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Paclitaxel

PubChem CID
36314
Structure
Paclitaxel_small.png
Molecular Formula
Synonyms
  • paclitaxel
  • TAXOL
  • 33069-62-4
  • P88XT4IS4D
  • Taxol A
Molecular Weight
853.9 g/mol
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Dates
  • Create:
    2005-03-26
  • Modify:
    2025-01-25
Description
Paclitaxel can cause developmental toxicity, female reproductive toxicity and male reproductive toxicity according to state or federal government labeling requirements.
Taxol appears as needles (from aqueous methanol) or fine white powder. An anti-cancer drug.
Paclitaxel is a tetracyclic diterpenoid isolated originally from the bark of the Pacific yew tree, Taxus brevifolia. It is a mitotic inhibitor used in cancer chemotherapy. Note that the use of the former generic name 'taxol' is now limited, as Taxol is a registered trade mark. It has a role as a microtubule-stabilising agent, a metabolite, a human metabolite and an antineoplastic agent. It is a tetracyclic diterpenoid and a taxane diterpenoid. It is functionally related to a baccatin III.
See also: Paclitaxel Ceribate (is active moiety of); Paclitaxel Poliglumex (is active moiety of); 7-Acetyltaxol (annotation moved to) ... View More ...

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Paclitaxel.png

1.2 3D Status

Conformer generation is disallowed since too many atoms

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

[(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-diacetyloxy-15-[(2R,3S)-3-benzamido-2-hydroxy-3-phenylpropanoyl]oxy-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.03,10.04,7]heptadec-13-en-2-yl] benzoate
Computed by Lexichem TK 2.7.0 (PubChem release 2021.10.14)

2.1.2 InChI

InChI=1S/C47H51NO14/c1-25-31(60-43(56)36(52)35(28-16-10-7-11-17-28)48-41(54)29-18-12-8-13-19-29)23-47(57)40(61-42(55)30-20-14-9-15-21-30)38-45(6,32(51)22-33-46(38,24-58-33)62-27(3)50)39(53)37(59-26(2)49)34(25)44(47,4)5/h7-21,31-33,35-38,40,51-52,57H,22-24H2,1-6H3,(H,48,54)/t31-,32-,33+,35-,36+,37+,38-,40-,45+,46-,47+/m0/s1
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.3 InChIKey

RCINICONZNJXQF-MZXODVADSA-N
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.4 SMILES

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](C5=CC=CC=C5)NC(=O)C6=CC=CC=C6)O)O)OC(=O)C7=CC=CC=C7)(CO4)OC(=O)C)O)C)OC(=O)C
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

2.2 Molecular Formula

C47H51NO14
Computed by PubChem 2.2 (PubChem release 2021.10.14)

2.3 Other Identifiers

2.3.1 CAS

33069-62-4
92950-39-5

2.3.2 Deprecated CAS

1203669-79-7, 157069-30-2

2.3.3 European Community (EC) Number

2.3.4 UNII

2.3.5 UN Number

2.3.6 ChEBI ID

2.3.7 ChEMBL ID

2.3.8 DrugBank ID

2.3.9 DSSTox Substance ID

2.3.10 HMDB ID

2.3.11 KEGG ID

2.3.12 Metabolomics Workbench ID

2.3.13 NCI Thesaurus Code

2.3.14 Nikkaji Number

2.3.15 NSC Number

2.3.16 PharmGKB ID

2.3.17 Pharos Ligand ID

2.3.18 RXCUI

2.3.19 Wikidata

2.3.20 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • 7 epi Taxol
  • 7-epi-Taxol
  • Anzatax
  • Bris Taxol
  • NSC 125973
  • NSC-125973
  • NSC125973
  • Onxol
  • Paclitaxel
  • Paclitaxel, (4 alpha)-Isomer
  • Paxene
  • Praxel
  • Taxol
  • Taxol A
  • Taxol, Bris

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
853.9 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
XLogP3
Property Value
2.5
Reference
Computed by XLogP3 3.0 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Donor Count
Property Value
4
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Acceptor Count
Property Value
14
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Rotatable Bond Count
Property Value
14
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Exact Mass
Property Value
853.33095530 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Monoisotopic Mass
Property Value
853.33095530 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Topological Polar Surface Area
Property Value
221 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Heavy Atom Count
Property Value
62
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
1790
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Isotope Atom Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Atom Stereocenter Count
Property Value
11
Reference
Computed by PubChem
Property Name
Undefined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Covalently-Bonded Unit Count
Property Value
1
Reference
Computed by PubChem
Property Name
Compound Is Canonicalized
Property Value
Yes
Reference
Computed by PubChem (release 2021.10.14)

3.2 Experimental Properties

3.2.1 Physical Description

Taxol appears as needles (from aqueous methanol) or fine white powder. An anti-cancer drug.
Solid; [Merck Index] White to off-white solid; [HSDB] Powder; [Sigma-Aldrich MSDS]
Solid

3.2.2 Color / Form

White to off-white crystalline powder
US Natl Inst Health; DailyMed. Current Medication Information. Paclitaxel Solution. Sept 2007. Available from, as of May 21, 2008: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=5327
Needles from aqueous methanol
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 1204

3.2.3 Melting Point

415 to 421 °F (NTP, 1992)
National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.
216-217 °C
FDA label
213-216 °C (decomposition)
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 1204
213 - 216 °C

3.2.4 Solubility

Insoluble
FDA label
Insoluble in water
US Natl Inst Health; DailyMed. Current Medication Information. Paclitaxel Solution. Sept 2007. Available from, as of May 21, 2008: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=5327
5.56e-03 g/L

3.2.5 LogP

3
3

3.2.6 Stability / Shelf Life

Stability
Bulk: Bulk samples stored at room temperature for 30 days showed no TLC or HPLC decomposition as indicated by UV absorption The bulk compound stored at 60 oC for three weeks also showed no decomposition After four weeks very minor decomposition was detected by TLC Ultraviolet Absorption : (MeOH) max = 227 2nm E = 28,500 - 30,900 High Performance Liquid Chromatography : Column: IBM ODS, 5um 46 x 250mm Mobile Phase: 63% MeOH/37% water Flow Rate: 1.0 mL/min Detection: UV at 230 nm Sample Preparation: Dissolve approximately 6 mg sample in 10 mL methanol Mix 1 mL of this solution with 1 mL of internal standard solution Internal Standard: 20 mg Paraben in 25 mL methanol Retention Volume: 19.3 mL (NSC 125973) 7.7 mL (I.S.)

3.2.7 Optical Rotation

Specific optical rotation: -49 deg at 20 °C/D (methanol); UV max absorption 2 (methanol): 227, 273, nm (E= 29,800,1700)
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 1204
(c = 1, MeOH) [a]20D = -53 +- 20 degrees

3.2.8 Other Experimental Properties

Clear colorless to slightly yellow viscous solution /Paclitxel Injection USP/
US Natl Inst Health; DailyMed. Current Medication Information. Paclitaxel Solution. Sept 2007. Available from, as of May 21, 2008: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=5327

3.3 Chemical Classes

Other Uses -> Biochemical Research

3.3.1 Drugs

Pharmaceuticals -> Antibiotics
S6 | ITNANTIBIOTIC | Antibiotic List from the ITN MSCA ANSWER | DOI:10.5281/zenodo.2621956
Pharmaceuticals -> Listed in ZINC15
S55 | ZINC15PHARMA | Pharmaceuticals from ZINC15 | DOI:10.5281/zenodo.3247749
3.3.1.1 Human Drugs
Breast Feeding; Lactation; Milk, Human; Antineoplastic Agents, Phytogenic; Antimitotic Agents; Tubulin Modulators
Human drug -> Discontinued
Human drug -> Prescription
Human drug -> Prescription; Discontinued; Active ingredient (PACLITAXEL)
Human drugs -> Antineoplastic agents, Taxanes -> Human pharmacotherapeutic group -> EMA Drug Category
Human drugs -> Antineoplastic agents -> Human pharmacotherapeutic group -> EMA Drug Category
Paediatric drug
Cytotoxic medicines

4 Spectral Information

4.1 1D NMR Spectra

4.1.1 13C NMR Spectra

1 of 2
Copyright
Copyright © 2016-2024 W. Robien, Inst. of Org. Chem., Univ. of Vienna. All Rights Reserved.
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2 of 2
Copyright
Copyright © 2016-2024 W. Robien, Inst. of Org. Chem., Univ. of Vienna. All Rights Reserved.
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4.2 Mass Spectrometry

4.2.1 MS-MS

Spectra ID
Ionization Mode
positive
Top 5 Peaks

105.03289 100

240.100906 46.45

122.059433 39.94

286.10614 21.33

263.141815 16.72

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Notes
instrument=qTof

4.2.2 LC-MS

1 of 5
View All
Authors
Tobias Schulze, Martin Krauss, Helmholtz Centre for Environmental Research GmbH - UFZ, Leipzig, Germany
Instrument
LTQ Orbitrap XL Thermo Scientific
Instrument Type
LC-ESI-ITFT
MS Level
MS2
Ionization Mode
POSITIVE
Ionization
ESI
Collision Energy
25% (nominal)
Fragmentation Mode
HCD
Column Name
Kinetex Evo C18 2.6 um 50x2.1 mm, Phenomenex
Retention Time
12.340 min
Precursor m/z
854.3382
Precursor Adduct
[M+H]+
Top 5 Peaks
158.39 999
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License
CC0
2 of 5
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Authors
Tobias Schulze, Martin Krauss, Helmholtz Centre for Environmental Research GmbH - UFZ, Leipzig, Germany
Instrument
LTQ Orbitrap XL Thermo Scientific
Instrument Type
LC-ESI-ITFT
MS Level
MS2
Ionization Mode
POSITIVE
Ionization
ESI
Collision Energy
30% (nominal)
Fragmentation Mode
HCD
Column Name
Kinetex Evo C18 2.6 um 50x2.1 mm, Phenomenex
Retention Time
12.340 min
Precursor m/z
854.3382
Precursor Adduct
[M+H]+
Top 5 Peaks
158.3901 999
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License
CC0

