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Valproic Acid

PubChem CID
3121
Structure
Valproic Acid_small.png
Valproic Acid_3D_Structure.png
Molecular Formula
Synonyms
  • VALPROIC ACID
  • 2-Propylpentanoic acid
  • 99-66-1
  • 2-Propylvaleric acid
  • Dipropylacetic acid
Molecular Weight
144.21 g/mol
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Dates
  • Create:
    2005-03-25
  • Modify:
    2025-01-18
Description
Valproate (Valproic acid) can cause developmental toxicity according to an independent committee of scientific and health experts.
Valproic acid is a clear colorless liquid. (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.
Valproic acid is a branched-chain saturated fatty acid that comprises of a propyl substituent on a pentanoic acid stem. It has a role as an anticonvulsant, a GABA agent, an EC 3.5.1.98 (histone deacetylase) inhibitor, a teratogenic agent, a psychotropic drug, a neuroprotective agent and an antimanic drug. It is a branched-chain saturated fatty acid and a branched-chain fatty acid. It is functionally related to a valeric acid. It is a conjugate acid of a valproate.
See also: Valproate Sodium (has salt form); Divalproex Sodium (active moiety of); Magnesium Valproate (has salt form) ... View More ...

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Valproic Acid.png

1.2 3D Conformer

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

2-propylpentanoic acid
Computed by Lexichem TK 2.7.0 (PubChem release 2021.10.14)

2.1.2 InChI

InChI=1S/C8H16O2/c1-3-5-7(6-4-2)8(9)10/h7H,3-6H2,1-2H3,(H,9,10)
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.3 InChIKey

NIJJYAXOARWZEE-UHFFFAOYSA-N
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.4 SMILES

CCCC(CCC)C(=O)O
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

2.2 Molecular Formula

C8H16O2
Computed by PubChem 2.2 (PubChem release 2021.10.14)

2.3 Other Identifiers

2.3.1 CAS

99-66-1

2.3.3 European Community (EC) Number

2.3.4 UNII

2.3.5 ChEBI ID

2.3.6 ChEMBL ID

2.3.7 DrugBank ID

2.3.8 DSSTox Substance ID

2.3.9 HMDB ID

2.3.10 KEGG ID

2.3.11 Lipid Maps ID (LM_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

  • 2 Propylpentanoic Acid
  • 2-Propylpentanoic Acid
  • Calcium Valproate
  • Convulsofin
  • Depakene
  • Depakine
  • Depakote
  • Dipropyl Acetate
  • Divalproex
  • Divalproex Sodium
  • Ergenyl
  • Magnesium Valproate
  • Propylisopropylacetic Acid
  • Semisodium Valproate
  • Sodium Valproate
  • Valproate
  • Valproate Calcium
  • Valproate Sodium
  • Valproic Acid
  • Valproic Acid, Sodium Salt (2:1)
  • Vupral

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
144.21 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
XLogP3
Property Value
2.8
Reference
Computed by XLogP3 3.0 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Donor Count
Property Value
1
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Acceptor Count
Property Value
2
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Rotatable Bond Count
Property Value
5
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Exact Mass
Property Value
144.115029749 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Monoisotopic Mass
Property Value
144.115029749 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Topological Polar Surface Area
Property Value
37.3 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Heavy Atom Count
Property Value
10
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
93.4
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
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

Valproic acid is a clear colorless liquid. (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.
Liquid

3.2.2 Color / Form

Colorless liquid
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 3087

3.2.3 Odor

Characteristic odor
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1839

3.2.4 Boiling Point

428 °F at 760 mmHg (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.
222
ChemIDplus
219.5 °C
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1839
BP: 219 to 220 °C
Kubitschke J et al; Carboxylic acids, aliphatic. Ullmann's Encyclopedia of Industrial Chemistry. 7th ed. (1999-2014). New York, NY: John Wiley & Sons. Online Posting Date: 30 May 2014
222 °C

3.2.5 Flash Point

232 °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.

3.2.6 Solubility

less than 1 mg/mL at 72 °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.
1.3 mg/mL
FDA label (2006)
In water, 2.0X10+3 mg/L at 20 °C
Kubitschke J et al; Carboxylic acids, aliphatic. Ullmann's Encyclopedia of Industrial Chemistry. 7th ed. (1999-2014). New York, NY: John Wiley & Sons. Online Posting Date: 30 May 2014
Very soluble in organic solvents
Physicians Desk Reference 61st ed, Thomson PDR, Montvale, NJ 2007., p. 417
Freely soluble in 1N sodium hydroxide, methanol, alcohol, acetone, chloroform, benzene, ether, n-heptane; slightly soluble in 0.1 N hydrochloric acid
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1839
2 mg/mL at 20 °C

3.2.7 Density

0.922 at 32 °F (NTP, 1992) - Less dense than water; will float
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.
0.904 g/cu cm at 25 °C
Haynes, W.M. (ed.). CRC Handbook of Chemistry and Physics. 94th Edition. CRC Press LLC, Boca Raton: FL 2013-2014, p. 3-470

3.2.8 LogP

2.75
ChemIDplus
log Kow = 2.75
Sangster J; LOGKOW Databank. A databank of evaluated octanol-water partition coefficients (Log P) on microcomputer diskette. Montreal, Quebec, Canada: Sangster Research Laboratories (1993)
2.75
SANGSTER (1993)

3.2.9 LogS

-1.86
ADME Research, USCD

3.2.10 Decomposition

When heated to decomposition it emits acrid smoke and irritating fumes.
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 3087

3.2.11 Refractive Index

Index of refraction = 1.425 at 24.5 °C/D
Haynes, W.M. (ed.). CRC Handbook of Chemistry and Physics. 94th Edition. CRC Press LLC, Boca Raton: FL 2013-2014, p. 3-470

3.2.12 Dissociation Constants

pKa
4.8
FDA label (2006)
pKa = 4.6
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1839
White, odorless, crystalline, deliquescent powder. pKa 4.8. Hygroscopic. One gram is soluble in 0.4 mL water; 1.5 mL ethanol; 5 mL methanol. Practically insoluble in common organic solvents /Valproic acid sodium salt (1:1)/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1839

3.2.13 Collision Cross Section

126.73 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

130.67 Ų [M+Na]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

Ross et al. JASMS 2022; 33; 1061-1072. DOI:10.1021/jasms.2c00111

3.2.14 Kovats Retention Index

Standard non-polar
1098.8 , 1084 , 1084
Semi-standard non-polar
1116

3.3 SpringerMaterials Properties

3.4 Chemical Classes

3.4.1 Drugs

Pharmaceuticals -> unsed in Switzerland 2014-2016
S113 | SWISSPHARMA24 | 2024 Swiss Pharmaceutical List with Metabolites | DOI:10.5281/zenodo.10501043
Pharmaceuticals
S10 | SWISSPHARMA | Pharmaceutical List with Consumption Data | DOI:10.5281/zenodo.2623484
Pharmaceuticals -> NSAIDs
S56 | UOATARGPHARMA | Target Pharmaceutical/Drug List from University of Athens | DOI:10.5281/zenodo.3248837
Pharmaceuticals -> Listed in ZINC15
S55 | ZINC15PHARMA | Pharmaceuticals from ZINC15 | DOI:10.5281/zenodo.3247749
3.4.1.1 Human Drugs
Breast Feeding; Lactation; Milk, Human; Anticonvulsants; Antimanic Agents; GABA Agents
Human drug -> Prescription; Discontinued; Active ingredient (VALPROIC ACID)
Human drug -> Discontinued
Pharmaceuticals
S72 | NTUPHTW | Pharmaceutically Active Substances from National Taiwan University | DOI:10.5281/zenodo.3955664

3.4.2 Endocrine Disruptors

Potential endocrine disrupting compound
S109 | PARCEDC | List of 7074 potential endocrine disrupting compounds (EDCs) by PARC T4.2 | DOI:10.5281/zenodo.10944198

3.4.3 Lipids

Fatty Acyls [FA] -> Fatty Acids and Conjugates [FA01] -> Branched fatty acids [FA0102]

