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Vorinostat

PubChem CID
5311
Structure
Vorinostat_small.png
Vorinostat_3D_Structure.png
Vorinostat__Crystal_Structure.png
Molecular Formula
Synonyms
  • Vorinostat
  • 149647-78-9
  • SAHA
  • suberoylanilide hydroxamic acid
  • N-hydroxy-N'-phenyloctanediamide
Molecular Weight
264.32 g/mol
Computed by PubChem 2.2 (PubChem release 2024.11.20)
Dates
  • Create:
    2005-03-25
  • Modify:
    2025-01-04
Description
Vorinostat is a dicarboxylic acid diamide comprising suberic (octanedioic) acid coupled to aniline and hydroxylamine. A histone deacetylase inhibitor, it is marketed under the name Zolinza for the treatment of cutaneous T cell lymphoma (CTCL). It has a role as an EC 3.5.1.98 (histone deacetylase) inhibitor, an apoptosis inducer and an antineoplastic agent. It is a hydroxamic acid and a dicarboxylic acid diamide. It is functionally related to a suberic acid, a hydroxylamine and an aniline.
Vorinostat is a drug that has been approved by the U.S. Food and Drug Administration (FDA) under the brand name Zolinza for the treatment of a certain type of cancer.Vorinostat is also being studied as an investigational drug as part of a strategy to cure HIV infection.As an investigational HIV drug, vorinostat belongs to a group of drugs called latency-reversing agents.
Vorinostat (rINN) or suberoylanilide hydroxamic acid (SAHA), is a drug currently under investigation for the treatment of cutaneous T cell lymphoma (CTCL), a type of skin cancer, to be used when the disease persists, gets worse, or comes back during or after treatment with other medicines. It is the first in a new class of agents known as histone deacetylase inhibitors. A recent study suggested that vorinostat also possesses some activity against recurrent glioblastoma multiforme, resulting in a median overall survival of 5.7 months (compared to 4 - 4.4 months in earlier studies). Further brain tumor trials are planned using combinations of vorinostat with other drugs.

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Vorinostat.png

1.2 3D Conformer

1.3 Crystal Structures

1 of 6
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CCDC Number
Crystal Structure Data
Crystal Structure Depiction
Crystal Structure Depiction

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

N'-hydroxy-N-phenyloctanediamide
Computed by Lexichem TK 2.7.0 (PubChem release 2024.11.20)

2.1.2 InChI

InChI=1S/C14H20N2O3/c17-13(15-12-8-4-3-5-9-12)10-6-1-2-7-11-14(18)16-19/h3-5,8-9,19H,1-2,6-7,10-11H2,(H,15,17)(H,16,18)
Computed by InChI 1.07.0 (PubChem release 2024.11.20)

2.1.3 InChIKey

WAEXFXRVDQXREF-UHFFFAOYSA-N
Computed by InChI 1.07.0 (PubChem release 2024.11.20)

2.1.4 SMILES

C1=CC=C(C=C1)NC(=O)CCCCCCC(=O)NO
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

2.2 Molecular Formula

C14H20N2O3
Computed by PubChem 2.2 (PubChem release 2024.11.20)

2.3 Other Identifiers

2.3.1 CAS

2.3.2 European Community (EC) Number

2.3.3 UNII

2.3.4 ChEBI ID

2.3.5 ChEMBL ID

2.3.6 DrugBank ID

2.3.7 DSSTox Substance ID

2.3.8 HMDB ID

2.3.9 KEGG ID

2.3.10 Metabolomics Workbench ID

2.3.11 NCI Thesaurus Code

2.3.12 Nikkaji Number

2.3.13 NSC Number

2.3.14 PharmGKB ID

2.3.15 Pharos Ligand ID

2.3.16 RXCUI

2.3.17 Wikidata

2.3.18 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • 18F Suberoylanilide Hydroxamic Acid
  • 18F-SAHA
  • 18F-suberoylanilide hydroxamic acid
  • M344
  • MK 0683
  • MK-0683
  • MK0683
  • N Hydroxy N' phenyloctanediamide
  • N-hydroxy-N'-phenyloctanediamide
  • N1 Hydroxy N8 phenyloctanediamide
  • N1-hydroxy-N8-phenyloctanediamide
  • NHNPODA
  • suberanilohydroxamic acid
  • suberoyl anilide hydroxamic acid
  • suberoylanilide hydroxamic acid
  • Vorinostat
  • zolinza

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
264.32 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2024.11.20)
Property Name
XLogP3
Property Value
1.9
Reference
Computed by XLogP3 3.0 (PubChem release 2024.11.20)
Property Name
Hydrogen Bond Donor Count
Property Value
3
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Hydrogen Bond Acceptor Count
Property Value
3
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Rotatable Bond Count
Property Value
8
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Exact Mass
Property Value
264.14739250 Da
Reference
Computed by PubChem 2.2 (PubChem release 2024.11.20)
Property Name
Monoisotopic Mass
Property Value
264.14739250 Da
Reference
Computed by PubChem 2.2 (PubChem release 2024.11.20)
Property Name
Topological Polar Surface Area
Property Value
78.4 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Heavy Atom Count
Property Value
19
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
276
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Isotope Atom Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Atom Stereocenter Count
Property Value
0
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

Solid

3.2.2 Color / Form

White to light orange powder
Physicians Desk Reference 65th ed. PDR Network, LLC, Montvale, NJ. 2011, p. 2363
White solid
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 1728

3.2.3 Melting Point

159-160.5 °C
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 1728

3.2.4 Solubility

Slightly soluble in ethanol, isopropanol and acetone; freely soluble in dimethylsulfide; insoluble in methylene chloride
Physicians Desk Reference 65th ed. PDR Network, LLC, Montvale, NJ. 2011, p. 2363
7.16e-02 g/L

3.2.5 pH

pH = 6.6 (saturated water solution)
Physicians Desk Reference 65th ed. PDR Network, LLC, Montvale, NJ. 2011, p. 2363

3.2.6 Dissociation Constants

pKa
9.2
pKa = 9.2
Physicians Desk Reference 65th ed. PDR Network, LLC, Montvale, NJ. 2011, p. 2363

3.2.7 Other Experimental Properties

... no chiral centers and is non-hygroscopic
Wishart DS et al; DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. PMID:18048412. Available from, as of May 19, 2011: https://www.drugbank.ca