4.2.3 Other MS

1 of 3
View All
MoNA ID
MS Category
Experimental
MS Type
Other
Precursor Type
[M+Na]+
Top 5 Peaks

591.221118138149 0.07

308.0897076983055 0.07

531.1971982357466 0.05

411.1764266126977 0.04

533.2143411338807 0.03

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2 of 3
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MoNA ID
MS Category
Experimental
MS Type
Other
Precursor Type
[M+NH4]+
Top 5 Peaks

509.21583238897574 0.09

286.1090091168227 0.06

165.06830009561898 0.04

309.14887707525037 0.04

551.2288473039301 0.04

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4.3 IR Spectra

4.3.1 FTIR Spectra

Instrument Name
Bio-Rad FTS
Technique
KBr0
Source of Spectrum
Forensic Spectral Research
Source of Sample
Cayman Chemical Company
Catalog Number
<a href=https://www.caymanchem.com/product/10461>10461</a>
Lot Number
0460099-56
Copyright
Copyright © 2012-2024 John Wiley & Sons, Inc. All Rights Reserved.
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4.3.2 ATR-IR Spectra

Instrument Name
Bio-Rad FTS
Technique
ATR-Neat
Source of Spectrum
Forensic Spectral Research
Source of Sample
Cayman Chemical Company
Catalog Number
<a href=https://www.caymanchem.com/product/10461>10461</a>
Lot Number
0460099-56
Copyright
Copyright © 2019-2024 John Wiley & Sons, Inc. All Rights Reserved.
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6 Chemical Vendors

7 Drug and Medication Information

7.1 Drug Indication

Used in the treatment of Kaposi's sarcoma and cancer of the lung, ovarian, and breast. Abraxane® is specfically indicated for the treatment of metastatic breast cancer and locally advanced or metastatic non-small cell lung cancer.
Apealea in combination with carboplatin is indicated for the treatment of adult patients with first relapse of platinum‑sensitive epithelial ovarian cancer , primary peritoneal cancer and fallopian tube cancer .

7.2 LiverTox Summary

Paclitaxel is an antineoplastic agent which acts by inhibitor of cellular mitosis and which currently plays a central role in the therapy of ovarian, breast, and lung cancer. Therapy with paclitaxel has been associated with a low rate of serum enzyme elevations, but has not been clearly linked to cases of clinically apparent acute liver injury.

7.3 Drug Classes

Breast Feeding; Lactation; Milk, Human; Antineoplastic Agents, Phytogenic; Antimitotic Agents; Tubulin Modulators
Antineoplastic Agents

7.4 WHO Essential Medicines

Drug
Drug Classes
Cytotoxic medicines
Formulation
Parenteral - General injections - IV: 6 mg per mL
Indication
(1) Other specified malignant neoplasms of the ovary; (2) Other specified malignant neoplasms of bronchus or lung; (3) Malignant neoplasms of nasopharynx; (4) Kaposi sarcoma of unspecified primary site; (5) Other specified malignant neoplasms of breast; (6) Other specified carcinomas of ovary; (7) Malignant neoplasms of breast; (8) Malignant neoplasms of cervix uteri

7.5 FDA Approved Drugs

7.6 FDA Orange Book

7.7 FDA National Drug Code Directory

7.8 Drug Labels

Drug and label
Active ingredient and drug

7.9 Cancer Drugs

Drug Name
Paclitaxel
FDA Approved
Yes
Drug Use

Paclitaxel is approved to be used alone or with other drugs to treat:

• AIDS-relatedKaposi sarcoma. It is used as second-line therapy.

• Breast cancer. It is used:

• In patients with node-positive cancer. It is given as adjuvant therapy with doxorubicin hydrochloride-containing combination chemotherapy.

• In patients with metastatic cancer that did not respond to combination chemotherapy.

• Non-small cell lung cancer. It is used with cisplatin as first-line therapy in patients whose cancer cannot be treated with surgery or radiation therapy.

• Ovarian cancer that is advanced. It is used with cisplatin as first-line therapy or alone in patients who have already received other treatment.

Paclitaxel is also being studied in the treatment of other types of cancer.Paclitaxel is also available in a different form called paclitaxel albumin-stabilized nanoparticle formulation.

7.10 Clinical Trials

7.10.1 ClinicalTrials.gov

7.10.2 EU Clinical Trials Register

7.10.3 NIPH Clinical Trials Search of Japan

7.11 EMA Drug Information

1 of 6
View All
Medicine
Category
Human drugs
Therapeutic area
Ovarian Neoplasms
Active Substance
paclitaxel
INN/Common name
paclitaxel
Pharmacotherapeutic Classes
Antineoplastic agents, Taxanes
Status
This medicine is authorized for use in the European Union
Company
Inceptua AB
Market Date
2018-11-20
2 of 6
View All
Medicine
Category
Human drugs
Therapeutic area
Breast Neoplasms; Pancreatic Neoplasms; Carcinoma, Non-Small-Cell Lung
Active Substance
paclitaxel
INN/Common name
paclitaxel
Pharmacotherapeutic Classes
Antineoplastic agents
Status
This medicine is authorized for use in the European Union
Company
Bristol-Myers Squibb Pharma EEIG
Market Date
2008-01-11

7.12 Japan PMDA Drugs

Brand Name
Abraxane
Non-proprietary Name
Paclitaxel
Approval Note
Partial Change Approval
Approval Date
September 2019
Review Document

7.13 Therapeutic Uses

Antineoplastic Agents, Phytogenic; Radiation-Sensitizing Agents
National Library of Medicine's Medical Subject Headings online file (MeSH, 1999)
Standard formulation paclitaxel requires the use of solvents, such as Cremphor-EL, which contribute to some of the toxicities commonly associated with paclitaxel-based therapy. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a novel solvent-free formulation of paclitaxel. The formulation is prepared by high-pressure homogenization of paclitaxel in the presence of serum albumin into a nanoparticle colloidal suspension. The human albumin-stabilized paclitaxel particles have an average size of 130 nm. Nab-paclitaxel has several practical advantages over Cremphor-EL-paclitaxel, including a shorter infusion time (30 min) and no need for premedications for hypersensitivity reactions. The nab-paclitaxel formulation eliminates the impact of Cremphor-EL on paclitaxel pharmacokinetics and utilizes the endogenous albumin transport mechanisms to concentrate nab-paclitaxel within the tumor. A recent Phase III trial compared nab- and Cremphor-EL-paclitaxel in patients with metastatic breast cancer. Patients treated with nab-paclitaxel experienced a higher response, longer time to tumor progression and, in patients receiving second-line or greater therapy, a longer median survival. Patients treated with nab-paclitaxel had a significantly lower rate of severe neutropenia and a higher rate of sensory neuropathy. The preclinical and clinical data indicate that the nab-paclitaxel formulation has significant advantages over Cremphor-EL-paclitaxel.
Stinchcombe TE; Nanomed 2 (4): 415-23 (2007)
As first line and subsequent therapy for the treatment of advanced carcinoma of the ovary. As first-line therapy, paclitaxel is indicated in combination with cisplatin.
Novak, K.M. (ed.). Drug Facts and Comparisons2008 Edition. Wolters Kluwer Health. St. Louis, Missouri 2008., p. 2833
Adjuvant treatment of node-positive breast cancer administration sequentially to standard doxorubicin-containing combination chemotherapy. In the clinical trial, there was an overall favorable effect on disease-free and overall survival in the total population of patients with receptor-positive and receptor-negative tumors, but the benefit has been specifically demonstrated by available data (mean follow-up, 30 months) only in the patients with estrogen and progesterone receptor-negative tumors. Indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Previous therapy should have included an anthracycline unless clinically contraindicated.
Novak, K.M. (ed.). Drug Facts and Comparisons2008 Edition. Wolters Kluwer Health. St. Louis, Missouri 2008., p. 2833
For more Therapeutic Uses (Complete) data for TAXOL (9 total), please visit the HSDB record page.

7.14 Drug Warnings

Administer paclitaxel under the supervision of a health care provider experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilitates are readily available.
Novak, K.M. (ed.). Drug Facts and Comparisons2008 Edition. Wolters Kluwer Health. St. Louis, Missouri 2008., p. 2833
Do not give paclitaxel therapy to patients with solid tumors who have baseline neutrophil counts of less than 1,500 cells/cu mm, and do not give to patients with AIDS-related Kaposi sarcoma if the baseline neutrophil count is less than 1,000 cells/cu mm. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, perform frequent peripheral blood cell counts on all patients receiving paclitaxel.
Novak, K.M. (ed.). Drug Facts and Comparisons2008 Edition. Wolters Kluwer Health. St. Louis, Missouri 2008., p. 2833
Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension requiring treatment, angioedema, and generalized urticaria have occurred in 2% to 4% of patients receiving paclitaxel in clinical trials. Fatal reactions have occurred in patients despite premedication. Pretreat all patients with corticosteroids, diphenhydramine, and H2 antagonists. Do not rechallenge patients who experience severe hypersensitivity reactions to paclitaxel with the drug.
Novak, K.M. (ed.). Drug Facts and Comparisons2008 Edition. Wolters Kluwer Health. St. Louis, Missouri 2008., p. 2833
An albumin form of paclitaxel may substantially affect a drug's functional properties relative to those of drug in solution. Do not substitute for or with other paclitaxel formulations. /Paclitaxel (albumin-bound)/
Novak, K.M. (ed.). Drug Facts and Comparisons2008 Edition. Wolters Kluwer Health. St. Louis, Missouri 2008., p. 2833
For more Drug Warnings (Complete) data for TAXOL (62 total), please visit the HSDB record page.

8 Pharmacology and Biochemistry

8.1 Pharmacodynamics

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.

8.2 MeSH Pharmacological Classification

Antineoplastic Agents, Phytogenic
Agents obtained from higher plants that have demonstrable cytostatic or antineoplastic activity. (See all compounds classified as Antineoplastic Agents, Phytogenic.)
Tubulin Modulators
Agents that interact with TUBULIN to inhibit or promote polymerization of MICROTUBULES. (See all compounds classified as Tubulin Modulators.)