4 Spectral Information

4.1 1D NMR Spectra

1D NMR Spectra

4.1.1 1H NMR Spectra

1 of 3
View All
Spectra ID
Instrument Type
Varian
Frequency
500 MHz
Solvent
Water
pH
7.00
Shifts [ppm]:Intensity
1.46:2.27, 1.24:26.40, 1.42:5.38, 1.43:3.99, 1.44:5.58, 2.20:3.99, 2.19:1.94, 1.26:26.96, 1.35:10.42, 1.40:6.15, 1.43:4.77, 1.31:4.08, 1.32:4.41, 0.86:100.00, 1.40:6.85, 1.21:3.12, 1.38:3.88, 1.41:3.73, 1.32:3.46, 1.36:4.10, 2.25:1.77, 1.34:6.68, 1.33:8.15, 1.42:6.04, 0.85:44.95, 1.33:2.23, 1.27:15.93, 2.21:5.34, 1.44:2.40, 1.28:4.56, 2.23:5.27, 1.42:7.22, 1.34:2.41, 1.23:13.57, 1.41:5.28, 1.40:6.28, 1.38:5.95, 2.24:3.84, 2.22:7.76, 1.36:9.04, 0.88:52.43
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2 of 3
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Spectra ID
Instrument Type
JEOL
Frequency
90 MHz
Solvent
CDCl3
Shifts [ppm]:Intensity
2.48:38.00, 2.33:67.00, 0.87:292.00, 2.45:36.00, 2.40:67.00, 2.44:43.00, 1.64:59.00, 1.34:246.00, 1.24:162.00, 0.83:247.00, 2.37:44.00, 1.28:112.00, 2.46:35.00, 2.43:44.00, 1.53:307.00, 2.39:67.00, 1.65:55.00, 2.25:32.00, 1.67:61.00, 0.99:485.00, 1.41:270.00, 2.35:50.00, 1.37:333.00, 0.94:300.00, 0.85:201.00, 1.03:61.00, 1.66:55.00, 11.67:77.00, 0.92:1000.00, 1.57:104.00, 1.49:288.00, 0.98:466.00, 0.81:129.00, 1.44:237.00, 1.55:170.00, 1.16:69.00, 1.20:65.00, 2.46:36.00, 1.35:265.00, 1.26:90.00, 1.47:395.00, 1.15:61.00, 1.25:91.00, 1.46:386.00, 1.42:391.00, 1.73:60.00, 2.47:34.00, 1.62:197.00, 1.04:59.00, 2.42:57.00, 1.31:198.00, 1.52:238.00, 1.45:359.00, 1.69:88.00, 2.36:49.00
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4.1.2 13C NMR Spectra

1 of 2
Spectra ID
Instrument Type
Varian
Frequency
25.16 MHz
Solvent
CDCl3
Shifts [ppm]:Intensity
13.99:843.00, 34.42:956.00, 183.51:515.00, 20.61:1000.00, 45.24:544.00
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2 of 2
Source of Spectrum
Sigma-Aldrich Co. LLC.
Source of Sample
Sigma-Aldrich Co. LLC.
Catalog Number
224251
Copyright
Copyright © 2021-2024 Sigma-Aldrich Co. LLC. - Database Compilation Copyright © 2021 John Wiley & Sons, Inc. All Rights Reserved.
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4.2 2D NMR Spectra

4.2.1 1H-13C NMR Spectra

2D NMR Spectra Type
1H-13C HSQC
Spectra ID
Instrument Type
Bruker
Frequency
600 MHz
Solvent
Water
pH
7.00
Shifts [ppm] (F2:F1):Intensity
1.35:37.90:0.56, 0.84:16.17:0.66, 1.41:37.90:0.47, 2.22:51.45:0.50, 0.89:16.17:0.70, 1.24:23.24:1.00
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4.3 Mass Spectrometry

4.3.1 GC-MS

1 of 6
View All
NIST Number
343602
Library
Main library
Total Peaks
54
m/z Top Peak
73
m/z 2nd Highest
102
m/z 3rd Highest
41
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2 of 6
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NIST Number
334915
Library
Replicate library
Total Peaks
46
m/z Top Peak
73
m/z 2nd Highest
102
m/z 3rd Highest
41
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4.3.2 MS-MS

1 of 6
View All
Spectra ID
Ionization Mode
Negative
Top 5 Peaks
143.10843 100
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2 of 6
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Spectra ID
Ionization Mode
Positive
Top 5 Peaks

71.04924 100

43.05433 79.70

145.12223 63.50

117.09079 41.10

69.07008 30.70

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4.3.3 LC-MS

1 of 10
View All
Authors
Kakazu Y, Horai H, Institute for Advanced Biosciences, Keio Univ.
Instrument
API3000, Applied Biosystems
Instrument Type
LC-ESI-QQ
MS Level
MS2
Ionization Mode
NEGATIVE
Collision Energy
10 V
Precursor m/z
143
Precursor Adduct
[M-H]-
Top 5 Peaks

143.3 999

96.8 11

70.8 6

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License
CC BY-NC-SA
2 of 10
View All
Authors
Kakazu Y, Horai H, Institute for Advanced Biosciences, Keio Univ.
Instrument
API3000, Applied Biosystems
Instrument Type
LC-ESI-QQ
MS Level
MS2
Ionization Mode
NEGATIVE
Collision Energy
20 V
Precursor m/z
143
Precursor Adduct
[M-H]-
Top 5 Peaks
96.6 999
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License
CC BY-NC-SA

4.4 IR Spectra

4.4.1 FTIR Spectra

1 of 2
Technique
CAPILLARY CELL: NEAT
Source of Sample
Research Organic/Inorganic Corporation, Sun Valley, California
Copyright
Copyright © 1980, 1981-2024 John Wiley & Sons, Inc. All Rights Reserved.
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2 of 2
Technique
Neat
Source of Spectrum
Sigma-Aldrich Co. LLC.
Source of Sample
Aldrich
Catalog Number
224251
Copyright
Copyright © 2018-2024 Sigma-Aldrich Co. LLC. - Database Compilation Copyright © 2018-2024 John Wiley & Sons, Inc. All Rights Reserved.
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4.4.2 ATR-IR Spectra

1 of 2
Instrument Name
Bio-Rad FTS
Technique
ATR-Film (MeCl2) (DuraSamplIR II)
Source of Spectrum
Forensic Spectral Research
Source of Sample
Sigma-Aldrich Inc.
Catalog Number
Free acid of P4543
Lot Number
Free acid of 39K1652
Copyright
Copyright © 2012-2024 John Wiley & Sons, Inc. All Rights Reserved.
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2 of 2
Source of Sample
Aldrich
Catalog Number
224251
Copyright
Copyright © 2018-2024 Sigma-Aldrich Co. LLC. - Database Compilation Copyright © 2018-2024 John Wiley & Sons, Inc. All Rights Reserved.
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4.4.3 Vapor Phase IR Spectra

Source of Spectrum
Sigma-Aldrich Co. LLC.
Source of Sample
Sigma-Aldrich Co. LLC.
Catalog Number
224251
Copyright
Copyright © 2021-2024 Sigma-Aldrich Co. LLC. - Database Compilation Copyright © 2021 John Wiley & Sons, Inc. All Rights Reserved.
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4.5 Raman Spectra

Catalog Number
224251
Copyright
Copyright © 2017-2024 Sigma-Aldrich Co. LLC. - Database Compilation Copyright © 2017-2024 John Wiley & Sons, Inc. All Rights Reserved.
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6 Chemical Vendors

7 Drug and Medication Information

7.1 Drug Indication

**Indicated** for: 1) Use as monotherapy or adjunctive therapy in the management of complex partial seizures and simple or complex absence seizures. 2) Adjunctive therapy in the management of multiple seizure types that include absence seizures. 3) Prophylaxis of migraine headaches. 4) Acute management of mania associated with bipolar disorder. **Off-label** uses include: 1) Maintenance therapy for bipolar disorder. 2) Treatment for acute bipolar depression. 3) Emergency treatment of status epilepticus.

7.2 LiverTox Summary

Valproate or valproic acid is a branched chain organic acid that is used as therapy of epilepsy, bipolar disorders and migraine headaches and is a well known cause of several distinctive forms of acute and chronic liver injury.