3.3 Chemical Classes

3.3.1 Drugs

Pharmaceuticals -> Listed in ZINC15
S55 | ZINC15PHARMA | Pharmaceuticals from ZINC15 | DOI:10.5281/zenodo.3247749
3.3.1.1 Human Drugs
Human drug -> Active ingredient (VORINOSTAT)
Human drug -> Prescription
Paediatric drug

4 Spectral Information

4.1 Mass Spectrometry

4.1.1 MS-MS

1 of 4
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Spectra ID
Instrument Type
LC-ESI-Hybrid FT
Ionization Mode
Positive
Top 5 Peaks

300.231689 23744

298.215057 6352

301.234253 3576

184.076721 3456

159.067245 3452

Thumbnail
Thumbnail
Notes
From GNPS Library
2 of 4
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Spectra ID
Ionization Mode
positive
Top 5 Peaks

232.133286 100

94.065704 70.57

139.075439 52.31

83.086205 33

111.080872 26.39

Thumbnail
Thumbnail
Notes
instrument=Ion Trap

4.1.2 LC-MS

1 of 15
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Authors
F. Jud [dtc], K. Arturi [dtc], J. Hollender [dtc], A. Dax [com]
Instrument
Exploris 240 Thermo Scientific
Instrument Type
LC-ESI-QFT
MS Level
MS2
Ionization Mode
POSITIVE
Ionization
ESI
Collision Energy
15 % (nominal)
Fragmentation Mode
HCD
Column Name
XBridge C18 3.5um, 2.1x50mm, Waters
Retention Time
4.916 min
Precursor m/z
265.1547
Precursor Adduct
[M+H]+
Top 5 Peaks

265.1546 999

232.133 586

172.0966 349

94.0651 57

Thumbnail
Thumbnail
License
CC BY-SA
2 of 15
View All
Authors
F. Jud [dtc], K. Arturi [dtc], J. Hollender [dtc], A. Dax [com]
Instrument
Exploris 240 Thermo Scientific
Instrument Type
LC-ESI-QFT
MS Level
MS2
Ionization Mode
POSITIVE
Ionization
ESI
Collision Energy
30 % (nominal)
Fragmentation Mode
HCD
Column Name
XBridge C18 3.5um, 2.1x50mm, Waters
Retention Time
4.916 min
Precursor m/z
265.1547
Precursor Adduct
[M+H]+
Top 5 Peaks

232.133 999

172.0966 464

94.0651 211

139.0753 204

83.0855 83

Thumbnail
Thumbnail
License
CC BY-SA

6 Chemical Vendors

7 Drug and Medication Information

7.1 Drug Indication

For the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma who have progressive, persistent or recurrent disease on or following two systemic therapies.
Malignant pleural mesothelioma, Treatment of Cutaneous T-Cell Lymphoma

7.2 LiverTox Summary

Vorinostat is an oral histone deacetylase inhibitor and antineoplastic agent that is approved for use in refractory or relapsed cutaneous T cell lymphoma. Vorinostat is associated with modest rate of minor serum enzyme elevations during therapy, but has not been linked to cases of clinically apparent liver injury.

7.3 Drug Classes

Antineoplastic Agents

7.4 FDA Approved Drugs

7.5 FDA Orange Book

7.6 FDA National Drug Code Directory

7.7 Drug Labels

Drug and label
Active ingredient and drug

7.8 HIV / AIDS and Opportunistic Infection Drugs

What is Vorinostat
Vorinostat is a drug that has been approved by the U.S. Food and Drug Administration (FDA) under the brand name Zolinza for the treatment of a certain type of cancer.Vorinostat is also being studied as an investigational drug as part of a strategy to cure HIV infection.As an investigational HIV drug, vorinostat belongs to a group of drugs called latency-reversing agents.
Drug Class
Latency-Reversing Agents

7.9 Cancer Drugs

Drug Name
Vorinostat
Brand Name(s)
Zolinza
FDA Approved
Yes
Drug Use

Vorinostat is approved to treat:

• Cutaneous T-cell lymphoma that has not gotten better, has gotten worse, or has recurred (come back) during or after two systemic therapies.

Vorinostat is also being studied in the treatment of other types of cancer.

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

Type
Paediatric investigation
Active Substance
Therapeutic Area
Oncology
Drug Form
Capsule, hard
Administration Route
Oral use
Decision Type
W: decision granting a waiver in all age groups for all conditions or indications
Decision Date
2010-04-30

7.12 Therapeutic Uses

Antineoplastic Agents; Histone Deacetylase Inhibitors
National Library of Medicine's Medical Subject Headings online file (MeSH, 2009)
Vorinostat is indicated for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma who have progressive, persistent or recurrent disease on or following two systemic therapies. /Included in US product label/
US Natl Inst Health; DailyMed. Current Medication Information for ZOLINZA (vorinostat) capsule (October 2010). Available from, as of July 11, 2011: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=cd86ee78-2781-468b-930c-3c4677bcc092

7.13 Drug Warnings

Risk of pulmonary embolism and deep-vein thrombosis. Clinicians should be alert to signs and symptoms of such effects, especially in patients with a prior history of thromboembolic events.
American Society of Health-System Pharmacists 2011; Drug Information 2011. Bethesda, MD. 2011, p. 1275
Risk of dose-related thrombocytopenia and anemia. Dosage should be adjusted or therapy discontinued if thrombocytopenia or anemia occurs.
American Society of Health-System Pharmacists 2011; Drug Information 2011. Bethesda, MD. 2011, p. 1275
Risk of nausea, vomiting, and diarrhea; antiemetic and/or antidiarrheal agents may be required. To prevent dehydration, fluid and electrolyte replacement should be administered. Preexisting nausea, vomiting, and diarrhea should be adequately controlled before initiating therapy.
American Society of Health-System Pharmacists 2011; Drug Information 2011. Bethesda, MD. 2011, p. 1275
Risk of hyperglycemia. Serum glucose concentrations should be monitored, especially in patients with known or possible diabetes mellitus. Diet and/or antidiabetic therapy should be adjusted, if needed.
American Society of Health-System Pharmacists 2011; Drug Information 2011. Bethesda, MD. 2011, p. 1275
For more Drug Warnings (Complete) data for Vorinostat (23 total), please visit the HSDB record page.

8 Pharmacology and Biochemistry

8.1 MeSH Pharmacological Classification

Histone Deacetylase Inhibitors
Compounds that inhibit HISTONE DEACETYLASES. This class of drugs may influence gene expression by increasing the level of acetylated HISTONES in specific CHROMATIN domains. (See all compounds classified as Histone Deacetylase Inhibitors.)
Antineoplastic Agents
Substances that inhibit or prevent the proliferation of NEOPLASMS. (See all compounds classified as Antineoplastic Agents.)