8.3 FDA Pharmacological Classification

1 of 2
FDA UNII
P88XT4IS4D
Active Moiety
PACLITAXEL
Pharmacological Classes
Physiologic Effects [PE] - Microtubule Inhibition
Pharmacological Classes
Established Pharmacologic Class [EPC] - Microtubule Inhibitor
FDA Pharmacology Summary
Paclitaxel is a Microtubule Inhibitor. The physiologic effect of paclitaxel is by means of Microtubule Inhibition.
2 of 2
Non-Proprietary Name
PACLITAXEL
Pharmacological Classes
Microtubule Inhibition [PE]; Microtubule Inhibitor [EPC]

8.4 ATC Code

L01CD01
S76 | LUXPHARMA | Pharmaceuticals Marketed in Luxembourg | Pharmaceuticals marketed in Luxembourg, as published by d'Gesondheetskeess (CNS, la caisse nationale de sante, www.cns.lu), mapped by name to structures using CompTox by R. Singh et al. (in prep.). List downloaded from https://cns.public.lu/en/legislations/textes-coordonnes/liste-med-comm.html. Dataset DOI:10.5281/zenodo.4587355

L - Antineoplastic and immunomodulating agents

L01 - Antineoplastic agents

L01C - Plant alkaloids and other natural products

L01CD - Taxanes

L01CD01 - Paclitaxel

8.5 Absorption, Distribution and Excretion

Absorption
When a 24 hour infusion of 135 mg/m^2 is given to ovarian cancer patients, the maximum plasma concentration (Cmax) is 195 ng/mL, while the AUC is 6300 ng•h/mL.
Route of Elimination
In 5 patients administered a 225 or 250 mg/m2 dose of radiolabeled paclitaxel as a 3-hour infusion, a mean of 71% of the radioactivity was excreted in the feces in 120 hours, and 14% was recovered in the urine.
Volume of Distribution
227 to 688 L/m^2 [apparent volume of distribution at steady-state, 24 hour infusion]
Clearance

21.7 L/h/m2 [Dose 135 mg/m2, infusion duration 24 h]

23.8 L/h/m2 [Dose 175 mg/m2, infusion duration 24 h]

7 L/h/m2 [Dose 135 mg/m2, infusion duration 3 h]

12.2 L/h/m2 [Dose 175 mg/m2, infusion duration 3 h]

Paclitaxel bound to nanoparticles of the serum protein albumin is delivered via endothelial transport mediated by albumin receptors, and the resulting concentration of paclitaxel in tumor cells is increased compared with that achieved using an equivalent dose of conventional paclitaxel. Like conventional paclitaxel, albumin-bound paclitaxel has a large volume of distribution. Following 30-minute or 3-hour IV infusion of 80-375 mg/sq m albumin-bound paclitaxel, the volume of distribution averaged 632 L/sq m. The volume of distribution of albumin-bound paclitaxel 260 mg/sq m by 30-minute IV infusion was 53% larger than the volume of distribution of conventional paclitaxel 175 mg/sq m by 3-hour IV infusion. /Paclitaxel (albumin-bound)/
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 1188
Following IV administration, paclitaxel is widely distributed into body fluids and tissues. Paclitaxel has a large volume of distribution that appears to be affected by dose and duration of infusion. Following administration of paclitaxel doses of 135 or 175 mg/sq m by IV infusion over 24 hours in patients with advanced ovarian cancer, the mean apparent volume of distribution at steady state ranged from 227-688 L/sq m. The steady-state volume of distribution ranged from 18.9-260 L/sq m in children with solid tumors or refractory leukemia receiving paclitaxel 200-500 mg/sq m by 24-hour IV infusion. Paclitaxel does not appear to readily penetrate the CNS, but paclitaxel has been detected in ascitic fluid following IV infusion of the drug. It is not known whether paclitaxel is distributed into human milk, but in lactating rats given radiolabeled paclitaxel, concentrations of radioactivity in milk were higher than those in plasma and declined in parallel with plasma concentrations of the drug.
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 1188
For the dose range 80-375 mg/sq m, increase in dose of albumin-bound paclitaxel was associated with a proportional increase in AUC.354 The duration of infusion did not affect the pharmacokinetic disposition of albumin-bound paclitaxel. Following 30-minute or 3-hour IV infusion of albumin-bound paclitaxel 260 mg/sq m, the peak plasma concentration averaged 18,741 ng/mL. /Paclitaxel (albumin-bound)/
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 1188
Peak plasma concentrations and areas under the plasma concentration-time curve (AUCs) following IV administration of paclitaxel exhibit marked interindividual variation. Plasma concentrations of paclitaxel increase during continuous IV administration of the drug and decline immediately following completion of the infusion. Following 24-hour IV infusion of paclitaxel at doses of 135 or 175 mg/sq m in patients with advanced ovarian cancer, peak plasma concentrations averaged 195 or 365 ng/mL, respectively; the increase in dose (30%) was associated with a disproportionately greater increase in peak plasma concentration (87%), but the increase in AUC was proportional. When paclitaxel was administered by continuous IV infusion over 3 hours at doses of 135 or 175 mg/sq m in patients with advanced ovarian cancer, peak plasma concentrations averaged 2.17 or 3.65 ug/mL, respectively; the increase in dose (30%) was associated with disproportionately greater increases in peak plasma concentration (68%) and AUC (89%).
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 1188
For more Absorption, Distribution and Excretion (Complete) data for TAXOL (8 total), please visit the HSDB record page.

8.6 Metabolism / Metabolites

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.
Paclitaxel is extensively metabolized in the liver. Metabolism of paclitaxel to its major metabolite, 6alpha-hydroxypaclitaxel, is mediated by cytochrome P-450 isoenzyme CYP2C8,1 185 187 202 354 while metabolism to 2 of its minor metabolites, 3'-p-hydroxypaclitaxel and 6alpha,3'-p-dihydroxypaclitaxel, is catalyzed by CYP3A4.
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 1188
The elimination of nonradioactive taxol in bile and urine was investigated in the rat after administration via the caudal vein (10 mg/kg). As in humans, no metabolites of taxol were detected by HPLC in rat urine, and only 10% of the injected taxol was recovered in urine over a 24 hr period. In contrast, 11.5% and 29% of the injected taxol was recovered in rat bile as unchanged taxol and metabolites, respectively. Among the nine taxol metabolites detected by HPLC, the side chain at C13, which is required for pharmacological activity, had been removed in only one minor metabolite, baccatin III. The chemical structures of the two major hydroxylated metabolites were determined by MS (fast atom bombardment and desorption chemical ionization) and (1)H NMR spectroscopy. One was a taxol derivative hydroxylated on the phenyl group at C3 of the side chain at C13, while the other corresponded to a taxol derivative hydroxylated in the m-position on the benzoate of the side chain at C2. Although these two major taxol metabolites were as active as taxol in preventing cold microtubule disassembly, they were, respectively, 9 and 39 times less cytotoxic as taxol on in vitro L1210 leukemia growth. These results show for the first time that there is a significant hepatic metabolism of taxol.
Monsarrat B et al; Drug Metab Dispos Biol Fate Chem 18 (6): 895-901 (1990)
To investigate how taxane's substituents at C3' affect its metabolism, ... the metabolism of cephalomannine and paclitaxel, a pair of analogs that differ slightly at the C3' position /was compared/. After cephalomannine was incubated with human liver microsomes in an NADPH-generating system, two monohydroxylated metabolites (M1 and M2) were detected by liquid chromatography/tandem mass spectrometry. C4'' (M1) and C6alpha (M2) were proposed as the possible hydroxylation sites, and the structure of M1 was confirmed by (1)H NMR. Chemical inhibition studies and assays with recombinant human cytochromes P450 (P450s) indicated that 4''-hydroxycephalomannine was generated predominantly by CYP3A4 and 6alpha-hydroxycephalomannine by CYP2C8. The overall biotransformation rate between paclitaxel and cephalomannine differed slightly (184 vs. 145 pmol/min/mg), but the average ratio of metabolites hydroxylated at the C13 side chain to C6alpha for paclitaxel and cephalomannine varied significantly (15:85 vs. 64:36) in five human liver samples. Compared with paclitaxel, the major hydroxylation site transferred from C6alpha to C4'', and the main metabolizing P450 changed from CYP2C8 to CYP3A4 for cephalomannine. In the incubation system with rat or minipig liver microsomes, only 4''-hydroxycephalomannine was detected, and its formation was inhibited by CYP3A inhibitors. Molecular docking by AutoDock suggested that cephalomannine adopted an orientation in favor of 4''-hydroxylation, whereas paclitaxel adopted an orientation favoring 3'-p-hydroxylation. Kinetic studies showed that CYP3A4 catalyzed cephalomannine more efficiently than paclitaxel due to an increased V(m). Our results demonstrate that relatively minor modification of taxane at C3' has major consequence on the metabolism.
Zhang JW et al; Drug Metab Dispos 36 (2): 418-26 (2008)
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. Route of Elimination: In 5 patients administered a 225 or 250 mg/m2 dose of radiolabeled paclitaxel as a 3-hour infusion, a mean of 71% of the radioactivity was excreted in the feces in 120 hours, and 14% was recovered in the urine. Half Life: When a 24 hour infusion of 135 mg/m^2 is given to ovarian cancer patients, the elimination half=life is 52.7 hours.