7.3 Drug Classes

Breast Feeding; Lactation; Milk, Human; Anticonvulsants; Antimanic Agents; GABA Agents
Anticonvulsants

7.4 FDA Medication Guides

1 of 2
Drug
Active Ingredient
VALPROIC ACID
Form;Route
CAPSULE;ORAL
Company
ABBVIE
Date
5/19/20
Drug
Active Ingredient
VALPROIC ACID
Form;Route
SYRUP;ORAL
Company
ABBVIE
Date
5/19/20
2 of 2
Drug
Active Ingredient
VALPROIC ACID
Form;Route
CAPSULE, DELAYED RELEASE;ORAL
Company
BIONPHARMA INC
Date
11/30/21

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 Clinical Trials

7.9.1 ClinicalTrials.gov

7.9.2 EU Clinical Trials Register

7.9.3 NIPH Clinical Trials Search of Japan

7.10 Therapeutic Uses

/EXP THER/ Emerging evidence suggests that adenomyosis, like endometriosis, may also be an epigenetic disease. In this study, we evaluated the effect of valproic acid (VPA) in ICR mice with adenomyosis, induced by neonatal dosing with tamoxifen. For all mice, we evaluated the bodyweight and the response to thermal stimuli by hotplate and tail-flick tests 4, 8, and 12 weeks after dosing, respectively, and then treated mice with low- and high-dose of VPA, progesterone (P4), P4 + VPA, or vehicle only. Three weeks after treatment, both bodyweight and thermal response tests were evaluated again before sacrifice, and the depth of myometrial infiltration was evaluated. We found that: (i) the induction of adenomyosis resulted in progressive generalized hyperalgesia as measured by hotplate and tail-flick tests, along with decreased bodyweight; (ii) treatment with VPA, P4, or a combination was efficacious in improving generalized hyperalgesia; and (iii) drug treatment appeared to reduce the myometrial infiltration, but the difference did not reach statistical significance. Thus, VPA seems to be a promising therapeutics for treating adenomyosis, as reported recently in some case series in humans.
Liu X and Guo SW; J Obstet Gynaecol Res 37 (7): 696-708 (2011)
/EXP THER/ Purpose: 5-Azacytidine (5-AZA) is a DNA-hypomethylating agent. Valproic acid is a histone deacetylase inhibitor. Combining hypomethylating agents and histone deacetylase inhibitors produces synergistic anticancer activity in vitro and in vivo. On the basis of this evidence, /this study/ conducted a phase I study of the combination of 5-AZA and valproic acid in patients with advanced cancers. Experimental Design: 5-AZA was administered s.c. daily for 10 days. Valproic acid was given orally daily with a goal to titrate to plasma levels of 75 to 100 mug/mL (therapeutic for seizures). Cycles were 28 days long. 5-AZA was started at 20 mg/m(2) and escalated using an adaptive algorithm based on the toxicity profile in the prior cohort (6 + 6 design). Peripheral blood mononuclear cell global DNA methylation and histone H3 acetylation were estimated with the long interspersed nucleotide elements pyrosequencing assay and Western blots, respectively, on days 1 and 10 of each cycle when patients agreed to provide them. Results: Fifty-five patients were enrolled. Median age was 60 years (range, 12-77 years). The maximum tolerated dose was 75 mg/m(2) of 5-AZA in combination with valproic acid. Dose-limiting toxicities were neutropenic fever and thrombocytopenia, which occurred at a dose of 94 mg/m(2) of 5-AZA. Stable disease lasting 4 to 12 months (median, 6 months) was observed in 14 patients (25%). A significant decrease in global DNA methylation and induction of histone acetylation were observed. Conclusion: The combination of 5-AZA and valproic acid is safe at doses up to 75 mg/m(2) for 5-AZA in patients with advanced malignancies.
Braiteh F et al; Clin Cancer Res 14 (19): 6296-301 (2008)
/EXP THER/ Amphetamine (AMPH)-induced hyper-locomotion has been well manifested in an animal model of psychiatric diseases such as drug addiction and bipolar disorder. /This study/ investigated the effects on AMPH-induced locomotor activity of chronically microinjected valproic acid into the nucleus accumbens (NAcc). Rats with guide cannular implanted bilaterally were divided into three groups and either saline or valproic acid (100 or 300 ug/0.5 uL/side) was microinjected into the NAcc once daily for 7 days. On day 8, half of each group received either saline or AMPH (1mg/kg, i.p.), respectively, and locomotor activity was measured for 2 hr. The increases of both horizontal locomotion and rearing by AMPH were attenuated in the rat pre-treated with valproic acid compared to saline in a dose-dependent manner. These results indicate that neuronal modifications in the NAcc induced by chronic valproic acid can modulate amphetamine-induced locomotor activity.
Kim WY et al; Neurosci Lett 432 (1): 54-7 (2008)
/EXP THER/ Purpose: Non-small-cell lung cancer (NSCLC) accounts for the majority of lung cancer and is the most common cause of cancer death in industrialized countries. Epigenetic modifications are observed universally during the tumorigenesis of lung cancer. The development of epigenetic-modulating agents utilizing the synergism between hypomethylating agents and histone deacetylase (HDAC) inhibitors provides a novel therapeutic approach in treating NSCLC. Methods: /This study/ performed a phase I trial combining 5-aza-2'-deoxycytidine (decitabine) and valproic acid (VPA), in patients with advanced stage NSCLC. Patients were treated with escalating doses of decitabine (5-15 mg/sq m) IV for 10 days in combination with VPA (10-20 mg/kg/day) PO on days 5-21 of a 28-day cycle. Pharmacokinetic and pharmacodynamic analysis included decitabine pharmacokinetics and fetal hemoglobin expression. Results: Eight patients were accrued to this phase I study. All patients had advanced NSCLC and had received prior chemotherapy. Eastern Cooperative Oncology Group performance status was 0-2. Major toxicities included myelosuppression and neurotoxicity. Dose-limiting toxicity was seen in two patients suffering grade 3 neurotoxicity during cycle one including disorientation, lethargy, memory loss, and ataxia at dose level 1. One patient had grade 3 neutropenia at the de-escalated dose. No objective response was observed, and stable disease was seen in one patient. Fetal hemoglobin levels increased after cycle one in all seven patients with evaluable results. Conclusions: /This study/ observed that decitabine and valproic acid are an effective combination in reactivating hypermethylated genes as demonstrated by re-expressing fetal hemoglobin. This combination in patients with advanced stage IV NSCLC, however, is limited by unacceptable neurological toxicity at a relatively low dosage. Combining hypomethylating agents with alternative HDAC inhibitors that lack the toxicity of VPA should be explored further.
Chu BF et al; Cancer Chemother Pharmacol 71 (1): 115-21 (2013)
For more Therapeutic Uses (Complete) data for VALPROIC ACID (8 total), please visit the HSDB record page.

7.11 Drug Warnings

/BOXED WARNING/ WARNING: LIFE THREATENING ADVERSE REACTIONS. Hepatotoxicity: General Population: Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months. Children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease. When Depakene products are used in this patient group, they should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. The incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute liver failure and resultant deaths in patients with hereditary neurometabolic syndromes caused by DNA mutations of the mitochondrial DNA Polymerase gamma (POLG) gene (e.g. Alpers Huttenlocher Syndrome). Depakene is contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorder. In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, Depakene should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with Depakene for the development of acute liver injury with regular clinical assessments and serum liver testing. POLG mutation screening should be performed in accordance with current clinical practice. Fetal Risk: Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida). In addition, valproate can cause decreased IQ scores following in utero exposure. Valproate should only be used to treat pregnant women with epilepsy if other medications have failed to control their symptoms or are otherwise unacceptable. Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective contraception while using valproate. Pancreatitis: Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Cases have been reported shortly after initial use as well as after several years of use. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated.
NIH; DailyMed. Current Medication Information for DEPAKENE- valproic acid capsule, liquid filled (Updated: March 2015). Available from, as of April 24, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6b4331f5-4475-417a-6a9d-09c2f8334235
Because of these changes in valproate clearance, monitoring of valproate and concomitant drug concentrations should be increased whenever enzyme inducing drugs are introduced or withdrawn.
NIH; DailyMed. Current Medication Information for DEPAKENE- valproic acid capsule, liquid filled (Revised: July 2014). Available from, as of November 20, 2014: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6b4331f5-4475-417a-6a9d-09c2f8334235
Since valproate may interact with concurrently administered drugs which are capable of enzyme induction, periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the early course of therapy.
NIH; DailyMed. Current Medication Information for DEPAKENE- valproic acid capsule, liquid filled (Revised: July 2014). Available from, as of November 20, 2014: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6b4331f5-4475-417a-6a9d-09c2f8334235
Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false interpretation of the urine ketone test.
NIH; DailyMed. Current Medication Information for DEPAKENE- valproic acid capsule, liquid filled (Revised: July 2014). Available from, as of November 20, 2014: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6b4331f5-4475-417a-6a9d-09c2f8334235
For more Drug Warnings (Complete) data for VALPROIC ACID (58 total), please visit the HSDB record page.