8.2 FDA Pharmacological Classification

1 of 2
FDA UNII
58IFB293JI
Active Moiety
VORINOSTAT
Pharmacological Classes
Established Pharmacologic Class [EPC] - Histone Deacetylase Inhibitor
Pharmacological Classes
Mechanisms of Action [MoA] - Histone Deacetylase Inhibitors
FDA Pharmacology Summary
Vorinostat is a Histone Deacetylase Inhibitor. The mechanism of action of vorinostat is as a Histone Deacetylase Inhibitor.
2 of 2
Non-Proprietary Name
VORINOSTAT
Pharmacological Classes
Histone Deacetylase Inhibitors [MoA]; Histone Deacetylase Inhibitor [EPC]

8.3 ATC Code

L - Antineoplastic and immunomodulating agents

L01 - Antineoplastic agents

L01X - Other antineoplastic agents

L01XH - Histone deacetylase (hdac) inhibitors

L01XH01 - Vorinostat

8.4 Absorption, Distribution and Excretion

Route of Elimination
In vitro studies using human liver microsomes indicate negligible biotransformation by cytochromes P450 (CYP). Vorinostat is eliminated predominantly through metabolism with less than 1% of the dose recovered as unchanged drug in urine, indicating that renal excretion does not play a role in the elimination of vorinostat. However, renal excretion does not play a role in the elimination of vorinostat.
The pharmacokinetics of vorinostat were evaluated in 23 patients with relapsed or refractory advanced cancer. After oral administration of a single 400-mg dose of vorinostat with a high-fat meal, the mean +/- standard deviation area under the curve (AUC) and peak serum concentration (Cmax) and the median (range) time to maximum concentration (Tmax) were 5.5+/-1.8 uM.hr, 1.2+/-0.62 uM and 4 (2-10) hours, respectively.
US Natl Inst Health; DailyMed. Current Medication Information for ZOLINZA (vorinostat) capsule (October 2010). Available from, as of July 11, 2011: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=cd86ee78-2781-468b-930c-3c4677bcc092
In the fasted state, oral administration of a single 400-mg dose of vorinostat resulted in a mean AUC and Cmax and median Tmax of 4.2+/-1.9 uM.hr and 1.2+/-0.35 uM and 1.5 (0.5-10) hours, respectively. Therefore, oral administration of vorinostat with a high-fat meal resulted in an increase (33%) in the extent of absorption and a modest decrease in the rate of absorption (Tmax delayed 2.5 hours) compared to the fasted state. However, these small effects are not expected to be clinically meaningful. In clinical trials of patients with CTCL, vorinostat was taken with food.
US Natl Inst Health; DailyMed. Current Medication Information for ZOLINZA (vorinostat) capsule (October 2010). Available from, as of July 11, 2011: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=cd86ee78-2781-468b-930c-3c4677bcc092
At steady state in the fed-state, oral administration of multiple 400-mg doses of vorinostat resulted in a mean AUC and Cmax and a median Tmax of 6.0+/-2.0 uM.hr, 1.2+/-0.53 uM and 4 (0.5-14) hours, respectively.
US Natl Inst Health; DailyMed. Current Medication Information for ZOLINZA (vorinostat) capsule (October 2010). Available from, as of July 11, 2011: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=cd86ee78-2781-468b-930c-3c4677bcc092
Vorinostat is approximately 71% bound to human plasma proteins over the range of concentrations of 0.5 to 50 ug/mL.
US Natl Inst Health; DailyMed. Current Medication Information for ZOLINZA (vorinostat) capsule (October 2010). Available from, as of July 11, 2011: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=cd86ee78-2781-468b-930c-3c4677bcc092
For more Absorption, Distribution and Excretion (Complete) data for Vorinostat (9 total), please visit the HSDB record page.

8.5 Metabolism / Metabolites

The major pathways of vorinostat metabolism involve glucuronidation and hydrolysis followed by β-oxidation. Human serum levels of two metabolites, O-glucuronide of vorinostat and 4-anilino-4-oxobutanoic acid were measured. Both metabolites are pharmacologically inactive. Compared to vorinostat, the mean steady state serum exposures in humans of the O-glucuronide of vorinostat and 4-anilino-4-oxobutanoic acid were 4-fold and 13-fold higher, respectively. In vitro studies using human liver microsomes indicate negligible biotransformation by cytochromes P450 (CYP).
Vorinostat is extensively metabolized to inactive metabolites, principally by glucuronidation and hydrolysis followed by beta-oxidation. The drug is not metabolized by cytochrome P-450 (CYP) isoenzymes.
American Society of Health-System Pharmacists 2011; Drug Information 2011. Bethesda, MD. 2011, p. 1276
The major pathways of vorinostat metabolism involve glucuronidation and hydrolysis followed by beta-oxidation. Human serum levels of two metabolites, O-glucuronide of vorinostat and 4-anilino-4-oxobutanoic acid were measured. Both metabolites are pharmacologically inactive. Compared to vorinostat, the mean steady state serum exposures in humans of the O-glucuronide of vorinostat and 4-anilino-4-oxobutanoic acid were 4-fold and 13-fold higher, respectively.
US Natl Inst Health; DailyMed. Current Medication Information for ZOLINZA (vorinostat) capsule (October 2010). Available from, as of July 11, 2011: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=cd86ee78-2781-468b-930c-3c4677bcc092
The mean urinary recovery of two pharmacologically inactive metabolites at steady state was 16+/-5.8% of vorinostat dose as the O glucuronide of vorinostat, and 36+/-8.6% of vorinostat dose as 4-anilino-4-oxobutanoic acid. Total urinary recovery of vorinostat and these two metabolites averaged 52+/-13.3% of vorinostat dose.
US Natl Inst Health; DailyMed. Current Medication Information for ZOLINZA (vorinostat) capsule (October 2010). Available from, as of July 11, 2011: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=cd86ee78-2781-468b-930c-3c4677bcc092

8.6 Biological Half-Life

2 hours
... Patients (n = 23) received single doses of 400 mg vorinostat on day 1 (fasted) and day 5 (fed) with 48 hours of pharmacokinetic sampling on both days. Patients received 400 mg vorinostat once daily on days 7 to 28. On day 28, vorinostat was given (fed) with pharmacokinetic sampling for 24 hours after dose. The apparent t(1/2) of vorinostat was short (approximately 1.5 hours). ...
Rubin EH et al; Clin Cancer Res 12 (23): 7039-45 (2006)
The mean terminal half-life was /approximately/ 2.0 hours for both vorinostat and the O-glucuronide metabolite, while that of the 4-anilino-4-oxobutanoic acid metabolite was 11 hours.
US Natl Inst Health; DailyMed. Current Medication Information for ZOLINZA (vorinostat) capsule (October 2010). Available from, as of July 11, 2011: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=cd86ee78-2781-468b-930c-3c4677bcc092