8.7 Biological Half-Life

When a 24 hour infusion of 135 mg/m^2 is given to ovarian cancer patients, the elimination half=life is 52.7 hours.
5.3-17.4 hours after 1 and 6 hour infusions at dosing levels of 15-275 mg/sq m
Lelkin, J.B., Paloucek, F.P., Poisoning & Toxicology Compendium. LEXI-COMP Inc. & American Pharmaceutical Association, Hudson, OH 1998., p. 433
Following IV infusion of paclitaxel over periods ranging from 6-24 hours in adults with malignancy, plasma concentrations of paclitaxel appeared to decline in a biphasic manner in some studies, with an average distribution half-life of 0.34 hours and an average elimination half-life of 5.8 hours. However, additional studies, particularly those in which paclitaxel is administered over shorter periods of infusion, show that the drug exhibits nonlinear pharmacokinetic behavior. In patients receiving paclitaxel 175 mg/sq m administered by 3-hour IV infusion, the distribution half-life averages 0.27 hours and the elimination half-life averages 2.33 hours.
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 1188
Following 30-minute or 3-hour IV infusion of 80-375 mg/sq m albumin-bound paclitaxel, ... terminal half-life albumin-bound paclitaxel was about 27 hours. ... /Paclitaxel (albumin-bound)/
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 1188

8.8 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.
Evidence suggests that paclitaxel also may induce cell death by triggering apoptosis. In addition, paclitaxel and docetaxel enhance the effects of ionizing radiation, possibly by blocking cells in the G2 phase, the phase of the cell cycle in which cells are most radiosensitive.
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 1187
Paclitaxel is an antimicrotubule antineoplastic agent. Unlike some other common antimicrotubule agents (e.g., vinca alkaloids, colchicine, podophyllotoxin), which inhibit microtubule assembly, paclitaxel and docetaxel (a semisynthetic taxoid) promote microtubule assembly. Microtubules are organelles that exist in a state of dynamic equilibrium with their components, tubulin dimers. They are an essential part of the mitotic spindle and also are involved in maintenance of cell shape and motility, and transport between organelles within the cell. By binding in a reversible, concentration-dependent manner to the beta-subunit of tubulin at the N-terminal domain, paclitaxel enhances the polymerization of tubulin, the protein subunit of the spindle microtubules, even in the absence of factors that are normally required for microtubule assembly (e.g., guanosine triphosphate [GTP]), and induces the formation of stable, nonfunctional microtubules. Paclitaxel promotes microtubule stability even under conditions that typically cause depolymerization in vitro (e.g., cold temperature, the addition of calcium, the presence of antimitotic drugs). While the precise mechanism of action of the drug is not understood fully, paclitaxel disrupts the dynamic equilibrium within the microtubule system and blocks cells in the late G2 phase and M phase of the cell cycle, inhibiting cell replication.
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 1187
... Taxol induces tubulin polymerization and forms extremely stable and nonfunctional microtubules. Taxol has demonstrated broad activity in preclinical screening studies, and antineoplastic activity has been observed in several classically refractory tumors. These tumors include cisplatin resistant ovarian carcinoma in phase II trials and malignant melanoma and non-small cell lung carcinoma in phase I studies.
Rowinsky EK et al; J Natl Cancer Inst 82 (15): 1247-59 (1990)

8.9 Human Metabolite Information

8.9.1 Cellular Locations

  • Cytoplasm
  • Extracellular
  • Membrane

8.9.2 Metabolite Pathways

8.10 Biochemical Reactions

8.11 Transformations

9 Use and Manufacturing

9.1 Uses

Sources/Uses
A compound extracted from the Pacific yew tree Taxus brevifolia with antineoplastic activity. Paclitaxel binds to tubulin and inhibits the disassembly of microtubules, thereby resulting in the inhibition of cell division. This agent also induces apoptosis by binding to and blocking the function of the apoptosis inhibitor protein Bcl-2 (B-cell Leukemia 2). (NCI Thesaurus) [ChemIDplus] Used to study microtubules and as an antineoplastic; [Merck Index]
Merck Index - O'Neil MJ, Heckelman PE, Dobbelaar PH, Roman KJ (eds). The Merck Index, An Encyclopedia of Chemicals, Drugs, and Biologicals, 15th Ed. Cambridge, UK: The Royal Society of Chemistry, 2013.
Tool in study of structure and function of microtubules.
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 1204
... therapy of ovarian, breast, lung, esophogeal, bladder, and head and neck cancers
Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 11th ed. New York, NY: McGraw-Hill, 2006., p. 1352
... antiplatelet therapy
Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 11th ed. New York, NY: McGraw-Hill, 2006., p. 842
THERAP CAT: Antineoplastic; antirestenotic
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 1204
MEDICATION

Use (kg; approx.) in Germany (2009): >25

Use (kg) in USA (2002): 39

Consumption (g per capita; approx.) in Germany (2009): 0.000305

Consumption (g per capita) in the USA (2002): 0.000139

Calculated removal (%): 62.3

Used in the treatment of Kaposi's sarcoma and cancer of the lung, ovarian, and breast. Abraxane™ is specfically indicated for the treatment of metastatic breast cancer and locally advanced or metastatic non-small cell lung cancer.

9.1.1 Use Classification

Human drugs -> Antineoplastic agents, Taxanes -> Human pharmacotherapeutic group -> EMA Drug Category
Human drugs -> Antineoplastic agents -> Human pharmacotherapeutic group -> EMA Drug Category
Human Drugs -> EU pediatric investigation plans
Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients

9.2 Methods of Manufacturing

... First isolated, as the l-form, from the bark of the Pacific yew tree, Taxus breviofolia, Taxacaea
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 1204
Semisynthetic process extracting deacetylbaccatin III (precursor of taxol) from a yew plant, Taxus baccata, using needles and twigs from the plant rather than bark tissue.
Chem & Eng News 70 (41): 30-2 (1992)
Taxomyces andreanae, a fungal endophyte, was isolated from the phloem ... of the Pacific yew, Taxus brevifolia. The fungus is hyphomyceteous and, when grown in a semi-synthetic liquid medium, produced taxol and related cmpd. ... Both (1-14)C acetic acid and L-(U-14)C phenylalanine served as precursors of (14)C taxol in fungal cultures. No taxol was detected in zero time cultures or in the small agar plugs used to inoculate the culture flasks.
Stierle A et al; Science 60 (5105): 154 (1993)

9.3 Formulations / Preparations

Parenteral: For injection, concentrate, for IV infusion: 6 mg/mL Onxol (with dehydrated alcohol 49.7% (v/v) and polyoxyl 35 castor oil 527 mg/mL) (Teva), Paclitaxel Injection (with dehydrated alcohol 49.7% (v/v) and polyoxyl 35 castor oil 527 mg/mL) (Bedford, Mayne, UDL), Taxol (with dehydrated alcohol 49.7% (v/v) and polyoxyl 35 castor oil 527 mg/mL) (Bristol-Myers Squibb).
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 1189
Parenteral: For injectable suspension, for IV infusion: 100 mg (of paclitaxel) Abraxane (Abraxis). /Paclitaxel (albumin-bound)/
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 1189
Paclitaxel is commercially available as protein-bound particles consisting of paclitaxel bound to albumin; the mean particle size of albumin-bound paclitaxel is about 130 nm. Albumin-bound paclitaxel is a sterile, white to yellow lyophilized powder that must be reconstituted for use as an injectable suspension; there are no solvents. Each single-use vial contains 100 mg of paclitaxel and approximately 900 mg of human albumin.
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 1188
Because paclitaxel is extremely hydrophobic, the commercially available injection concentrate is a sterile, nonaqueous solution of the drug in polyoxyl 35 castor oil (Cremophor EL, polyoxyethylated castor oil) and dehydrated alcohol. Commercially available paclitaxel for injection concentrate is a clear, colorless to slightly yellow, viscous solution. Following dilution of paclitaxel for injection concentrate with 5% dextrose and 0.9% sodium chloride injection or 5% dextrose and Ringer's injection, solutions containing 0.6 or 1.2 mg of paclitaxel per mL maintain a pH of 4.4-5.6 for up to 27 hours.
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 1188

9.4 General Manufacturing Information

Because of the limited number of plants available, 4 million Taxus trees have been planted to allow for continued supply of this drug.
Chem & Eng News 70 (41): 30-2 (1992)
Antimicrotubule agent extracted from the Pacific yew tree ... being investigated for the use in treatment of lymphoma and mammary carcinoma in veterinary medicine
Aiello, S.E. (ed). The Merck Veterinary Manual. 8th ed. Merck & Co., Inc., National Publishing Inc., Philadelphia, PA. 1998., p. 1843

10 Identification

10.1 Analytic Laboratory Methods

Analyte: paclitaxel; matrix: pharmaceutical preparation (injection solution); procedure: micellar electrokinetic capillary chromatography with ultraviolet detection at 230 nm
Shao LK, Locke DC; Anal Chem 70: 897-906 (1998). As cited in: Lunn G; HPLC and CE Methods for Pharmaceutical Analysis. CD-ROM. New York, NY: John Wiley & Sons (2000)
Analyte: paclitaxel; matrix: pharmaceutical preparation (bulk, injection solution); procedure: reversed-phase high-performance liquid chromatography with ultraviolet detection at 230 nm; limit of detection: 310-370 ng/mL
Shao LK, Locke DC; Anal Chem 69: 2008-2016 (1997). As cited in: Lunn G; HPLC and CE Methods for Pharmaceutical Analysis. CD-ROM. New York, NY: John Wiley & Sons (2000)
Analyte: paclitaxel; matrix: pharmaceutical preparation (injection solution); procedure: high-performance liquid chromatography with ultraviolet detection at 227 nm
Burm JP et al; Am J Hosp Pharm 51: 1201-1204 (1994). As cited in: Lunn G; HPLC and CE Methods for Pharmaceutical Analysis. CD-ROM. New York, NY: John Wiley & Sons (2000)
Analyte: paclitaxel; matrix: pharmaceutical preparation (injection solution); procedure: high-performance liquid chromatography with ultraviolet detection at 254 nm
Xu Q et al; Am J Hosp Pharm 51: 3058-3060 (1994). As cited in: Lunn G; HPLC and CE Methods for Pharmaceutical Analysis. CD-ROM. New York, NY: John Wiley & Sons (2000)
For more Analytic Laboratory Methods (Complete) data for TAXOL (11 total), please visit the HSDB record page.