7.12 Reported Fatal Dose

The lowest published fatal dose is 15 g (750 mg/kg) in a 20 month old child, but adult patients have survived after ingestions of 75 g.
OLSON, K.R. (Ed). Poisoning and Drug Overdose, Sixth Edition. McGraw-Hill, New York, NY 2012, p. 394

8 Pharmacology and Biochemistry

8.1 Pharmacodynamics

Valproate has been shown to reduce the incidence of complex partial seizures and migraine headaches. It also improves symptom control in bipolar mania. Although the exact mechanisms responsible are unknown, it is thought that valproate produces increased cortical inhibition to contribute to control of neural synchrony. It is also thought that valproate exerts a neuroprotective effect preventing damage and neural degeneration in epilepsy, migraines, and bipolar disorder. Valproate is hepatotoxic and teratogenic. The reasons for this are unclear but have been attributed to the genomic effects of the drug. A small proof-of concept study found that valproate increases clearance of human immunodeficiency virus (HIV) when combined with highly active antiretroviral therapy (HAART) by reactivating the virus to allow clearance, however, a larger multicentre trial failed to show a significant effect on HIV reservoirs when added to HAART. The FDA labeling contains a warning regarding HIV reactivation during valproate use..

8.2 MeSH Pharmacological Classification

Enzyme Inhibitors
Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. (See all compounds classified as Enzyme Inhibitors.)
Antimanic Agents
Agents that are used to treat bipolar disorders or mania associated with other affective disorders. (See all compounds classified as Antimanic Agents.)
Anticonvulsants
Drugs used to prevent SEIZURES or reduce their severity. (See all compounds classified as Anticonvulsants.)
GABA Agents
Substances used for their pharmacological actions on GABAergic systems. GABAergic agents include agonists, antagonists, degradation or uptake inhibitors, depleters, precursors, and modulators of receptor function. (See all compounds classified as GABA Agents.)

8.3 FDA Pharmacological Classification

1 of 2
FDA UNII
614OI1Z5WI
Active Moiety
VALPROIC ACID
Pharmacological Classes
Established Pharmacologic Class [EPC] - Anti-epileptic Agent
Pharmacological Classes
Physiologic Effects [PE] - Decreased Central Nervous System Disorganized Electrical Activity
Pharmacological Classes
Established Pharmacologic Class [EPC] - Mood Stabilizer
FDA Pharmacology Summary
Valproic acid is an Anti-epileptic Agent and Mood Stabilizer. The physiologic effect of valproic acid is by means of Decreased Central Nervous System Disorganized Electrical Activity.
2 of 2
Non-Proprietary Name
VALPROIC ACID
Pharmacological Classes
Anti-epileptic Agent [EPC]; Mood Stabilizer [EPC]; Decreased Central Nervous System Disorganized Electrical Activity [PE]

8.4 ATC Code

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

N - Nervous system

N03 - Antiepileptics

N03A - Antiepileptics

N03AG - Fatty acid derivatives

N03AG01 - Valproic acid

8.5 Absorption, Distribution and Excretion

Absorption
The intravenous and oral forms of valproic acid are expected to produce the same AUC, Cmax, and Cmin at steady-state. The oral delayed-release tablet formulation has a Tmax of 4 hours. Differences in absorption rate are expected from other formulations but are not considered to be clinically important in the context of chronic therapy beyond impacting frequency of dosing. Differences in absorption may create earlier Tmax or higher Cmax values on initiation of therapy and may be affected differently by meals. The extended release tablet formulation had Tmax increase from 4 hours to 8 hours when taken with food. In comparison, the sprinkle capsule formulation had Tmax increase from 3.3 hours to 4.8 hours. Bioavailability is reported to be approximately 90% with all oral formulations with enteric-coated forms possibly reaching 100%.
Route of Elimination
Most drug is eliminated through hepatic metabolism, about 30-50%. The other major contributing pathway is mitochondrial β-oxidation, about 40%. Other oxidative pathways make up an additional 15-20%. Less than 3% is excreted unchanged in the urine.
Volume of Distribution
11 L/1.73m<sup>2</sup>.
Clearance
0.56 L/hr/m<sup>2</sup> Pediatric patients between 3 months and 10 years of age have 50% higher clearances by weight. Pediatric patients 10 years of age or older approximate adult values.
Valproic acid and its salt, sodium valproate, are excreted into human milk in low concentrations. Milk concentrations up to 15% of the corresponding level in the mother's serum have been measured. In two infants, serum levels of valporate were 1.5% and 6.0% of maternal values.
Briggs, G.G., Freeman, R.K., Yaffee, S.J.; Drugs in Pregancy and Lactation Nineth Edition. Wolters Kluwer/Lippincott Williams & Wilkins, Philadelphia, PA. 2011, p. 1543
Placenta transfer study in non-human primate (NHP) is one of the crucial components in the assessment of developmental toxicity because of the similarity between NHP and humans. To establish the method to determine placenta transfer in non-human primate, toxicokinetics of valproic acid (VPA), a drug used to treat epilepsy in pregnant women, were determined in pregnant cynomolgus monkeys. After mating, pregnancy-proven females were daily administered with VPA at dose levels of 0, 20, 60 and 180 mg/kg by oral route during the organogenesis period from gestation day (GD) 20 to 50. Concentrations of VPA and its metabolite, 4-ene-VPA, in maternal plasma on GDs 20 and 50, and concentrations of VPA and 4-ene-VPA in placenta, amniotic fluid and fetus on GD 50 were analyzed using LC/MS/MS. Following single oral administration of VPA to pregnant monkeys, concentrations of VPA and 4-ene-VPA were generally quantifiable in the plasma from all treatment groups up to 4-24 hours post-dose, demonstrating that VPA was absorbed and the monkeys were systemically exposed to VPA and 4-ene-VPA. After repeated administration of VPA to the monkeys, VPA was detected in amniotic fluid, placenta and fetus from all treatment groups, demonstrating that VPA was transferred via placenta and the fetus was exposed to VPA, and the exposures were increased with increasing dose. Concentrations of 4-ene-VPA in amniotic fluid and fetus were below the limit of quantification, but small amount of 4-ene-VPA was detected in placenta. In conclusion, pregnant monkeys were exposed to VPA and 4-ene-VPA after oral administration of VPA at dose levels of 20, 60 and 180 mg/kg during the organogenesis period. VPA was transferred via placenta and the fetus was exposed to VPA with dose-dependent exposure. The metabolite, 4-ene VPA, was not detected in both amniotic fluid and fetus, but small amount of 4-ene-VPA was detected in placenta. These results demonstrated that proper procedures to investigate placenta transfer in NHP, such as mating and diagnosis of pregnancy via examining gestational sac with ultrasonography, collection of amniotic fluid, placenta and fetus after Caesarean section followed by adequate bioanalysis and toxicokinetic analysis, were established in this study using cynomolugus monkeys.
Jeong EJ et al; Toxicol Res 26 (4): 275-83 (2010)
Valproic acid - rapid absorption from GI tract; slight delay when taken with food. Protein binding is high (90 to 95%) at serum concentrations up to 50 ug/mL. As the concentration increases from 50 to 100 ug/mL, the percentage bound decreases to 80 to 85% and the free fraction becomes progressively larger, thus increasing the concentration gradient into the brain.
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 2854
Valproate is distributed into breast milk. Concentrations in breast milk have been reported to be 1 to 10% of the total maternal serum concentration. /Valproate/
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 2855
For more Absorption, Distribution and Excretion (Complete) data for VALPROIC ACID (8 total), please visit the HSDB record page.