8.7 Mechanism of Action

Vorinostat inhibits the enzymatic activity of histone deacetylases HDAC1, HDAC2 and HDAC3 (Class I) and HDAC6 (Class II) at nanomolar concentrations (IC50< 86 nM). These enzymes catalyze the removal of acetyl groups from the lysine residues of histones proteins. In some cancer cells, there is an overexpression of HDACs, or an aberrant recruitment of HDACs to oncogenic transcription factors causing hypoacetylation of core nucleosomal histones. By inhibiting histone deacetylase, vorinostat causes the accumulation of acetylated histones and induces cell cycle arrest and/or apoptosis of some transformed cells. The mechanism of the antineoplastic effect of vorinostat has not been fully characterized.
Vorinostat, a histone deacetylase inhibitor, is an antineoplastic agent. The mechanism of the antineoplastic effect of vorinostat has not been fully characterized. Vorinostat inhibits the enzymatic activity of histone deacetylases HDAC1, HDAC2, and HDAC3 (Class I) and HDAC6 (Class II) at nanomolar concentrations. HDAC enzymes catalyze the removal of acetyl groups from the lysine residues of proteins, including histones and transcription factors. Overexpression of HDAC enzymes or aberrant recruitment of HDAC enzymes to oncogenic transcription factors causing hypoacetylation of core nucleosomal histones has been observed in some cancer cells. Hypoacetylation of histones is associated with a condensed chromatin structure and repression of gene transcription. Inhibition of HDAC activity allows for the accumulation of acetyl groups on the histone lysine residues, resulting in an open chromatin structure and transcriptional activation. In vitro, vorinostat causes the accumulation of acetylated histones and induces cell cycle arrest and/or apoptosis of some transformed cells.
American Society of Health-System Pharmacists 2011; Drug Information 2011. Bethesda, MD. 2011, p. 1276
Although the pathophysiological processes involved in dopamine (DA) neuron degeneration in Parkinson's disease (PD) are not completely known, apoptotic cell death has been suggested to be involved and can be modeled in DAergic cell lines using the mitochondrial toxin 1-methyl-4-phenylpyridinium (MPP(+)). Recently, it has been suggested that histone deacetylase inhibitors (HDACIs) may reduce apoptotic cell death in various model systems. However, their utility in interfering with DA cell death remains unclear. The HDACIs sodium butyrate (NaB), valproate (VPA) and suberoylanilide hydroxamic acid (SAHA) were tested for their ability to prevent MPP(+)-mediated cytotoxicity in human derived SK-N-SH and rat derived MES 23.5 cells. All three HDACIs at least partially prevented MPP(+)-mediated apoptotic cell death. The protective effects of these HDACIs coincided with significant increases in histone acetylation. These results suggest that HDACIs may be potentially neuroprotective against DA cell death ...
Kidd SK, Schneider JS; Brain Res 1354: 172-8 (2010)
Histone deacetylase inhibitors (HDACi) developed as anti-cancer agents have a high degree of selectivity for killing cancer cells. HDACi induce acetylation of histones and nonhistone proteins, which affect gene expression, cell cycle progression, cell migration, and cell death. The mechanism of the tumor selective action of HDACi is unclear. Here, /the authors/ show that the HDACi, vorinostat (Suberoylanilide hydroxamic acid, SAHA), induces DNA double-strand breaks (DSBs) in normal (HFS) and cancer (LNCaP, A549) cells. Normal cells in contrast to cancer cells repair the DSBs despite continued culture with vorinostat. In transformed cells, phosphorylated H2AX (gammaH2AX), a marker of DNA DSBs, levels increased with continued culture with vorinostat, whereas in normal cells, this marker decreased with time. Vorinostat induced the accumulation of acetylated histones within 30 min, which could alter chromatin structure-exposing DNA to damage. After a 24-hr culture of cells with vorinostat, and reculture without the HDACi, gammaH2AX was undetectable by 2 hr in normal cells, while persisting in transformed cells for the duration of culture. Further, /investigators/ found that vorinostat suppressed DNA DSB repair proteins, e.g., RAD50, MRE11, in cancer but not normal cells. Thus, the HDACi, vorinostat, induces DNA damage which normal but not cancer cells can repair. This DNA damage is associated with cancer cell death. These findings can explain, in part, the selectivity of vorinostat in causing cancer cell death at concentrations that cause little or no normal cell death.
Lee JH et al; Proc Natl Acad Sci U S A 107 (33): 14639-44 (2010)
... Some histone deacetylase inhibitors, such as trichostatin A and scriptaid, have improved the full-term development of mouse clones significantly, but the mechanisms allowing for this are unclear. Here, /the authors/ found that two other specific inhibitors, suberoylanilide hydroxamic acid and oxamflatin, could also reduce the rate of apoptosis in blastocysts, improve the full-term development of cloned mice, and increase establishment of nuclear transfer-generated embryonic stem cell lines significantly without leading to obvious abnormalities. However, another inhibitor, valproic acid, could not improve cloning efficiency. Suberoylanilide hydroxamic acid, oxamflatin, trichostatin A, and scriptaid are inhibitors for classes I and IIa/b histone deacetylase, whereas valproic acid is an inhibitor for classes I and IIa, suggesting that inhibiting class IIb histone deacetylase is an important step for reprogramming mouse cloning efficiency.
Ono T et al; Biol Reprod 83 (6): 929-37 (2010)
For more Mechanism of Action (Complete) data for Vorinostat (23 total), please visit the HSDB record page.