10.2 Clinical Laboratory Methods

Analyte: paclitaxel; matrix: blood (plasma), urine; procedure: micellar electrokinetic chromatography with ultraviolet detection at 230 nm; limit of detection: 20 ng/mL (plasma), 50 ng/mL (urine)
Hempel G et al; J Chromatogr A 745: 173-179 (1996). As cited in: Lunn G; HPLC and CE Methods for Pharmaceutical Analysis. CD-ROM. New York, NY: John Wiley & Sons (2000)
Analyte: paclitaxel; matrix: blood (plasma); procedure: high-performance liquid chromatography with ultraviolet detection at 227 nm; limit of detection: 10 ng/mL
Willey TA et al; J Chromatogr 621: 231-238 (1993). As cited in: Lunn G; HPLC and CE Methods for Pharmaceutical Analysis. CD-ROM. New York, NY: John Wiley & Sons (2000)
el-Yazigi A, Yusuf A; Ther Drug Monit 17: 511-515 (1995). As cited in: Lunn G; HPLC and CE Methods for Pharmaceutical Analysis. CD-ROM. New York, NY: John Wiley & Sons (2000)
Analyte: paclitaxel; matrix: blood (plasma); procedure: reversed-phase high-performance liquid chromatography with ultraviolet detection at 227 nm; limit of detection: 0.15 nM
Sharma A et al; J Chromatogr B 655: 315-319 (1994). As cited in: Lunn G; HPLC and CE Methods for Pharmaceutical Analysis. CD-ROM. New York, NY: John Wiley & Sons (2000)
For more Clinical Laboratory Methods (Complete) data for TAXOL (11 total), please visit the HSDB record page.

11 Safety and Hazards

11.1 Hazards Identification

11.1.1 GHS Classification

Pictogram(s)
Corrosive
Irritant
Health Hazard
Signal
Danger
GHS Hazard Statements

H315 (87.5%): Causes skin irritation [Warning Skin corrosion/irritation]

H317 (74.2%): May cause an allergic skin reaction [Warning Sensitization, Skin]

H318 (85.9%): Causes serious eye damage [Danger Serious eye damage/eye irritation]

H334 (17.2%): May cause allergy or asthma symptoms or breathing difficulties if inhaled [Danger Sensitization, respiratory]

H335 (87.1%): May cause respiratory irritation [Warning Specific target organ toxicity, single exposure; Respiratory tract irritation]

H340 (12.9%): May cause genetic defects [Danger Germ cell mutagenicity]

H341 (28.1%): Suspected of causing genetic defects [Warning Germ cell mutagenicity]

H360 (24.6%): May damage fertility or the unborn child [Danger Reproductive toxicity]

H361 (73.8%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]

H372 (14.1%): Causes damage to organs through prolonged or repeated exposure [Danger Specific target organ toxicity, repeated exposure]

H413 (57%): May cause long lasting harmful effects to aquatic life [Hazardous to the aquatic environment, long-term hazard]

Precautionary Statement Codes

P203, P233, P260, P261, P264, P264+P265, P270, P271, P272, P273, P280, P284, P302+P352, P304+P340, P305+P354+P338, P317, P318, P319, P321, P332+P317, P333+P317, P342+P316, P362+P364, P403, P403+P233, P405, and P501

(The corresponding statement to each P-code can be found at the GHS Classification page.)

ECHA C&L Notifications Summary

Aggregated GHS information provided per 256 reports by companies from 27 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.

11.1.2 Hazard Classes and Categories

Skin Irrit. 2 (87.5%)

Skin Sens. 1 (74.2%)

Eye Dam. 1 (85.9%)

Resp. Sens. 1 (17.2%)

STOT SE 3 (87.1%)

Muta. 1B (12.9%)

Muta. 2 (28.1%)

Repr. 1B (24.6%)

Repr. 2 (73.8%)

STOT RE 1 (14.1%)

Aquatic Chronic 4 (57%)

11.1.3 Health Hazards

Excerpt from ERG Guide 154 [Substances - Toxic and/or Corrosive (Non-Combustible)]:

TOXIC and/or CORROSIVE; inhalation, ingestion or skin contact with material may cause severe injury or death. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause environmental contamination. (ERG, 2024)

11.1.4 Fire Hazards

Flash point data for this chemical are not available. It is probably combustible. (NTP, 1992)
National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.

11.1.5 Hazards Summary

An irritant that may cause serious eye injury; May cause skin and respiratory sensitization; May cause liver and kidney injury and bone depression; Suspected mutagen and of being toxic to fertility or the developing child; [Sigma-Aldrich MSDS]

11.2 First Aid Measures

11.2.1 First Aid

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop.

SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop, IMMEDIATELY call a physician and be prepared to transport the victim to a hospital for treatment.

INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. If symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop, call a physician and be prepared to transport the victim to a hospital. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing.

INGESTION: DO NOT INDUCE VOMITING. If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Be prepared to transport the victim to a hospital if advised by a physician. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital. (NTP, 1992)

National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.

11.3 Fire Fighting

Fires involving this material can be controlled with a dry chemical, carbon dioxide, or Halon extinguisher. (NTP, 1992)
National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.

11.4 Accidental Release Measures

11.4.1 Isolation and Evacuation

Excerpt from ERG Guide 154 [Substances - Toxic and/or Corrosive (Non-Combustible)]:

IMMEDIATE PRECAUTIONARY MEASURE: Isolate spill or leak area in all directions for at least 50 meters (150 feet) for liquids and at least 25 meters (75 feet) for solids.

SPILL: Increase the immediate precautionary measure distance, in the downwind direction, as necessary.

FIRE: If tank, rail tank car or highway tank is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. (ERG, 2024)

11.4.2 Disposal Methods

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All contaminated disposables should be contained in sealable bags for transfer to larger waste containers. /Antineoplastic agents/
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 875
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All bottles must be discarded as contaminated waste after decontamination of the biohazard cabinet. All protective apparel (gown, gloves, goggles, and respirator) should be discarded as contaminated waste. /Antineoplastic agents/
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 875
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The contaminated filters must be removed, bagged in thick plastic and prepared for disposal in a hazardous waste dump site or incinerator licensed by the Environmental Protection Agency (EPA). /Antineoplastic agents/
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 875
For more Disposal Methods (Complete) data for TAXOL (8 total), please visit the HSDB record page.

11.4.3 Preventive Measures

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Accidental contamination of the health-care environment, resulting in exposure of personnel, patients, visitors, and family members to hazardous substances, is prevented by maintaining the physical integrity and security of packages of hazardous drugs. 1. Access to all areas where hazardous drugs are stored is limited to specified authorized staff. 2. A method should be present for identifying to personnel those drugs that require special precautions (eg, cytotoxics). One way to accomplish this is to apply appropriate warning labels to all hazardous drug containers, shelves, and bins where the drug products are stored. ... 3. A method of identifying, for patients and family members, those drugs that require special precautions in the home should be in place. This may be accomplished in the health-care setting, by providing specific labeling for discharge medications, along with written instructions. 4. Methods for identifying shipping cartons of hazardous drugs should be required from manufacturers and distributors of these drugs. 5. Written procedures for handling damaged packages of hazardous drugs should be maintained. Personnel involved in shipping and receiving hazardous drugs should be trained in these procedures, including the proper use of protective garments and equipment. Damaged shipping cartons of hazardous drugs should be received and opened in an isolated area (eg, in a laboratory fume hood, if available, not in a vertical laminar airflow biological safety cabinet used for preparing sterile products). /Antineoplastic agents/
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 875
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Facilities (eg, shelves, carts, counters, and trays) for storing hazardous drugs are designed to prevent breakage and to limit contamination in the event of leakage. Bins, shelves with barriers at the front, or other design features that reduce the chance of drug containers falling to the floor should be used. Hazardous drugs requiring refrigeration should be stored separately from nonhazardous drugs in individual bins designed to prevent breakage and to contain leakage. /Antineoplastic agents/
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 875
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Until the reproductive risks (or lack thereof) associated with handling hazardous drugs within a safety program have been substantiated, staff who are pregnant or breast-feeding should be allowed to avoid contact with these drugs. Policies should be in effect that provide these individuals with alternative tasks or responsibilities if they so desire. /Antineoplastic agents/
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 875
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The pharmacy should provide access to information on toxicity, treatment of acute exposure (if available), chemical inactivators, solubility and stability of hazardous drugs (including investigational agents) used in the workplace. /Antineoplastic agents/
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 875
For more Preventive Measures (Complete) data for TAXOL (20 total), please visit the HSDB record page.

11.5 Handling and Storage

11.5.1 Nonfire Spill Response

SMALL SPILLS AND LEAKAGE: If you spill this chemical, you should dampen the solid spill material with water, then transfer the dampened material to a suitable container. Use absorbent paper dampened with water to pick up any remaining material. Seal your contaminated clothing and the absorbent paper in a vapor-tight plastic bag for eventual disposal. Wash all contaminated surfaces with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned.

STORAGE PRECAUTIONS: You should protect this material from moisture, and store it in a freezer. (NTP, 1992)

National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.

11.5.2 Storage Conditions

Commercially available albumin-bound paclitaxel for injectable suspension should be stored in unopened vials at 20-25 °C and retained in the original package for protection from bright light. Neither freezing nor refrigeration adversely affects albumin-bound paclitaxel for injectable suspension. When stored under recommended conditions, unopened vials of commercially available albumin-bound paclitaxel for injectable suspension are stable until the date indicated on the package. /Paclitaxel (albumin-bound)/
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 1189
The manufacturer states that, when diluted as directed, paclitaxel solutions are stable for up to 27 hours when stored at approximately 25 °C under ambient lighting conditions.
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 1188
Commercially available paclitaxel for injection concentrate should be stored in unopened vials at 20-25 °C and retained in the original package for protection from light. Neither freezing nor refrigeration adversely affects paclitaxel for injection concentrate. Refrigeration may result in precipitation of the drug or formulation vehicle; however, the precipitate typically will dissolve at room temperature without loss of potency. If freezing occurs, paclitaxel for injection concentrate may be thawed at room temperature until precipitate dissolves; the manufacturer states that the chemical or physical stability of the injection is not affected. If the solution remains cloudy or if an insoluble precipitate remains at room temperature, the vial should be discarded. When stored under recommended conditions, unopened vials of commercially available paclitaxel for injection concentrate are stable until the date indicated on the package.
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 1188