8.6 Metabolism / Metabolites

Most drug is metabolized to glucuronide conjugates (30-50%) of the parent drug or of metabolites. Another large portion is metabolized through mitochondrial β-oxidation (40%). The remainder of metabolism (15-20%) occurs through oxidation, hydroxylation, and dehydrogenation at the ω, ω<sub>1</sub>, and ω<sub>2</sub> positions resulting in the formation of hydroxyls, ketones, carboxyls, a lactone metabolite, double bonds, and combinations.
The aim of this study was to investigate the relationship between hepatotoxicity, levels of glucuronide conjugates of valproic acid (VPA), and the toxic metabolites of VPA (4-ene VPA and 2,4-diene VPA). /The study/ also examined whether hepatotoxicity could be predicted by the urinary excretion levels of VPA and its toxic metabolites. VPA was administrated orally in rats in amounts ranging from 20 mg/kg to 500 mg/kg. Free and total (free plus glucuronide conjugated) VPA, 4-ene VPA, and 2,4-diene VPA were quantified in urine and liver using gas chromatography-mass spectrometry. Serum levels of aspartate aminotransferase, alanine aminotransferase, and alpha-glutathione S-transferase (alpha-GST) were also determined to measure the level of hepatotoxicity. The serum alpha-GST level increased slightly at the 20 mg/kg dose, and substantially increased at the 100 and 500 mg/kg dose; aspartate aminotransferase and alanine aminotransferase levels did not change with the administration of increasing doses of VPA. The liver concentration of free 4-ene VPA and the urinary excretion of total 4-ene VPA were the only measures that correlated with the increase in the serum alpha-GST level (p < 0.094 and p < 0.023 respectively). From these results, /it is concluded/ that hepatotoxicity of VPA correlates with liver concentration of 4-ene VPA and can be predicted by the urinary excretion of total 4-ene VPA.
Lee MS et al; Arch Pharm Res 32 (7): 1029-35 (2009)
BACKGROUND AND OBJECTIVE: Sodium valproate is a widely prescribed broad-spectrum antiepileptic drug. It shows high inter-individual variability in pharmacokinetics and pharmacodynamics and has a narrow therapeutic range. /This study/ evaluated the effects of polymorphic uridine diphosphate glucuronosyltransferase (UGT)1A6 (541A>G, 552A>C) metabolizing enzyme on the pharmacokinetics of sodium valproate in the patients with epilepsy who showed toxicity to therapy. METHODS: Genotype analysis of the patients was made with polymerase chain-restriction fragment length polymorphism (RFLP) with sequencing. Plasma drug concentrations were measured with reversed phase high-performance liquid chromatography (HPLC) and concentration-time data were analyzed by using a non-compartmental approach. RESULTS: The results of this study suggested a significant genotypic as well as allelic association with valproic acid toxicity for UGT1A6 (541A>G) or UGT1A6 (552A>C) polymorphic enzymes. The elimination half-life (t 1/2 = 40.2 hr) of valproic acid was longer and the clearance rate (CL = 917 mL/hr) was lower in the poor metabolizers group of UGT1A6 (552A>C) polymorphism who showed toxicity than in the intermediate metabolizers group (t 1/2= 35.5 hr, CL = 1,022 mL/hr) or the extensive metabolizers group (t 1/2= 25.4 hr, CL = 1,404 mL/hr). CONCLUSION: /These/ findings suggest that the UGT1A6 (552A>C) genetic polymorphism plays a significant role in the steady state concentration of valproic acid, and it thereby has an impact on the toxicity of the valproic acid used in the patients with epilepsy.
Munisamy M et al; Mol Diagn Ther 17 (5): 319-26 (2013)
Biotransformation /of valproic acid/ is primarily hepatic. Some metabolites may have pharmacologic or toxic activity. Rate of metabolism is faster in children and in patients concurrently using enzyme-inducing medications, such as phenytoin, phenobarbital, primidone, and carbamazepine.
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 2854
Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30- 50% of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial -oxidation is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually, less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose is excreted unchanged in urine.
Physicians Desk Reference 61st ed, Thomson PDR, Montvale, NJ 2007., p. 418
Valproic acid has known human metabolites that include 4-ene-valproate, (2S,3S,4S,5R)-3,4,5-Trihydroxy-6-(2-propylpentanoyloxy)oxane-2-carboxylic acid, 5-Hydroxyvalproate, 4-Hydroxyvalproate, and 3-Hydroxyvalproate.
S73 | METXBIODB | Metabolite Reaction Database from BioTransformer | DOI:10.5281/zenodo.4056560
Valproic acid is rapidly absorbed from gastrointestinal tract. Valproic acid is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50% of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial oxidation is the other major metabolic pathway, typically accounting for over 40% of the dose. These products include 2-n-propylpent-2-enoic acid (delta 2,3 VPE) and several coenzyme A (CoA) derivatives including VPA-CoA, and delta 2,3 VPE-CoA. Usually, less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose is excreted unchanged in urine (A308). Half Life: 9-16 hours (following oral administration of 250 mg to 1000 mg).
A308: Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. PMID:18048412

8.7 Biological Half-Life

13-19 hours. The half-life in neonates ranges from 10-67 hours while the half-life in pediatric patients under 2 months of age ranges from 7-13 hours.
In children the half-life of valproic acid alone is 10 to 11 hours; when other medications are added, half-life may be reduced to 8 to 9 hours. Half-lives of up to 30 hours have been reported in overdosage.
International Programme on Chemical Safety (IPCS); Poisons Information Monograph: Valproic Acid (PIM 551) (1997) Available from, as of May 30, 2007: https://www.inchem.org/pages/pims.html
Variable, from 6 to 16 hours; may be considerably longer in patients with hepatic function impairment, in the elderly, and in children up to 18 months of age; may be considerably shorter in patients receiving hepatic enzyme-inducing anticonvulsants. In one study, the half life in children under 10 days ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children greater than 2 months.
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 2854