8.8 Human Metabolite Information

8.8.1 Cellular Locations

  • Cytoplasm
  • Extracellular
  • Membrane

9 Use and Manufacturing

9.1 Uses

Inhibits enzymatic activity of histone deactylases
US Natl Inst Health; DailyMed. Current Medical Information. Available from, as of Jul 19, 2011: https://dailymed.nlm.nih.gov/dailymed/about.cfm
MEDICATION

9.1.1 Use Classification

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

It is prepared from suberic acid via the monoanilide, which after esterification with methanol is reacted with hydroxylamine.
Kleemann A; Ullmann's Encyclopedia of Industrial Chemistry 7th ed. (2010). NY, NY: John Wiley & Sons; Antineoplastic Agents, 1. Nonhormonal. Online Posting Date: September 15, 2010

9.3 Formulations / Preparations

Oral: Capsules: 100 mg, Zolinza (Merck).
American Society of Health-System Pharmacists 2011; Drug Information 2011. Bethesda, MD. 2011, p. 1276

10 Safety and Hazards

10.1 Hazards Identification

10.1.1 GHS Classification

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

H302 (58.9%): Harmful if swallowed [Warning Acute toxicity, oral]

H341 (99.1%): Suspected of causing genetic defects [Warning Germ cell mutagenicity]

H360 (72.9%): May damage fertility or the unborn child [Danger Reproductive toxicity]

H360FD (26.2%): May damage fertility; May damage the unborn child [Danger Reproductive toxicity]

H372 (59.8%): Causes damage to organs through prolonged or repeated exposure [Danger Specific target organ toxicity, repeated exposure]

H400 (60.7%): Very toxic to aquatic life [Warning Hazardous to the aquatic environment, acute hazard]

H410 (58.9%): Very toxic to aquatic life with long lasting effects [Warning Hazardous to the aquatic environment, long-term hazard]

Precautionary Statement Codes

P203, P260, P264, P270, P273, P280, P301+P317, P318, P319, P330, P391, 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 107 reports by companies from 7 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.

10.1.2 Hazard Classes and Categories

Acute Tox. 4 (58.9%)

Muta. 2 (99.1%)

Repr. 1A (72.9%)

Repr. 1B (26.2%)

STOT RE 1 (59.8%)

Aquatic Acute 1 (60.7%)

Aquatic Chronic 1 (58.9%)

10.2 Accidental Release Measures

10.2.1 Cleanup Methods

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Spill kits containing all materials needed to clean up spills of hazardous drugs should be assembled or purchased. These kits should be readily available in all areas where hazardous drugs are routinely handled. If hazardous drugs are being prepared or administered in a nonroutine area (home setting or unusual patient-care area), a spill kit should be obtained by the drug handler. The kit should include two pairs of disposable gloves (one outer pair of utility gloves and one inner latex pair); low-permeability, disposable protective garments (coveralls or gown and shoe covers); safety glasses or splash goggles; respirator; absorbent, plastic-backed sheets or spill pads; disposable toweling; at least 2 sealable thick plastic hazardous waste disposal bags (prelabeled with an appropriate warning label); a disposable scoop for collecting glass fragments; and a puncture-resistant container for glass fragments. All individuals who routinely handle hazardous drugs must be trained in proper spill management and cleanup procedures. Spills and breakages must be cleaned up immediately according to the following procedures. If the spill is not located in a confined space, the spill area should be identified and other people should be prevented from approaching and spreading the contamination. Wearing protective apparel from the spill kit, workers should remove any broken glass fragments and place them in the puncture-resistant container. Liquids should be absorbed with a spill pad; powder should be removed with damp disposable gauze pads or soft toweling. The hazardous material should be completely removed and the area rinsed with water and then cleaned with detergent. The spill cleanup should proceed progressively from areas of lesser to greater contamination. The detergent should be thoroughly rinsed and removed. All contaminated materials should be placed in the disposal bags provided and sealed and transported to a designated containment receptacle. Spills occurring in the biohazard cabinet should be cleaned up immediately; a spill kit should be used if the volume exceeds 150 ml or the contents of one drug vial or ampule. If there is broken glass, utility gloves should be worn to remove it and place it in the puncture-resistant container located in the biohazard cabinet. The biological safety cabinet, including the drain spillage trough, should be thoroughly cleaned. If the spill is not easily and thoroughly contained, the biological safety cabinet should be decontaminated after cleanup. If the spill contaminates the high efficiency particulate air filter, use of the biological safety cabinet should be suspended until the cabinet has been decontaminated and the high efficiency particulate air filter replaced. /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:/ If hazardous drugs are routinely prepared or administered in carpeted areas, special equipment is necessary to remove the spill. Absorbent powder should be substituted for pads or sheets and left in place on the spill for the time recommended by the manufacturer. The powder should then be picked up with a small vacuum unit reserved for hazardous drug cleanup. The carpet should then be cleaned according to usual procedures. The vacuum bag should be removed and discarded or cleaned, and the exterior of the vacuum cleaner should be washed with detergent and rinsed before being covered and stored. The contaminated powder should be discarded into a sealable plastic bag and segregated with other contaminated waste materials. Alternatively, inexpensive wet or dry vacuum units may be purchased for this express use and used with appropriate cleaners. All such units are contaminated, once used, and must be cleaned, stored, and ultimately discarded /properly/ ... The circumstances and handling of spills should be documented. Health-care personnel exposed during spill management should also complete an incident report or exposure form. /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

10.2.2 Disposal Methods

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.
/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 Vorinostat (8 total), please visit the HSDB record page.

10.2.3 Preventive Measures

Vorinostat capsules should not be opened or crushed. Direct contact of the powder in vorinostat capsules with the skin or mucous membranes should be avoided. If such contact occurs, wash thoroughly ... . Personnel should avoid exposure to crushed and/or broken capsules.
US Natl Inst Health; DailyMed. Current Medication Information for ZOLINZA (vorinostat) capsule (October 2010). Available from, as of July 11, 2011: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=cd86ee78-2781-468b-930c-3c4677bcc092
/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
For more Preventive Measures (Complete) data for Vorinostat (20 total), please visit the HSDB record page.

10.3 Handling and Storage

10.3.1 Storage Conditions

Store at 20-25 °C (68-77 °F), excursions permitted between 15-30 °C (59-86 °F).
US Natl Inst Health; DailyMed. Current Medication Information for ZOLINZA (vorinostat) capsule (October 2010). Available from, as of July 11, 2011: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=cd86ee78-2781-468b-930c-3c4677bcc092

10.4 Exposure Control and Personal Protection

10.4.1 Personal Protective Equipment (PPE)

/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

10.5 Transport Information

10.5.1 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

10.6 Regulatory Information

10.6.1 FDA Requirements

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including vorinostat, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.
DHHS/FDA; Electronic Orange Book-Approved Drug Products with Therapeutic Equivalence Evaluations. Available from, as of June 27, 2011: https://www.accessdata.fda.gov/scripts/cder/ob/docs/queryai.cfm

11 Toxicity

11.1 Toxicological Information

11.1.1 Hepatotoxicity

In clinical trials of vorinostat in patients with CTCL, the rates of serum enzyme elevations during therapy were rarely mentioned and only occasional episodes of mild elevations were recorded. Minor elevations in serum ALT levels occurred in 15% to 45% of patients, but values above 5 times ULN were rare and there were no reports of hepatitis, jaundice or clinically apparent liver injury among the treated subjects. Vorinostat has had limited clinical use, but there have been no published reports of its association with significant liver injury.