11.6 Exposure Control and Personal Protection

11.6.1 Personal Protective Equipment (PPE)

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with an organic vapor/acid gas cartridge (specific for organic vapors, HCl, acid gas and SO2) with a dust/mist filter. (NTP, 1992)
National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Protective apparel: Disposable closed-front gown or coveralls, disposable utility gloves over disposable latex gloves, NIOSH-approved air-purifying half-mask respirator equipped with a high efficiency filter, and eye protection should be worn. /Antineoplastic agents/
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 875
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Class 100 clean-air work stations, both horizontal and vertical airflow (with no containment characteristics), are inappropriate engineering controls for handling hazardous drugs because they provide no personnel protection and permit environmental contamination. Although there are no engineering controls designed specifically for the safe handling of hazardous chemicals as sterile products, Class II contained vertical-flow biological safety cabinets (biohazard cabinets) have been adopted for this use. Biohazard cabinetry is, however, designed for the handling of infectious agents, not hazardous chemicals. ... Based on design, ease of use, and cost considerations, Class II contained-vertical-flow biohazard cabinetry is currently recommended for use in preparing sterile doses of hazardous drugs. Class II cabinetry design and performance specifications are defined in NSF Standard 49. Biological safety cabinets selected for use with hazardous drugs should meet NSF Standard 49 specifications to ensure the maximum protection from these engineering controls. /Antineoplastic agents/
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 875
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers should wear powder free, disposable surgical latex gloves of good quality when preparing hazardous drugs. Selection criteria for gloves should include thickness (especially at the fingertips where stress is the greatest), fit, length, and tactile sensation. ... The practice of double gloving is supported by research that indicates that many glove materials vary in drug permeability even within lots; therefore, double gloving is recommended. ... In general, surgical latex gloves fit better, have appropriate elasticity for double gloving and maintaining the integrity of the glove-gown interface, and have sufficient tactile sensation (even during double gloving) for stringent aseptic procedures. ... Powdered gloves should be avoided. /Antineoplastic agents/
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 875
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers who are not protected by the containment environment of a biohazard cabinet should use respiratory protection when handling hazardous drugs. Respiratory protection should be an adjunct to and not a substitute for engineering controls. Surgical masks of all types provide no respiratory protection against powdered or liquid aerosols of hazardous drugs. In situations where workers may be exposed to potential eye contact with hazardous drugs, an appropriate plastic face shield or splash goggles should be worn. /Antineoplastic agents/
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 875
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ During compounding of hazardous drugs (eg, crushing, dissolving, and preparing an ointment), workers should wear low permeability gowns and double gloves. Compounding should take place in a protective area such as a disposable glove box. If compounding must be done in the open, an area away from drafts and traffic must be selected, and the worker should use appropriate respiratory protection. /Antineoplastic agents/
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 875

11.7 Stability and Reactivity

11.7.1 Air and Water Reactions

May be sensitive to prolonged exposure to moisture. (NTP, 1992).
National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.

11.7.2 Reactive Group

Alcohols and Polyols

Amides and Imides

Esters, Sulfate Esters, Phosphate Esters, Thiophosphate Esters, and Borate Esters

Hydrocarbons, Aliphatic Unsaturated

11.8 Transport Information

11.8.1 Shipment Methods and Regulations

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Methods for transporting hazardous drugs to the health-care setting should be consistent with environmental protection and national or local regulations for transporting hazardous substances. When hazardous drugs are being transported to the home-care setting, appropriate containers (eg, lined cardboard boxes) and procedures should be used to prevent breakage and contain leakage. ... The drugs must be securely capped or sealed and properly packaged and protected during transport to reduce further the chance of breakage and spillage in a public area such as a corridor or elevator. /Antineoplastic agents/
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 875

11.8.2 DOT Label

Poison

11.9 Regulatory Information

California Safe Cosmetics Program (CSCP) Reportable Ingredient

Hazard Traits - Developmental Toxicity; Reproductive Toxicity

Authoritative List - Prop 65

Report - regardless of intended function of ingredient in the product

11.10 Other Safety Information

11.10.1 Special Reports

Chem & Eng News 70 (41): 30-2 (1992); A discussion concerning the development and synthesis of taxol, a new antitumor drug.
Van Ingen G et al; Sudden Unexpected Death Due to Taxus Poisoning: A report of five cases, with review of the literature. Forensic Sci Int 56 (1): 81-7 (1992). The clinical and autopsy findings are summarized, the diagnostic aspects are discussed and the literature concerning Taxus is reviewed.
Correia JJ; Effects of Antimitotic Agents on Tubulin Nucleotide Interactions. Pharmacol Ther 52 (2): 127-47 (1991). The interaction of antimitotic drugs with guanine nucleotides in the tubulin-microtubule system is reviewed. Taxol stoichiometrically induces microtubule formation and, in the presence of guanosine triphosphate, assembly associated guanosine triphosphate hydrolysis.

12 Toxicity

12.1 Toxicological Information

12.1.1 Toxicity Summary

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.

12.1.2 Hepatotoxicity

Paclitaxel has been associated with serum aminotransferase elevations in 7% to 26% of patients, but values greater than 5 times the upper limit of normal (ULN) in only 2% of those receiving the highest doses. Similar rates of alkaline phosphatase elevations and occasional mild bilirubin elevations also occur. The abnormalities are usually asymptomatic, mild and self-limited, rarely requiring dose modification or discontinuation. Paclitaxel has not been linked convincingly to instances of delayed, idiosyncratic clinically apparent liver injury with jaundice. However, the hypersensitivity reactions that occur with infusions of paclitaxel can be severe and accompanied by acute hepatic necrosis. The liver injury may be relatively mild and anicteric (Case 1), but can also be severe with rapid onset of multiorgan failure and death. At least one instance of acute liver failure following a hypersensitivity reaction to paclitaxel has been published in the literature and recent modifications of the product labels for paclitaxel and docetaxel mention the occurrence of toxic deaths following severe infusion reactions. Because paclitaxel is often given with other antineoplastic agents, liver injury arising during therapy cannot always be reliably attributed to paclitaxel rather than to other specific agents. Furthermore, paclitaxel in combination with other anticancer agents may be associated with reactivation of hepatitis B, increased risk of opportunistic viral infections, sinusoidal obstruction syndrome or sepsis, any of which can cause liver test abnormalities or clinically apparent liver injury.

Likelihood score: D (possible cause of acute hepatic necrosis associated with a hypersensitivity reaction to the initial infusions).

12.1.3 Drug Induced Liver Injury

Compound
paclitaxel
DILI Annotation
Less-DILI-Concern
Severity Grade
4
Label Section
Adverse reactions
References

M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007

M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

12.1.4 Carcinogen Classification

Carcinogen Classification
No indication of carcinogenicity to humans (not listed by IARC).

12.1.5 Effects During Pregnancy and Lactation

◉ Summary of Use during Lactation

Most sources consider breastfeeding to be contraindicated during maternal antineoplastic drug therapy. It might be possible to breastfeed safely during intermittent therapy with an appropriate period of breastfeeding abstinence. Some have suggested a breastfeeding abstinence period of 6 to 10 days, but more recent pharmacokinetic modeling using a worst-case scenario suggests that 6 days would be adequate to minimize both systemic and gut toxicity after the colostral phase.

Chemotherapy may adversely affect the normal microbiome and chemical makeup of breastmilk. Women who receive chemotherapy during pregnancy are more likely to have difficulty nursing their infant than typical mothers.

◉ Effects in Breastfed Infants

Relevant published information was not found as of the revision date.

◉ Effects on Lactation and Breastmilk

A telephone follow-up study was conducted on 74 women who received cancer chemotherapy at one center during the second or third trimester of pregnancy to determine if they were successful at breastfeeding postpartum. Only 34% of the women were able to exclusively breastfeed their infants, and 66% of the women reported experiencing breastfeeding difficulties. This was in comparison to a 91% breastfeeding success rate in 22 other mothers diagnosed during pregnancy, but not treated with chemotherapy. Other statistically significant correlations included: 1. mothers with breastfeeding difficulties had an average of 5.5 cycles of chemotherapy compared with 3.8 cycles among mothers who had no difficulties; and 2. mothers with breastfeeding difficulties received their first cycle of chemotherapy on average 3.4 weeks earlier in pregnancy. Of the 9 women who received a taxane-containing regimen, 7 had breastfeeding difficulties.

12.1.6 Exposure Routes

When a 24 hour infusion of 135 mg/m^2 is given to ovarian cancer patients, the maximum plasma concentration (Cmax) is 195 ng/mL, while the AUC is 6300 ng*h/mL.

12.1.7 Adverse Effects

Occupational hepatotoxin - Secondary hepatotoxins: the potential for toxic effect in the occupational setting is based on cases of poisoning by human ingestion or animal experimentation.

Skin Sensitizer - An agent that can induce an allergic reaction in the skin.

Asthma - Reversible bronchoconstriction (narrowing of bronchioles) initiated by the inhalation of irritating or allergenic agents.

12.1.8 Acute Effects

12.1.9 Toxicity Data

ToxicityData
Ratip LD50: 32530 ug/kg
National Technical Information Service PB83-170969
ToxicityData
Mouse ip LD50 128 mg/kg
National Technical Information Service PB83-170969
ToxicityData
Dog iv LD50 15 mg/kg
National Technical Information Service PB83-170969
Rat (ipr) LD<sub>50</sub>=32530 &micro;g/kg.