8.8 Mechanism of Action

The exact mechanisms by which valproate exerts it's effects on epilepsy, migraine headaches, and bipolar disorder are unknown however several pathways exist which may contribute to the drug's action. Valproate is known to inhibit succinic semialdehyde dehydrogenase. This inhibition results in an increase in succinic semialdehyde which acts as an inhibitor of GABA transaminase ultimately reducing GABA metabolism and increasing GABAergic neurotransmission. As GABA is an inhibitory neurotransmitter, this increase results in increased inhibitory activity. A possible secondary contributor to cortical inhibition is a direct suppression of voltage gated sodium channel activity and indirect suppression through effects on GABA. It has also been suggested that valproate impacts the extracellular signal-related kinase pathway (ERK). These effects appear to be dependent on mitogen-activated protein kinase (MEK) and result in the phosphorylation of ERK1/2. This activation increases expression of several downstream targets including ELK-1 with subsequent increases in c-fos, growth cone-associated protein-43 which contributes to neural plasticity, B-cell lymphoma/leukaemia-2 which is an anti-apoptotic protein, and brain-derived neurotrophic factor (BDNF) which is also involved in neural plasticity and growth. Increased neurogenesis and neurite growth due to valproate are attributed to the effects of this pathway. An additional downstream effect of increased BDNF expression appears to be an increase in GABAA receptors which contribute further to increased GABAergic activity. Valproate exerts a non-competitive indirect inhibitory effect on myo-inosital-1-phophate synthetase. This results in reduced de novo synthesis of inositol monophosphatase and subsequent inositol depletion. It is unknown how this contributed to valproate's effects on bipolar disorder but [lithium] is known to exert a similar inositol-depleting effect. Valproate exposure also appears to produce down-regulation of protein kinase C proteins (PKC)-α and -ε which are potentially related to bipolar disorder as PKC is unregulated in the frontal cortex of bipolar patients. This is further supported by a similar reduction in PKC with lithium. The inhibition of the PKC pathway may also be a contributor to migraine prophylaxis. Myristoylated alanine-rich C kinase substrate, a PKC substrate, is also downregulated by valproate and may contribute to changes in synaptic remodeling through effects on the cytoskeleton. Valproate also appears to impact fatty acid metabolism. Less incorporation of fatty acid substrates in sterols and glycerolipids is thought to impact membrane fluidity and result in increased action potential threshold potentially contributing to valproate's antiepileptic action. Valproate has been found to be a non-competitive direct inhibitor of brain microsomal long-chain fatty acyl-CoA synthetase. Inhibition of this enzyme decreases available arichidonyl-CoA, a substrate in the production of inflammatory prostaglandins. It is thought that this may be a mechanism behind valproate's efficacy in migraine prophylaxis as migraines are routinely treated with non-steroidal anti-inflammatory drugs which also inhibit prostaglandin production. Finally, valproate acts as a direct histone deactylase (HDAC) inhibitor. Hyperacetylation of lysine residues on histones promoted DNA relaxation and allows for increased gene transcription. The scope of valproate's genomic effects is wide with 461 genes being up or down-regulated. The relation of these genomic effects to therapeutic value is not fully characterized however H3 and H4 hyperacetylation correlates with improvement of symptoms in bipolar patients. Histone hyperacetylation at the BDNF gene, increasing BDNF expression, post-seizure is known to occur and is thought to be a neuroprotective mechanism which valproate may strengthen or prolong. H3 hyperacetylation is associated with a reduction in glyceraldehyde-3-phosphate dehydrogenase, a pro-apoptotic enzyme, contributing further to valproate's neuroprotective effects.
Valproic acid (VPA), a widely prescribed drug for seizures and bipolar disorder, has been shown to be an inhibitor of histone deacetylase (HDAC). /A/ previous study has demonstrated that VPA pretreatment reduces lipopolysaccharide (LPS)-induced dopaminergic (DA) neurotoxicity through the inhibition of microglia over-activation. The aim of this study was to determine the mechanism underlying VPA-induced attenuation of microglia over-activation using rodent primary neuron/glia or enriched glia cultures. Other histone deacetylase inhibitors (HDACIs) were compared with VPA for their effects on microglial activity. We found that VPA induced apoptosis of microglia cells in a time- and concentration-dependent manner. VPA-treated microglial cells showed typical apoptotic hallmarks including phosphatidylserine externalization, chromatin condensation and DNA fragmentation. Further studies revealed that trichostatin A (TSA) and sodium butyrate (SB), two structurally dissimilar HDACIs, also induced microglial apoptosis. The apoptosis of microglia was accompanied by the disruption of mitochondrial membrane potential and the enhancement of acetylation levels of the histone H3 protein. Moreover, pretreatment with SB or TSA caused a robust decrease in LPS-induced pro-inflammatory responses and protected DA neurons from damage in mesencephalic neuron-glia cultures. Taken together, /these/ results shed light on a novel mechanism whereby HDACIs induce neuroprotection and underscore the potential utility of HDACIs in preventing inflammation-related neurodegenerative disorders such as Parkinson's disease.
Chen PS et al; Neuroscience 149 (1): 203-12 (2007)
Several reports suggest putative interactions between valproic acid (VPA) treatment and the hypothalamus-pituitary-adrenal axis. Given that VPA alters mitochondrial functions, an action of this drug on a mitochondrial process such as steroid synthesis in adrenal cells should be expected. In order to disclose a putative action of VPA on the adrenocortical cell itself /this study/ evaluated VPA effects on regulatory steps of the acute stimulation of steroidogenesis in Y1 adrenocortical cells. This study demonstrates that VPA increases progesterone production in non-stimulated cells without inducing the levels of Steroidogenic Acute Regulatory (StAR) protein, which facilitates cholesterol transport. This result suggests that VPA increases mitochondrial cholesterol transport through a StAR-independent mechanism and is further supported by the fact that in isolated mitochondria VPA stimulates exogenous cholesterol metabolization to progesterone. VPA also reduces the cAMP-mediated increase of the StAR protein, mRNA levels, promoter activity and progesterone production. In summary, the present data show that VPA can alter steroid production in adrenal cells by a complex mechanism that mainly involves an action on cholesterol access to the inner mitochondrial membrane. The VPA-mediated increase of basal steroidogenesis could be linked to the increase of basal cortisolemia described in patients under VPA treatment.
Brion L et al; Toxicol In Vitro 25 (1): 7-12 (2011)
Although valproic acid (VPA) a proven anticonvulsant agent thought to have relatively few side-effects VPA has been referred as the third most common xenobiotic suspected of causing death due to liver injury. In this study the cellular pathways involved in VPA hepatotoxicity were investigated in isolated rat hepatocytes. Accelerated cytotoxicity mechanism screening (ACMS) techniques using fluorescent probes including, ortho-phthalaldehyde, rhodamine 123 and acridine orange were applied for measurement of ROS formation, glutathione depletion, mitochondrial membrane potential and Lysosomal membrane damage, respectively. /This studies/ results showed that cytotoxic action of VPA is mediated by lysosomal membrane leakiness along with reactive oxygen species (ROS) formation and decline of mitochondrial membrane potential before cell lysis ensued. Incubation of hepatocytes with VPA also caused rapid hepatocyte glutathione (GSH) depletion which is another marker of cellular oxidative stress. Most of the VPA induced GSH depletion could be attributed to the expulsion of GSSG. /These/ results also showed that CYP2EI is involved in the mechanism of VPA cytotoxicity. /It is concluded/ VPA hepatotoxicity is a result of metabolic activation by CYP2E1 and ROS formation, leading to lysosomal labialization, mitochondrial/lysosomal toxic cross-talk and finally general cellular proteolysis in the rat hepatocytes.
Pourahmad J et al; Toxicol In Vitro 26 (4): 545-51 (2012)
In utero exposure to valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, causes neural tube, heart, and limb defects. Valpromide (VPD), the amide derivative of VPA, does not inhibit HDAC activity and is a weak teratogen in vivo. The detailed mechanism of action of VPA as a teratogen is not known. The goal of this study was to test the hypothesis that VPA disrupts regulation of the expression of genes that are critical in chondrogenesis and osteogenesis during limb development. Murine gestation day-12 embryonic forelimbs were excised and exposed to VPA or VPD in a limb bud culture system. VPA caused a significant concentration- dependent increase in limb abnormalities, which was correlated with its HDAC inhibitory effect. The signaling of both Sox9 and Runx2, key regulators of chondrogenesis, was downregulated by VPA. In contrast, VPD had little effect on limb morphology and no significant effect on HDAC activity or the expression of marker genes. Thus, VPA exposure dysregulated the expression of target genes directly involved in chondrogenesis and osteogenesis in the developing limb. Disturbances in these signaling pathways are likely to be a consequence of HDAC inhibition because VPD did not affect their expressions.
Paradis FH and Hales BF. Toxicol Sci 131 (1): 234-41 (2013)
For more Mechanism of Action (Complete) data for VALPROIC ACID (15 total), please visit the HSDB record page.

8.9 Human Metabolite Information

8.9.1 Tissue Locations

  • Brain
  • Liver

8.9.2 Cellular Locations

  • Extracellular
  • Membrane

8.9.3 Metabolite Pathways

8.10 Biochemical Reactions

8.11 Transformations

9 Use and Manufacturing

9.1 Uses

EPA CPDat Chemical and Product Categories
The Chemical and Products Database, a resource for exposure-relevant data on chemicals in consumer products, Scientific Data, volume 5, Article number: 180125 (2018), DOI:10.1038/sdata.2018.125
Indicated as monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures that occur in either isolation or association with other types of seizures
Physicians Desk Reference 61st ed, Thomson PDR, Montvale, NJ 2007., p. 421
THERAPEUTIC CATEGORY (VETERINARY): Anticonvulsant
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1839
MEDICATION
Anticonvulsants; Antimanic Agents; Enzyme Inhibitors; GABA Agents
National Library of Medicine's Medical Subject Headings. Valproic Acid. Online file (MeSH, 2014). Available from, as of August 28, 2014: https://www.nlm.nih.gov/mesh/2014/mesh_browser/MBrowser.html

Use (kg) in Switzerland (2009): >7500

Use (kg; approx.) in Germany (2009): >75000

Use (kg; exact) in Germany (2009): 94896

Use (kg) in USA (2002): 229000

Use (kg) in France (2004): 112162

Consumption (g per capita) in Switzerland (2009): 0.96

Consumption (g per capita; approx.) in Germany (2009): 0.92

Consumption (g per capita; exact) in Germany (2009): 1.2

Consumption (g per capita) in the USA (2002): 0.81

Consumption (g per capita) in France (2004): 1.9

Excretion rate: 0.02

Calculated removal (%): 93.6

For treatment and management of seizure disorders, mania, and prophylactic treatment of migraine headache. In epileptics, valproic acid is used to control absence seizures, tonic-clonic seizures (grand mal), complex partial seizures, and the seizures associated with Lennox-Gastaut syndrome (A308).
A308: Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. PMID:18048412

9.1.1 Use Classification

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients
Pharmaceuticals
S72 | NTUPHTW | Pharmaceutically Active Substances from National Taiwan University | DOI:10.5281/zenodo.3955664