Likelihood score: E (unlikely cause of clinically apparent liver injury).

11.1.2 Drug Induced Liver Injury

Compound
vorinostat
DILI Annotation
No-DILI-Concern
Label Section
No match
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

11.1.3 Interactions

Vorinostat is not expected to affect the pharmacokinetics of other agents. As vorinostat is not eliminated via the CYP pathways, it is anticipated that vorinostat will not be subject to drug-drug interactions when co-administered with drugs that are known CYP inhibitors or inducers. However, no formal clinical studies have been conducted to evaluate drug interactions with vorinostat.
US Natl Inst Health; DailyMed. Current Medication Information for ZOLINZA (vorinostat) capsule (October 2010). Available from, as of July 11, 2011: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=cd86ee78-2781-468b-930c-3c4677bcc092
Potential prolongation of prothrombin time (PT) or international normalized ratio (INR) in patients receiving vorinostat concomitantly with coumarin-derivative antiacoagulants. PT and INR should be carefully monitored.
American Society of Health-System Pharmacists 2011; Drug Information 2011. Bethesda, MD. 2011, p. 1276
Potential severe thrombocytopenia and GI bleeding in patients receiving vorinostat concomitantly with other histone deacetylase (HDAC) inhibitors (eg, valproic acid). Platelet count should be monitored every 2 weeks for the first 2 months.
American Society of Health-System Pharmacists 2011; Drug Information 2011. Bethesda, MD. 2011, p. 1276
Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, has been shown to inhibit the development of N-methylnitrosourea (NMU)-induced rat mammary tumors when fed in the diet continuously for the duration of the carcinogenic process. The present study was designed to determine whether the inhibitory effects of SAHA occur during the initiation process or at subsequent stages in the carcinogenic process. In addition, animals with established NMU tumors were administered SAHA to determine whether SAHA could inhibit the continued growth of established mammary tumors. It was found that SAHA fed at 900 ppm in the diet inhibited tumor yields when administered from 14 days prior to NMU administration to termination (-14 to +130) and from +14 and +28 days to termination. However, SAHA had no effect on tumor yields when administered from -14 to +14 or from -14 to +50 days and then returned to the control diets for the remainder of the experimental period (130 days). These results indicate that the inhibitory effects of SAHA are not exerted at the initiation phase of NMU-induced mammary tumorigenesis and appear, instead, to inhibit the subsequent stages in tumor development. Of most interest was the ability of SAHA to inhibit the growth of established mammary tumors. Administration of SAHA in the diet at 900 ppm resulted in significant inhibition of established tumor growth. Thirty-two percent of SAHA-treated tumors exhibited partial regression compared to 12% of controls, growth was stabilized in 24% of treated tumors compared to 12% of controls while 11% exhibited complete regression compared to 0% of controls. Collectively, SAHA-treated tumors exhibited a 7-fold reduction in growth compared to untreated tumors over the test period. ...
Cohen LA et al; Anticancer Res 22 (3): 1497-504 (2002)

11.1.4 Antidote and Emergency Treatment

No specific information is available on the treatment of overdosage of vorinostat. In the event of overdose, it is reasonable to employ the usual supportive measures, e.g., ... employ clinical monitoring, and institute supportive therapy, if required. It is not known if vorinostat is dialyzable.
US Natl Inst Health; DailyMed. Current Medication Information for ZOLINZA (vorinostat) capsule (October 2010). Available from, as of July 11, 2011: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=cd86ee78-2781-468b-930c-3c4677bcc092
/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160
/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160
/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160-1

11.1.5 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

11.1.6 Human Toxicity Excerpts

/SIGNS AND SYMPTOMS/ /Patients should recognize the/ risk of deep-vein thrombosis and pulmonary embolism. Importance of notifying a clinician immediately if sudden swelling in leg, leg pain or tenderness, increased warmth in area of swelling, skin redness, skin color change, sudden sharp chest pain, shortness of breath, cough with bloody secretions, sweating, rapid pulse, fainting, or anxiety occurs.
American Society of Health-System Pharmacists 2011; Drug Information 2011. Bethesda, MD. 2011, p. 1276
/ALTERNATIVE and IN VITRO TESTS/ High interindividual pharmacokinetic variability was observed in phase 1 studies of vorinostat (suberoylanilide hydroxamic acid), an oral histone deacetylase inhibitor. Thus, /investigators/ hypothesized that the variability can be explained by genetic variants of the uridine 5'-diphosphate-glucuronosyltransferases (UGTs) involved in vorinostat metabolism. Baculosomes expressing human UGTs and 52 human liver microsomes were screened for vorinostat glucuronidation activity to identify the potential enzymes and functional variants. UGT2B17 had the largest activity. Human liver microsomes with at least one copy of UGT2B17 showed significantly greater enzymatic activity than those with UGT2B17 null genotype (P<0.004). UGT2B17 plays an important role in vorinostat hepatic glucuronidation and the gene deletion polymorphism may influence vorinostat biotransformation and clearance. The clinical impact of this UGT2B17 genetic variant on vorinostat metabolism and drug effect is unknown.
Kang SP et al; Pharmacogenet Genomics 20 (10): 638-41 (2010)

