Phenotype data available Genotype Data Available Literature annotations available Has annotations
MTHFR
  • CO
  •   
  •   
  • FA
  •   
Publications
Phenotype data available Genotype Data Available Literature annotations available Has annotations
NR1I2
  •   
  •   
  •   
  • FA
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
PHB
  •   
  • PD
  •   
  • FA
  •   
Publications
No phenotype data Genotype Data Available Literature annotations available Has annotations
SLCO1B1
  • CO
  •   
  • PK
  • FA
  • GN
Publications
No phenotype data Genotype Data Available Literature annotations available Not annotated
SLCO1B3
  • CO
  •   
  • PK
  • FA
  • GN
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
TP53
  • CO
  •   
  •   
  • FA
  • GN
Publications
Phenotype data available No genotype data Literature annotations available Not annotated
TUBB
  •   
  • PD
  •   
  •   
  • GN
Publications
Phenotype data available No genotype data Literature annotations available Not annotated
VEGFA
  • CO
  •   
  •   
  •   
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
WDR7
  • CO
  •   
  •   
  • FA
  •   
Publications

A list of non-curated publications that mention this drug along with other genes is available.

Drug Targets

Gene Description
BCL2 Uncurated Annotation (source: Drug Bank)
TUBB1 Uncurated Annotation (source: Drug Bank)

PharmGKB Curated Pathways

A list of non-curated publications that mention this drug along with other drugs is available.

Drug Interactions

Drug Description
cisplatin Uncurated Annotation Cisplatin increases the effect and toxicity of paclitaxel (source: Drug Bank)
gemcitabine Uncurated Annotation Paclitaxel increases the effect/toxicity of gemcitabine (source: Drug Bank)

Curated Information

The following diseases are in curated knowledge about this drug.

  Disease Relationship Evidence
Phenotype data available Genotype Data Available Literature annotations available Not annotated
Breast Neoplasms
  • CO
  • PD
  • PK
  • FA
  • GN
Publications, Variants
No phenotype data No genotype data Literature annotations available Not annotated
Colorectal Neoplasms
  •   
  •   
  •   
  • FA
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Drug Resistance
  •   
  • PD
  •   
  • FA
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Drug Toxicity
  • CO
  •   
  • PK
  •   
  • GN
Publications, Variants
No phenotype data No genotype data Literature annotations available Not annotated
Esophageal Neoplasms
  • CO
  • PD
  • PK
  •   
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Liver Neoplasms
  • CO
  •   
  •   
  •   
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Lung Neoplasms
  • CO
  • PD
  • PK
  • FA
  • GN
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
Neoplasms
  •   
  •   
  • PK
  •   
  • GN
Publications, Variants
No phenotype data No genotype data Literature annotations available Not annotated
Neurotoxicity Syndromes
  • CO
  •   
  • PK
  •   
  • GN
Publications, Variants
No phenotype data No genotype data Literature annotations available Not annotated
Neutropenia
  • CO
  •   
  • PK
  •   
  • GN
Publications, Variants
No phenotype data No genotype data Literature annotations available Not annotated
Ovarian Neoplasms
  • CO
  • PD
  • PK
  • FA
  • GN
Publications, Variants
No phenotype data No genotype data Literature annotations available Not annotated
Peripheral Nervous System Diseases
  • CO
  •   
  • PK
  •   
  • GN
Publications

Non-Curated Information

A list of non-curated publications that mention this drug along with other diseases is available.

LinkOuts

Web Resource:
Wikipedia
DrugBank:
DB01229
ChEBI ID:
7887
KEGG Compound ID:
C07394
KEGG Drug ID:
D00491
PubChem Compound ID:
36314
PubChem Substance ID:
177831

Common Searches

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Non-Curated Publications

A list of non-curated publications that mention this drug is available.

PharmGKB integrates drug information from different sources: DrugBank, Open Eye Scientific Software.
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