9.2 Methods of Manufacturing

Valproic acid may be synthesized from 4-heptanol by successive conversions to 4-bromoheptane with HBr, to 4-cyanoheptane with HCN and to 2-propyl pentanoic (valproic) acid by alkaline hydrolysis of the 4-cyanoheptane.
IPCS; Poisons Information Monograph No. 551, Valproic Acid (October 1997). Available from, as of November 13, 2014: https://www.inchem.org/pages/pims.html
Ethyl cyanoacetate + n-propyl bromide (dehydrobromination/decarboxylation/nitrile hydrolysis).
Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994., p. 937

9.3 Formulations / Preparations

Oral: Solution: 250 mg (of valproic acid) per 5 mL Depakene Syrup (with parabens), (Abbott). Parenteral: Injection, for IV use: 100 mg (of valproic acid) per mL Depacon (with edetate disodium), (Abbott), Valproate Sodium Injection (with edetate disodium), (Abraxis), Valproate Sodium Injection (with edetate disodium), (Bedford). /Valproate sodium/
McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 2262
Oral: Capsules, liquid-filled: 250 mg Depakene (with parabens), (Abbott).
McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 2262
Oral: Capsules (containing coated particles): equivalent to valproic acid 125 mg Depakote Sprinkle, (Abbott). Tablets, delayed-release: equivalent to valproic acid 125 mg Depakote (with povidone), (Abbott), equivalent to valproic acid 250 mg Depakote (with povidone), (Abbott), equivalent to valproic acid 500 mg Depakote (with povidone), (Abbott). Tablets, extended-release: equivalent to valproic acid 250 mg Depakote ER, (Abbott) equivalent to valproic acid 500 mg Depakote ER, (Abbott). /Divalproex sodium/
McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 2262

10 Identification

10.1 Analytic Laboratory Methods

Valproic acid (VPA; an anticonvulsant drug) therapy is associated with hepatotoxicity as well as renal toxicity. An LC-MS-based metabolomics approach was undertaken in order to detect urinary VPA metabolites and to discover early biomarkers of the adverse effects induced by VPA. RESULTS: CD-1 mice were either subcutaneously injected with 600-mg VPA/kg body weight or vehicle only, and urine samples were collected at 6, 12, 24 and 48 hr postinjection. A metabolomics approach combined with principal component analysis was utilized to identify VPA-related metabolites and altered endogenous metabolites in urine. Some VPA metabolites indicated potential liver toxicity caused by VPA administration. Additionally, some altered endogenous metabolites suggested that renal function might be perturbed by VPA dosing. CONCLUSION: LC-MS-based metabolomics is capable of rapidly profiling VPA drug metabolites and is a powerful tool for the discovery of potential early biomarkers related to perturbations in liver and kidney function.
Sun J et al; Bioanalysis 2 (2): 207-16 (2010)
Three different doses of valproic acid (20, 100, and 500 mg/kg/d) are administered orally to Sprague-Dawley rats for 5 days, and the feasibility of metabolomics with gas chromatography-mass spectrometry as a predictor of the hepatotoxicity of valproic acid is evaluated. Body weight is found to decrease with the 100-mg/kg/d dose and significantly decrease with the 500-mg/kg/d dose. Mean excreted urine volume is lowest in the 500-mg/kg/d group among all groups. The plasma level of alpha-glutathione-S-transferase, a sensitive and earlier biomarker for hepatotoxicity, increases significantly with administration of 100 and 500 mg/kg/d; however, there is not a significant difference in alpha-glutathione-S-transferase plasma levels between the control and 20-mg/kg/d groups. Clusters in partial least squares discriminant analysis score plots show similar patterns, with changes in physiological conditions and plasma levels of alpha-glutathione-S-transferase; the cluster for the control and 20-mg/kg/d groups does not clearly separate, but the clusters are separate for 100- and 500-mg/kg/d groups. A biomarker of hepatotoxicity, 8-hydroxy-2'-deoxyguanosine and octanoylcarnitine, is identified from nontargeted and targeted metabolic profiling. These results validate that metabolic profiling using gas chromatography-mass spectrometry could be a useful tool for finding novel biomarkers. Thus, a nontargeted metabolic profiling method is established to evaluate the hepatotoxicity of valproic acid and demonstrates proof-of-concept that metabolomic approach with gas chromatography-mass spectrometry has great potential for predicting valproic acid-induced hepatotoxicity and discovering novel biomarkers.
Lee MS et al; Int J Toxicol 28 (5): 392-404 (2009)
Analyte: valproic acid; matrix: chemical identification; procedure: infrared absorption spectrophotometry with comparison to standards
U.S. Pharmacopeia. The United States Pharmacopeia, USP 30/The National Formulary, NF 25; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p3442 (2007)
Analyte: valproic acid; matrix: chemical identification; procedure: retention time of the major peak of the gas chromatogram with comparison to standards
U.S. Pharmacopeia. The United States Pharmacopeia, USP 30/The National Formulary, NF 25; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p3442 (2007)
For more Analytic Laboratory Methods (Complete) data for VALPROIC ACID (9 total), please visit the HSDB record page.

10.2 Clinical Laboratory Methods

CLAB The development of in vitro testing strategies for chemical and drug screening is a priority need in order to protect human health, to increase safety, to reduce the number of animals required for conventional testing methods and finally to meet the deadlines of current legislations. The aim of this work was to design an alternative testing method based on human embryonic stem cells for the detection of prenatal neural toxicity. For this purpose ... a model based on the generation of neural rosettes /was created/, reproducing in vitro the gastrulation events recapitulating the formation of the neural tube in vivo. To validate the model ... this complex cell system /was exposed/ to increasing concentrations of valproic acid, a known teratogenic agent, to analyze the morphological and molecular changes induced by the toxicant. Specific assays were applied to discriminate between cytotoxicity and specific neural toxicity. Transcriptomic analysis was performed with a microarray Affimetrix platform and validated by quantitative real time RT-PCR for the expression of genes involved in early neural development, neural tube formation and neural cells migration, key biological processes in which the effect of valproic acid is most relevant. The results demonstrated that neural rosette cells respond to valproic acid exposure with molecular and morphological changes similar to those observed in vivo, indicating that this method represents a promising alternative test for the detection of human prenatal neural toxicity.
Colleoni S et al; Curr Med Chem 19 (35): 6065-71 (2012)
Liquid chromatography-MS/MS determination in plasma.
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1839

11 Safety and Hazards

11.1 Hazards Identification

11.1.1 GHS Classification

1 of 2
View All
Pictogram(s)
Corrosive
Irritant
Health Hazard
Signal
Danger
GHS Hazard Statements

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]

H315 (92.9%): Causes skin irritation [Warning Skin corrosion/irritation]

H318 (12.7%): Causes serious eye damage [Danger Serious eye damage/eye irritation]

H319 (80.2%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]

H335 (31.7%): May cause respiratory irritation [Warning Specific target organ toxicity, single exposure; Respiratory tract irritation]

H360 (64.3%): May damage fertility or the unborn child [Danger Reproductive toxicity]

Precautionary Statement Codes

P203, P261, P264, P264+P265, P270, P271, P280, P301+P317, P302+P352, P304+P340, P305+P351+P338, P305+P354+P338, P317, P318, P319, P321, P330, P332+P317, P337+P317, P362+P364, 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 126 reports by companies from 17 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

Acute Tox. 4 (100%)

Skin Irrit. 2 (92.9%)

Eye Dam. 1 (12.7%)

Eye Irrit. 2 (80.2%)

STOT SE 3 (31.7%)

Repr. 1A (64.3%)

Acute toxicity (Oral) - Category 4

Reproductive toxicity - Category 1A, Additional category: Effects on or via lactation

Specific target organ toxicity - Single exposure - Category 1 (central nervous system), Category 3 (narcotic effects)

Specific target organ toxicity - Repeated exposure - Category 1 (central nervous system, haemal system, liver)

11.1.3 Health Hazards

SYMPTOMS: Symptoms of exposure to this compound may include gastrointestinal disturbances, hair loss, psychosis, altered bleeding time, altered liver enzymes and fatal hepatic failure. Other symptoms may include central nervous system depression, nausea, vomiting, indigestion, diarrhea, abdominal cramps, constipation, anorexia with weight loss, increased appetite with weight gain, tremor, ataxia, headache, nystagmus, diplopia, asterixis, spots before the eyes, dysarthria, dizziness, incoordination, coma, skin rash, erythema multiforme, generalized pruritus, emotional upset, depression, hyperactivity, behavioral deterioration, weakness, thrombocytopenia, petechiae, bruising, hematoma formation, frank hemorrhage, relative lymphocytosis, hypofibrinogenemia, leukopenia, eosinophilia, anemia, bone marrow suppression, irregular menses, secondary amenorrhea and breast enlargement. Changes in exocrine pancreas and sleep disturbances may also occur. It may also cause somnolence.