11.1.7 Non-Human Toxicity Excerpts

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Effects on the female reproductive system were identified in the oral fertility study when females were dosed for 14 days prior to mating through gestational day 7. Doses of 15, 50 and 150 mg/kg/day to rats resulted in approximate exposures of 0.15, 0.36 and 0.70 times the expected clinical exposure based on AUC. Dose dependent increases in corpora lutea were noted at >/=15 mg/kg/day, which resulted in increased peri-implantation losses were noted at >/=50 mg/kg/day. At 150 mg/kg/day, there were increases in the incidences of dead fetuses and in resorptions.
US Natl Inst Health; DailyMed. Current Medication Information for ZOLINZA (vorinostat) capsule (October 2010). Available from, as of July 11, 2011: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=cd86ee78-2781-468b-930c-3c4677bcc092
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ No effects on reproductive performance were observed in male rats dosed (20, 50, 150 mg/kg/day; approximate exposures of 0.15, 0.36 and 0.70 times the expected clinical exposure based on AUC), for 70 days prior to mating with untreated females.
US Natl Inst Health; DailyMed. Current Medication Information for ZOLINZA (vorinostat) capsule (October 2010). Available from, as of July 11, 2011: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=cd86ee78-2781-468b-930c-3c4677bcc092
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Doses up to 50 and 150 mg/kg/day were tested in rats and rabbits, respectively (~0.5 times the human exposure based on AUC0-24 hours). Treatment-related developmental effects including decreased mean live fetal weights, incomplete ossifications of the skull, thoracic vertebra, sternebra, and skeletal variations (cervical ribs, supernumerary ribs, vertebral count and sacral arch variations) in rats at the highest dose of vorinostat tested. Reductions in mean live fetal weight and an elevated incidence of incomplete ossification of the metacarpals were seen in rabbits dosed at 150 mg/kg/day. The no observed effect levels (NOELs) for these findings were 15 and 50 mg/kg/day (<0.1 times the human exposure based on AUC) in rats and rabbits, respectively. A dose-related increase in the incidence of malformations of the gall bladder was noted in all drug treatment groups in rabbits versus the concurrent control.
US Natl Inst Health; DailyMed. Current Medication Information for ZOLINZA (vorinostat) capsule (October 2010). Available from, as of July 11, 2011: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=cd86ee78-2781-468b-930c-3c4677bcc092
/GENOTOXICITY/ Vorinostat was mutagenic in vitro in the bacterial reverse mutation assays (Ames test), caused chromosomal aberrations in vitro in Chinese hamster ovary (CHO) cells and increased the incidence of micro-nucleated erythrocytes when administered to mice (Mouse Micronucleus Assay).
US Natl Inst Health; DailyMed. Current Medication Information for ZOLINZA (vorinostat) capsule (October 2010). Available from, as of July 11, 2011: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=cd86ee78-2781-468b-930c-3c4677bcc092
/ALTERNATIVE and IN VITRO TESTS/ This study was conducted to evaluate cytotoxicity due to co-treatment with low-dose Mitomycin-C (MMC) and the histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA) for glaucoma filtration surgery. In this study, the effect of co-treatment with MMC and SAHA to induce apoptosis in cultured conjunctival epithelial cells (CEs) in rabbit was investigated. The cytotoxic potential following co-treatment with MMC and SAHA in CEs via assay for reactive oxygen species (ROS) and lactate dehydrogenase (LDH) was also examined. Co-treatment with MMC and SAHA did not induce apoptosis in CEs. In addition, co-treatment with MMC and SAHA caused no significant alteration of ROS and LDH levels in CEs. This study therefore shows that low-dose MMC could still be used as an antimetabolite in co-treatment with SAHA to effectively inhibit fibrosis of Tenon's capsule fibroblasts (TCFs) following glaucoma filtration surgery, while minimizing cytotoxicity in CEs.
Kim TH et al; Arch Pharm Res 33 (8): 1261-7 (2010)

11.1.8 Populations at Special Risk

Of the total number of patients with CTCL in trials (N=107), 46 percent were 65 years of age and over, while 15 percent were 75 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
US Natl Inst Health; DailyMed. Current Medication Information for ZOLINZA (vorinostat) capsule (October 2010). Available from, as of July 11, 2011: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=cd86ee78-2781-468b-930c-3c4677bcc092
/Patients should recognize the/ importance of informing clinicians if they are or plan to become pregnant or plan to breast-feed. Advise pregnant women of risk to the fetus.
American Society of Health-System Pharmacists 2011; Drug Information 2011. Bethesda, MD. 2011, p. 1276
Vorinostat has not been studied in patients with hepatic impairment. Since the drug is extensively metabolized, it should be used with caution in patients with hepatic impairment.
American Society of Health-System Pharmacists 2011; Drug Information 2011. Bethesda, MD. 2011, p. 1276

11.1.9 Protein Binding

71%

12 Associated Disorders and Diseases

13 Literature

13.1 Consolidated References

13.2 NLM Curated PubMed Citations

13.3 Springer Nature References

13.4 Thieme References

13.5 Wiley References

13.6 Nature Journal References

13.7 Chemical Co-Occurrences in Literature

13.8 Chemical-Gene Co-Occurrences in Literature

13.9 Chemical-Disease Co-Occurrences in Literature

14 Patents

14.1 Depositor-Supplied Patent Identifiers

14.2 WIPO PATENTSCOPE

14.3 FDA Orange Book Patents

14.4 Chemical Co-Occurrences in Patents

14.5 Chemical-Disease Co-Occurrences in Patents

14.6 Chemical-Gene Co-Occurrences in Patents

15 Interactions and Pathways

15.1 Protein Bound 3D Structures

15.1.1 Ligands from Protein Bound 3D Structures

PDBe Ligand Code
PDBe Structure Code
PDBe Conformer

15.2 Chemical-Target Interactions

15.3 Drug-Drug Interactions

15.4 Drug-Food Interactions

Take with food.

16 Biological Test Results

16.1 BioAssay Results

17 Taxonomy

The LOTUS Initiative for Open Natural Products Research: frozen dataset union wikidata (with metadata) | DOI:10.5281/zenodo.5794106