12.1.10 Interactions

Concomitant administration of CNS depressants such as antihistamines or opiates with paclitaxel should be undertaken with caution as these drugs may cause potentiation of CNS depression caused by the alcohol contained in the paclitaxel formulation.
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 1187
Untreated and minimally pretreated solid tumor patients received alternating sequences of taxol and cisplatin. Sequential dose escalation of each agent using taxol doses of 110 or 135 mg/sq m and cisplatin doses of 50 or 75 mg/sq m resulted in four dosage permutations that induced grades 3 and 4 neutropenia in 72% to 84% and 50% to 53% of courses, respectively. Neutropenia was brief, and hospitalization for neutropenia and fever was required in 13% to 24% of courses. However, further escalation of taxol to 170 or 200 mg/sq m induced grade 4 neutropenia in 79% to 82% of courses. At the highest taxol-cisplatin dose level (200 mg/sq m to 75 mg/sq m), the mean neutrophil count nadir was 98/uL, and hospitalization for neutropenia and fever was required in 64% of courses. The sequence of cisplatin before taxol, which has less antitumor activity in vitro, induced more profound neutropenia than the alternate sequence. Pharmacologic studies indicated that this difference was probably due to 25% lower taxol clearance rates when cisplatin preceded taxol. ...
Rowinsky EK et al; J Clin Oncol 9 (9): 1692-703 (1991)
... Pharmacokinetic studies show that administration of cisplatin followed by conventional paclitaxel decreases paclitaxel clearance by approximately 25-33%. When cisplatin and paclitaxel must be administered sequentially, the sequence of paclitaxel followed by cisplatin is recommended. Increased severity of neutropenia and thrombocytopenia have been reported when paclitaxel is administered (by 24-hour IV infusion) followed by cyclophosphamide.
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 1187
Administration of paclitaxel followed by carboplatin was associated with similar rates of neutropenia but less severe thrombocytopenia compared with carboplatin alone; a pharmacodynamic mechanism for the interaction between the drugs has been postulated since the pharmacokinetics of the agents were unchanged.
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 1187
For more Interactions (Complete) data for TAXOL (8 total), please visit the HSDB record page.

12.1.11 Antidote and Emergency Treatment

Emergency and supportive measures. Maintain an open airway and assist ventilation if necessary. Treat coma, seizures, hypotension, and arrhythmias if they occur. Treat nausea and vomiting with metoclopramide and fluid loss caused by gastroenteritis with intravenous crystalloid fluids. /Antineoplastic agents/
Olson, K.R. (Ed.); Poisoning & Drug Overdose. 5th ed. Lange Medical Books/McGraw-Hill. New York, N.Y. 2007., p. 101
Bone marrow depression should be treated with the assistance of an experienced hematologist or oncologist. /Antineoplastic agents/
Olson, K.R. (Ed.); Poisoning & Drug Overdose. 5th ed. Lange Medical Books/McGraw-Hill. New York, N.Y. 2007., p. 100
Decontamination. Administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. /Antineoplastic agents/
Olson, K.R. (Ed.); Poisoning & Drug Overdose. 5th ed. Lange Medical Books/McGraw-Hill. New York, N.Y. 2007., p. 107
Enhanced elimination. Because of the rapid intracellular incorporation of most of these agents, dialysis and other extracorporeal removal procedures are generally not effective. /Antineoplastic agents/
Olson, K.R. (Ed.); Poisoning & Drug Overdose. 5th ed. Lange Medical Books/McGraw-Hill. New York, N.Y. 2007., p. 107

12.1.12 Medical Surveillance

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ There is no method available for routine monitoring of personnel for evidence of hazardous drug exposure. Tests for the presence of mutagens or chromosomal damage are not drug specific and are of value only in controlled studies. Chemical analysis of urine for the presence of hazardous drugs at the sensitivity level needed to detect occupational exposure is limited to a few drugs and is not yet commercially available. /Antineoplastic agents/
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 875

12.1.13 Human Toxicity Excerpts

/SIGNS AND SYMPTOMS/ Overdosage of conventional paclitaxel in pediatric patients may be associated with acute ethanol toxicity because of the presence of dehydrated alcohol in the formulation.
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 1187
/SIGNS AND SYMPTOMS/ Signs and symptoms of acute overdose: Ventricular arrhythmias, erythema, congestive heart failure, dyspnea, neuropathy (peripheral), myopathy, dysphagia, diplopia, chest pain, stomatitis, wheezing, neuritis, leukopenia; neutropenia; agranulocytosis; granulocytopenia.
Lelkin, J.B., Paloucek, F.P., Poisoning & Toxicology Compendium. LEXI-COMP Inc. & American Pharmaceutical Association, Hudson, OH 1998., p. 433
/SIGNS AND SYMPTOMS/ Limited information is available on acute overdosage of paclitaxel. Overdosage with paclitaxel would be expected to produce effects such as myelosuppression, peripheral or sensory neurotoxicity, and mucositis.
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 1187
/CASE REPORTS/ A 58-years-old woman with a metastatic ovarian carcinoma who had chest pain, nausea and collapse during their first Taxol infusion /is described/. The infusion was stopped and the patient was submitted to the intensive care unit (ICU) to exclude an acute coronary syndrome. The electrocardiography (ECG) showed a third-degree heart block and ST elevation in II, III and avF. In the initial and in the control laboratory investigation values of cardiac enzymes (creatinine kinase and Troponine T) remained normal. The control ECG after 30 minutes turned back to normal. After one day the patient was submitted back to a normal ward. ...
Schrader C et al; Eur J Med Res 10 (11): 498-501(2005)
For more Human Toxicity Excerpts (Complete) data for TAXOL (11 total), please visit the HSDB record page.

12.1.14 Non-Human Toxicity Excerpts

/LABORATORY ANIMALS: Acute Exposure/ Paclitaxel, an antineoplastic agent, was given to Crj: CD (SD) rats of both sexes at 38, 50, 65 and 85 mg/kg by single intravenous administration to investigate its acute toxicity. The results obtained are summarized as follows: 1. Tachypnea and decreased activity with prone position were noted for vehicle and all paclitaxel groups, and alopecia for all paclitaxel groups. 2. Deaths occurred for one out of 5 males and 2 out of 5 females at 85 mg/kg. One female died of respiratory insufficiency induced by vehicle on Day 0. One female and one male died of the systemic toxicity of paclitaxel such as hypoplasia of the bone marrow and lymphoid depletion of lymphatic organs on Days 6 and 12, respectively. 3. On Days 4 and 5, all paclitaxel groups showed decreases of reticulocyte and white blood cell counts, as well as decrease of differential count of neutrophils. These changes were generally recovered by a week after dosing. 4. Histopathological examinations revealed atrophy of the thymic medulla, hypoplasia of the bone marrow and lymphoid depletion of the spleen for a few males at 85 mg/kg, and hypospermatogenesis and tubular atrophy of the testes for all paclitaxel groups. Based on these results, 85 mg/kg of paclitaxel was lethal to rats, and hematopoietic, lymphoid and male reproductive systems were primarily affected under this condition.
Kadota T et al; J Toxicol Sci 19 (Suppl 1):1-9 (1994)
/LABORATORY ANIMALS: Acute Exposure/ Paclitaxel (single intravenous injection in a maximum tolerated dose of 4.6 mg/kg) to white outbred rats causes bone marrow hypoplasia, increased granulocyte and erythroid cell mitosis (metaphase-anaphase transition), and moderate pancytopenia developments in peripheral blood (hypoplastic anemia, deep, short-term neutropenia, lymphopenia and thrombocytopenia) in the first hours after injection. A considerable increase of polyploidy (4n) cells and a moderate increase in the structural changes (chromatid deletions) of chromosomes was observed on bone marrow metaphase plates in 24 hr. The drug introduction causes earlier increase in the rate of thymus cells mitosis, a growth in the number of thymocytes with apoptosis signs, and a moderate decrease in the thymus and spleen weight. All changes are reversible. Long-term (90 days after injection) observation revealed decreased lymphocyte count in the peripheral blood and bone marrow and earlier thymus involution.
Karpov GV et al; Eksp Klin Farmakol 70 (4): 39-43 (2007)
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Reproduction studies in rats receiving albumin-bound paclitaxel at IV doses of 6 mg/sq m (approximately 2% of the maximum recommended human dose on a mg/sq m basis) on gestation days 7 to 17 resulted in embryotoxicity and fetotoxicity. The drug caused intrauterine mortality, increased resorptions, reduced numbers of litters, increased fetal deaths, reduction in fetal body weight, and increased fetal anomalies including soft tissue and skeletal malformations, such as eye bulge, folded retina, microphthalmia, and dilation of brain ventricles. Fetal anomalies also occurred in the offspring of rats receiving lower doses of albumin-bound paclitaxel (IV doses of 3 mg/sq m or approximately 1% of the maximum recommended human dose on a mg/sq m basis).
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 1187
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Reproduction studies in rabbits receiving IV conventional paclitaxel doses of 3 mg/kg daily (approximately 0.2 times the maximum recommended human dose on a mg/sq m basis) during organogenesis revealed evidence of maternal toxicity, embryotoxicity, and fetotoxicity. The drug caused intrauterine mortality, increased resorptions, and increased fetal deaths. No teratogenic effects were observed in the offspring of rats receiving daily IV paclitaxel doses of 1 mg/kg; however, the teratogenic potential of higher paclitaxel doses could not be assessed because of extensive fetal mortality.
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 1186
For more Non-Human Toxicity Excerpts (Complete) data for TAXOL (13 total), please visit the HSDB record page.

12.1.15 Protein Binding

89%-98% bound to plasma protein. The presence of cimetidine, ranitidine, dexamethasone, or diphenhydramine did not affect protein binding of paclitaxel.

12.2 Ecological Information

12.2.1 Natural Pollution Sources

Taxol is a component found in the bark of the Pacific Yew tree, Taxus brevifolia.
Chem & Eng News 70 (41): 30-2 (1992)

12.2.2 Environmental Water Concentrations

While data specific to taxol were not located(SRC, 2008), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2). Studies have indicated that several polar pharmaceutically active compounds can leach through soils(1).
(1) Heberer T; Tox Lett 131: 5-17 (2002)
(2) Koplin DW et al; Environ Sci Toxicol 36: 1202-211 (2002)

12.2.3 Probable Routes of Human Exposure

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ ... exposure may be through inadvertent ingestion of the drug on foodstuffs (eg, workers' lunches), inhalation of drug dusts or droplets or direct skin contact. /Antineoplastic agents/
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 875

13 Associated Disorders and Diseases

Associated Occupational Diseases with Exposure to the Compound

Asthma, occupational [Category: Airway Disease]

Contact dermatitis, allergic [Category: Skin Disease]

14 Literature

14.1 Consolidated References

14.2 NLM Curated PubMed Citations

14.3 Springer Nature References

14.4 Thieme References

14.5 Wiley References

14.6 Nature Journal References

14.7 Chemical Co-Occurrences in Literature

14.8 Chemical-Gene Co-Occurrences in Literature

14.9 Chemical-Disease Co-Occurrences in Literature

15 Patents

15.1 Depositor-Supplied Patent Identifiers

15.2 WIPO PATENTSCOPE

15.3 FDA Orange Book Patents

15.4 Chemical Co-Occurrences in Patents

15.5 Chemical-Disease Co-Occurrences in Patents

15.6 Chemical-Gene Co-Occurrences in Patents

16 Interactions and Pathways

16.1 Protein Bound 3D Structures

16.1.1 Ligands from Protein Bound 3D Structures

PDBe Ligand Code
PDBe Structure Code
PDBe Conformer

16.2 Chemical-Target Interactions

16.3 Drug-Drug Interactions

16.4 Drug-Food Interactions

  • Avoid echinacea. Co-administration may decrease the effectiveness of immunosuppressants, and echinacea may induce CYP3A4 increasing paclitaxel metabolism.
  • Exercise caution with grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum concentration of paclitaxel.
  • Exercise caution with St. John's Wort. This herb induces the CYP3A4 metabolism of paclitaxel and may reduce its serum concentration.