18 Classification

18.1 MeSH Tree

18.2 NCI Thesaurus Tree

18.3 ChEBI Ontology

18.4 KEGG: Drug

18.5 KEGG: USP

18.6 KEGG: ATC

18.7 KEGG: Target-based Classification of Drugs

18.8 KEGG: Drug Groups

18.9 WHO ATC Classification System

18.10 FDA Pharm Classes

18.11 ChemIDplus

18.12 IUPHAR / BPS Guide to PHARMACOLOGY Target Classification

18.13 ChEMBL Target Tree

18.14 UN GHS Classification

18.15 NORMAN Suspect List Exchange Classification

18.16 EPA DSSTox Classification

18.17 LOTUS Tree

18.18 FDA Drug Type and Pharmacologic Classification

18.19 MolGenie Organic Chemistry Ontology

19 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. ChEMBL
    LICENSE
    Access to the web interface of ChEMBL is made under the EBI's Terms of Use (http://www.ebi.ac.uk/Information/termsofuse.html). The ChEMBL data is made available on a Creative Commons Attribution-Share Alike 3.0 Unported License (http://creativecommons.org/licenses/by-sa/3.0/).
    http://www.ebi.ac.uk/Information/termsofuse.html
  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. CAS Common Chemistry
    LICENSE
    The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated.
    https://creativecommons.org/licenses/by-nc/4.0/
  9. ChemIDplus
    ChemIDplus Chemical Information Classification
    https://pubchem.ncbi.nlm.nih.gov/source/ChemIDplus
  10. DTP/NCI
    LICENSE
    Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the source.
    https://www.cancer.gov/policies/copyright-reuse
  11. EPA DSSTox
    CompTox Chemicals Dashboard Chemical Lists
    https://comptox.epa.gov/dashboard/chemical-lists/
  12. European Chemicals Agency (ECHA)
    LICENSE
    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
  13. FDA Global Substance Registration System (GSRS)
    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
  14. Hazardous Substances Data Bank (HSDB)
  15. Human Metabolome Database (HMDB)
    LICENSE
    HMDB 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 (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications.
    http://www.hmdb.ca/citing
  16. ChEBI
  17. Drug Database, Clinicalinfo.hiv.gov
    LICENSE
    Unless otherwise noted, material presented on the HIV.gov website is considered Federal government information and is in the public domain. That means this information may be freely copied and distributed. We request that you use appropriate attribution to HIV.gov.
    https://www.hiv.gov/about-us/mission-and-team
  18. 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
  19. LiverTox
  20. LOTUS - the natural products occurrence database
    LICENSE
    The code for LOTUS is released under the GNU General Public License v3.0.
    https://lotus.nprod.net/
  21. NCI Thesaurus (NCIt)
    LICENSE
    Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the source.
    https://www.cancer.gov/policies/copyright-reuse
  22. Open Targets
    LICENSE
    Datasets generated by the Open Targets Platform are freely available for download.
    https://platform-docs.opentargets.org/licence
  23. ClinicalTrials.gov
    LICENSE
    The ClinicalTrials.gov data carry an international copyright outside the United States and its Territories or Possessions. Some ClinicalTrials.gov data may be subject to the copyright of third parties; you should consult these entities for any additional terms of use.
    https://clinicaltrials.gov/ct2/about-site/terms-conditions#Use
  24. Crystallography Open Database (COD)
    LICENSE
    All data in the COD and the database itself are dedicated to the public domain and licensed under the CC0 License. Users of the data should acknowledge the original authors of the structural data.
    https://creativecommons.org/publicdomain/zero/1.0/
  25. The Cambridge Structural Database
  26. DailyMed
  27. Drug Induced Liver Injury Rank (DILIrank) Dataset
    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
  28. European Medicines Agency (EMA)
    LICENSE
    Information on the European Medicines Agency's (EMA) website is subject to a disclaimer and copyright and limited reproduction notices.
    https://www.ema.europa.eu/en/about-us/legal-notice
  29. Drugs@FDA
    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
  30. EU Clinical Trials Register
  31. FDA Orange Book
    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
  32. National Drug Code (NDC) Directory
    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
  33. NIST Mass Spectrometry Data Center
    LICENSE
    Data covered by the Standard Reference Data Act of 1968 as amended.
    https://www.nist.gov/srd/public-law
    Suberoylanilide hydroxamic acid
    http://www.nist.gov/srd/nist1a.cfm
  34. Japan Chemical Substance Dictionary (Nikkaji)
  35. KEGG
    LICENSE
    Academic users may freely use the KEGG website. Non-academic use of KEGG generally requires a commercial license
    https://www.kegg.jp/kegg/legal.html
    Therapeutic category of drugs in Japan
    http://www.genome.jp/kegg-bin/get_htext?br08301.keg
    Anatomical Therapeutic Chemical (ATC) classification
    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
  36. Natural Product Activity and Species Source (NPASS)
  37. MassBank Europe
  38. Metabolomics Workbench
  39. Nature Chemical Biology
  40. NCI Cancer Drugs
  41. NIPH Clinical Trials Search of Japan
  42. NLM RxNorm Terminology
    LICENSE
    The RxNorm Terminology is created by the National Library of Medicine (NLM) and is in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from NLM. Credit to the U.S. National Library of Medicine as the source is appreciated but not required. The full RxNorm dataset requires a free license.
    https://www.nlm.nih.gov/research/umls/rxnorm/docs/termsofservice.html
  43. NORMAN Suspect List Exchange
    LICENSE
    Data: CC-BY 4.0; Code (hosted by ECI, LCSB): Artistic-2.0
    https://creativecommons.org/licenses/by/4.0/
    Vorinostat
    NORMAN Suspect List Exchange Classification
    https://www.norman-network.com/nds/SLE/
  44. PharmGKB
    LICENSE
    PharmGKB data are subject to the Creative Commons Attribution-ShareALike 4.0 license (https://creativecommons.org/licenses/by-sa/4.0/).
    https://www.pharmgkb.org/page/policies
  45. Pharos
    LICENSE
    Data accessed from Pharos and TCRD is publicly available from the primary sources listed above. Please respect their individual licenses regarding proper use and redistribution.
    https://pharos.nih.gov/about
  46. Protein Data Bank in Europe (PDBe)
  47. RCSB Protein Data Bank (RCSB PDB)
    LICENSE
    Data files contained in the PDB archive (ftp://ftp.wwpdb.org) are free of all copyright restrictions and made fully and freely available for both non-commercial and commercial use. Users of the data should attribute the original authors of that structural data.
    https://www.rcsb.org/pages/policies
  48. Springer Nature
  49. Thieme Chemistry
    LICENSE
    The Thieme Chemistry contribution within PubChem is provided under a CC-BY-NC-ND 4.0 license, unless otherwise stated.
    https://creativecommons.org/licenses/by-nc-nd/4.0/
  50. WHO Anatomical Therapeutic Chemical (ATC) Classification
    LICENSE
    Use of all or parts of the material requires reference to the WHO Collaborating Centre for Drug Statistics Methodology. Copying and distribution for commercial purposes is not allowed. Changing or manipulating the material is not allowed.
    https://www.whocc.no/copyright_disclaimer/
  51. Wikidata
  52. Wikipedia
  53. Wiley
  54. Medical Subject Headings (MeSH)
    LICENSE
    Works produced by the U.S. government are not subject to copyright protection in the United States. Any such works found on National Library of Medicine (NLM) Web sites may be freely used or reproduced without permission in the U.S.
    https://www.nlm.nih.gov/copyright.html
    Histone Deacetylase Inhibitors
    https://www.ncbi.nlm.nih.gov/mesh/68056572
  55. PubChem
  56. GHS Classification (UNECE)
  57. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  58. PATENTSCOPE (WIPO)
  59. NCBI
CONTENTS