16.5 Pathways

17 Biological Test Results

17.1 BioAssay Results

18 Taxonomy

The LOTUS Initiative for Open Natural Products Research: frozen dataset union wikidata (with metadata) | DOI:10.5281/zenodo.5794106
S29 | PHYTOTOXINS | Toxic Plant Phytotoxin (TPPT) Database | DOI:10.5281/zenodo.2652993

19 Classification

19.1 MeSH Tree

19.2 NCI Thesaurus Tree

19.3 ChEBI Ontology

19.4 KEGG: Drug

19.5 KEGG: USP

19.6 KEGG: ATC

19.7 KEGG: Target-based Classification of Drugs

19.8 KEGG: Drug Groups

19.9 WHO ATC Classification System

19.10 FDA Pharm Classes

19.11 ChemIDplus

19.12 CAMEO Chemicals

19.13 IUPHAR / BPS Guide to PHARMACOLOGY Target Classification

19.14 ChEMBL Target Tree

19.15 UN GHS Classification

19.16 NORMAN Suspect List Exchange Classification

19.17 EPA DSSTox Classification

19.18 LOTUS Tree

19.19 FDA Drug Type and Pharmacologic Classification

19.20 EPA Substance Registry Services Tree

19.21 MolGenie Organic Chemistry Ontology

20 Information Sources

  1. BindingDB
    LICENSE
    All data curated by BindingDB staff are provided under the Creative Commons Attribution 3.0 License (https://creativecommons.org/licenses/by/3.0/us/).
    https://www.bindingdb.org/rwd/bind/info.jsp
  2. Chemical Probes Portal
  3. Comparative Toxicogenomics Database (CTD)
    LICENSE
    It is to be used only for research and educational purposes. Any reproduction or use for commercial purpose is prohibited without the prior express written permission of NC State University.
    http://ctdbase.org/about/legal.jsp
  4. Drug Gene Interaction database (DGIdb)
    LICENSE
    The data used in DGIdb is all open access and where possible made available as raw data dumps in the downloads section.
    http://www.dgidb.org/downloads
  5. DrugBank
    LICENSE
    Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode)
    https://www.drugbank.ca/legal/terms_of_use
  6. IUPHAR/BPS Guide to PHARMACOLOGY
    LICENSE
    The Guide to PHARMACOLOGY database is licensed under the Open Data Commons Open Database License (ODbL) https://opendatacommons.org/licenses/odbl/. Its contents are licensed under a Creative Commons Attribution-ShareAlike 4.0 International License (http://creativecommons.org/licenses/by-sa/4.0/)
    https://www.guidetopharmacology.org/about.jsp#license
    Guide to Pharmacology Target Classification
    https://www.guidetopharmacology.org/targets.jsp
  7. Therapeutic Target Database (TTD)
  8. Toxin and Toxin Target Database (T3DB)
    LICENSE
    T3DB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (T3DB) and the original publication.
    http://www.t3db.ca/downloads
  9. California Office of Environmental Health Hazard Assessment (OEHHA)
  10. CAMEO Chemicals
    LICENSE
    CAMEO Chemicals and all other CAMEO products are available at no charge to those organizations and individuals (recipients) responsible for the safe handling of chemicals. However, some of the chemical data itself is subject to the copyright restrictions of the companies or organizations that provided the data.
    https://cameochemicals.noaa.gov/help/reference/terms_and_conditions.htm?d_f=false
    CAMEO Chemical Reactivity Classification
    https://cameochemicals.noaa.gov/browse/react
  11. ChEBI
  12. FDA Pharm Classes
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  13. LiverTox
  14. LOTUS - the natural products occurrence database
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    The code for LOTUS is released under the GNU General Public License v3.0.
    https://lotus.nprod.net/
  15. NCI Thesaurus (NCIt)
    LICENSE
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    https://www.cancer.gov/policies/copyright-reuse
  16. Open Targets
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    https://platform-docs.opentargets.org/licence
  17. California Safe Cosmetics Program (CSCP) Product Database
  18. CAS Common Chemistry
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    https://creativecommons.org/licenses/by-nc/4.0/
  19. ChemIDplus
    ChemIDplus Chemical Information Classification
    https://pubchem.ncbi.nlm.nih.gov/source/ChemIDplus
  20. DTP/NCI
    LICENSE
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    https://www.cancer.gov/policies/copyright-reuse
  21. EPA DSSTox
    CompTox Chemicals Dashboard Chemical Lists
    https://comptox.epa.gov/dashboard/chemical-lists/
  22. European Chemicals Agency (ECHA)
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    Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page.
    https://echa.europa.eu/web/guest/legal-notice
    (2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-1,2a,3,4,4a,6,9,10,11,12,12a,12b-Dodecahydro-4,6,9,11,12,12b-hexahydroxy-4a,8,13,13-tetramethyl-7,11-methano-5H-cyclodeca(3,4)benz(1,2-b)oxet-5-one 6,12b-diacetate, 12-benzoate, 9-ester with (2R,3S)-N-benzoyl-3-phenylisoserine
    https://echa.europa.eu/substance-information/-/substanceinfo/100.127.725
    (2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-1,2a,3,4,4a,6,9,10,11,12,12a,12b-Dodecahydro-4,6,9,11,12,12b-hexahydroxy-4a,8,13,13-tetramethyl-7,11-methano-5H-cyclodeca(3,4)benz(1,2-b)oxet-5-one 6,12b-diacetate, 12-benzoate, 9-ester with (2R,3S)-N-benzoyl-3-phenylisoserine (EC: 608-826-9)
    https://echa.europa.eu/information-on-chemicals/cl-inventory-database/-/discli/details/106818
  23. FDA Global Substance Registration System (GSRS)
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  24. Hazardous Substances Data Bank (HSDB)
  25. Human Metabolome Database (HMDB)
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    http://www.hmdb.ca/citing
  26. Haz-Map, Information on Hazardous Chemicals and Occupational Diseases
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    https://haz-map.com/About
  27. ChEMBL
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    http://www.ebi.ac.uk/Information/termsofuse.html
  28. NORMAN Suspect List Exchange
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    Data: CC-BY 4.0; Code (hosted by ECI, LCSB): Artistic-2.0
    https://creativecommons.org/licenses/by/4.0/
    Paclitaxel
    NORMAN Suspect List Exchange Classification
    https://www.norman-network.com/nds/SLE/
  29. ClinicalTrials.gov
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    https://clinicaltrials.gov/ct2/about-site/terms-conditions#Use
  30. DailyMed
  31. Drug Induced Liver Injury Rank (DILIrank) Dataset
    LICENSE
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  32. European Medicines Agency (EMA)
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    https://www.ema.europa.eu/en/about-us/legal-notice
  33. Drugs and Lactation Database (LactMed)
  34. Drugs@FDA
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  35. WHO Model Lists of Essential Medicines
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    https://www.who.int/about/policies/publishing/copyright
  36. EU Clinical Trials Register
  37. FDA Orange Book
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  38. WHO Anatomical Therapeutic Chemical (ATC) Classification
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    https://www.whocc.no/copyright_disclaimer/
  39. National Drug Code (NDC) Directory
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  40. NCI Investigational Drugs
  41. Japan Chemical Substance Dictionary (Nikkaji)
  42. Japan Pharmaceuticals and Medical Devices Agency (PMDA)
  43. KEGG
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    https://www.kegg.jp/kegg/legal.html
    Therapeutic category of drugs in Japan
    http://www.genome.jp/kegg-bin/get_htext?br08301.keg
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    http://www.genome.jp/kegg-bin/get_htext?br08303.keg
    Target-based classification of drugs
    http://www.genome.jp/kegg-bin/get_htext?br08310.keg
  44. Natural Product Activity and Species Source (NPASS)
  45. MassBank Europe
  46. MassBank of North America (MoNA)
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    https://mona.fiehnlab.ucdavis.edu/documentation/license
  47. Metabolomics Workbench
  48. Nature Chemical Biology
  49. Nature Chemistry
  50. NCI Cancer Drugs
  51. NIPH Clinical Trials Search of Japan
  52. NLM RxNorm Terminology
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    https://www.nlm.nih.gov/research/umls/rxnorm/docs/termsofservice.html
  53. PharmGKB
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    https://www.pharmgkb.org/page/policies
  54. Pharos
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    https://pharos.nih.gov/about
  55. Protein Data Bank in Europe (PDBe)
  56. RCSB Protein Data Bank (RCSB PDB)
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    https://www.rcsb.org/pages/policies
  57. Rhea - Annotated Reactions Database
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    https://www.rhea-db.org/help/license-disclaimer
  58. SpectraBase
  59. Springer Nature
  60. Thieme Chemistry
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    https://creativecommons.org/licenses/by-nc-nd/4.0/
  61. Wikidata
  62. Wikipedia
  63. Wiley
  64. Medical Subject Headings (MeSH)
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    https://www.nlm.nih.gov/copyright.html
    Antineoplastic Agents, Phytogenic
    https://www.ncbi.nlm.nih.gov/mesh/68000972
  65. PubChem
  66. GHS Classification (UNECE)
  67. EPA Substance Registry Services
  68. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  69. PATENTSCOPE (WIPO)
  70. NCBI
CONTENTS