ACUTE/CHRONIC HAZARDS: When heated to decomposition this compound may emit toxic fumes of carbon monoxide and carbon dioxide. (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.

11.1.4 Fire Hazards

This chemical is 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.

11.2 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 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.
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.

11.5 Handling and Storage

11.5.1 Nonfire Spill Response

SMALL SPILLS AND LEAKAGE: If you spill this chemical, FIRST REMOVE ALL SOURCES OF IGNITION. Then, use absorbent paper to pick up all liquid spill material. Your contaminated clothing and absorbent paper should be sealed in a vapor-tight plastic bag for eventual disposal. Solvent wash all contaminated surfaces with 60-70% ethanol followed by washing 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 store this chemical under ambient temperatures, and keep it away from oxidizing materials. (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

Store between 15 and 30 °C (59 and 86 °F), in a tight container. /Valproic Acid Capsules USP/
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 2860
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container. Protect from freezing. /Valproic Acid Syrup USP/
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 2860

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.

11.7 Stability and Reactivity

11.7.1 Air and Water Reactions

Insoluble in water.

11.7.2 Reactive Group

Acids, Carboxylic

11.7.3 Reactivity Profile

VALPROIC ACID is a carboxylic acid. Carboxylic acids donate hydrogen ions if a base is present to accept them. They react in this way with all bases, both organic (for example, the amines) and inorganic. Their reactions with bases, called "neutralizations", are accompanied by the evolution of substantial amounts of heat. Neutralization between an acid and a base produces water plus a salt. Carboxylic acids with six or fewer carbon atoms are freely or moderately soluble in water; those with more than six carbons are slightly soluble in water. Soluble carboxylic acid dissociate to an extent in water to yield hydrogen ions. The pH of solutions of carboxylic acids is therefore less than 7.0. Many insoluble carboxylic acids react rapidly with aqueous solutions containing a chemical base and dissolve as the neutralization generates a soluble salt. Carboxylic acids in aqueous solution and liquid or molten carboxylic acids can react with active metals to form gaseous hydrogen and a metal salt. Such reactions occur in principle for solid carboxylic acids as well, but are slow if the solid acid remains dry. Even "insoluble" carboxylic acids may absorb enough water from the air and dissolve sufficiently in it to corrode or dissolve iron, steel, and aluminum parts and containers. Carboxylic acids, like other acids, react with cyanide salts to generate gaseous hydrogen cyanide. The reaction is slower for dry, solid carboxylic acids. Insoluble carboxylic acids react with solutions of cyanides to cause the release of gaseous hydrogen cyanide. Flammable and/or toxic gases and heat are generated by the reaction of carboxylic acids with diazo compounds, dithiocarbamates, isocyanates, mercaptans, nitrides, and sulfides. Carboxylic acids, especially in aqueous solution, also react with sulfites, nitrites, thiosulfates (to give H2S and SO3), dithionites (SO2), to generate flammable and/or toxic gases and heat. Their reaction with carbonates and bicarbonates generates a harmless gas (carbon dioxide) but still heat. Like other organic compounds, carboxylic acids can be oxidized by strong oxidizing agents and reduced by strong reducing agents. These reactions generate heat. A wide variety of products is possible. Like other acids, carboxylic acids may initiate polymerization reactions; like other acids, they often catalyze (increase the rate of) chemical reactions. This chemical is incompatible with bases, oxidizing agents and reducing agents. It is corrosive. (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.

11.8 Regulatory Information

The Australian Inventory of Industrial Chemicals
Chemical: Pentanoic acid, 2-propyl-
California Safe Cosmetics Program (CSCP) Reportable Ingredient

Hazard Traits - Developmental Toxicity

Authoritative List - Prop 65

Report - regardless of intended function of ingredient in the product

REACH Registered Substance
New Zealand EPA Inventory of Chemical Status
2-Propylvaleric acid: Does not have an individual approval but may be used under an appropriate group standard

11.8.1 FDA Requirements

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including valproic acid, 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 November 12, 2014: https://www.fda.gov/cder/ob/

11.9 Other Safety Information

Chemical Assessment
Evaluation - Chemicals that are unlikely to require further regulation to manage risks to environment

11.9.1 Special Reports

Kitsiou-Tzeli S, et al; Acta Paed 83 (6): 672-3 (1994). Cytogenetic studies in children on long term treatment with anticonvulsant therapy.
Galas-Zgorzalewicz B, et al; Neurol Neurochir Pol 30 (2): 49-54 (1996). Clinical pharmacokinetics of carbamazepine and valproate in children and adolescents with epilepsy.
Levin TL, et al; Pediatr Radiol 27 (2): 192-3 (1997). Valproic acid associated pancreatitis and hepatic toxicity in children with endstage renal disease.

12 Toxicity

12.1 Toxicological Information

12.1.1 Toxicity Summary

IDENTIFICATION AND USE: Valproic acid is a colorless to pale yellow viscous liquid. Valproic acid is an antiepileptic drug and is used solely or in combination with other anticonvulsants in the treatment of simple (petit mal) and complex absence seizures. Valproic acid may be effective against myoclonic and atonic seizures in young children. HUMAN EXPOSURE AND TOXICITY: After oral administration, the drug is rapidly absorbed from the gastrointestinal tract and metabolized in the liver. Fatal hepatic failure has been reported in patients on valproic acid therapy, especially those on chronic use. Pancreatitis has also been reported in patients receiving normal therapeutic dosage. Reports showed that acute toxicity is rare, and usually follows a benign course. The most commonly reported adverse effects are anorexia, nausea and vomiting. Central nervous system effects include drowsiness, possibly apathy and withdrawal, confusion, restlessness, hyperactivity. Less frequently, seizures and coma may occur. Sedative effects are more pronounced when drug is used together with other anti-epileptic agents. Hematopoietic system effects include thrombocytopenia, abnormal bleeding time and partial thromboplastin time with decreased fibrinogen levels and prolonged prothrombin time leading to bruising, petechiae, hematoma, and epistaxis. The drug can induce pruritic macular rashes and transient alopecia. Altered thyroid functions was described. Death is rare but if it occurs it results from cardiopulmonary arrest secondary to hepatic failure. Safe use of valproic acid during pregnancy has not been established. Although several reports suggest an association between the use of valproic acid in pregnant epileptic women and an increased incidence of birth defects (particularly neural tube defects) in children born to these women, a causal relationship remains to be established. The drug crosses the placental barrier and has been found in breast milk. The mechanism of action of valproic acid is unknown. Effects of the drug may be related, at least in part, to increased brain concentrations of the inhibitory neurotransmitter GABA. ANIMAL STUDIES: Animal studies have shown that valproic acid inhibits GABA transferase and succinic aldehyde dehydrogenase, enzymes which are important for GABA catabolism. Results of one study indicate the drug inhibits neuronal activity by increasing potassium conductance. In animals, valproic acid protects against seizure induced by electrical stimulation, as well as those induced by pentylenetetrazol. In 2 year rat and chronic mouse studies, an increased incidence of subcutaneous fibrosarcoma occurred in male rats at the higher dosage level and a dose related trend for an increased incidence of benign pulmonary adenomas was observed in male mice. The importance of these findings to humans is not known. Adverse fetal effects have been observed in reproduction studies in rats and mice. Studies have not shown any evidence of mutagenic potential for the drug.
Valproic Acid binds to and inhibits GABA transaminase. This leads to increased brain concentrations of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter in the CNS. Acute poisoning by VPA can lead to severe CNS depression including coma, confusion, somnolence, dizziness or hallucinations. Hypotension, respiratory depression and hypo/hyperthermia are also common. VPA is also hepatotoxic, which is likely due to its mitochondrial toxicity. VPA appears to exert its mitochondrial toxicity by impairing mitochondrial functions leading to oxidative stress and cytochrome c expulsion, which leads to apoptosis (A15078). VPA is contraindicated in pregnancy due to its teratogenicity. VPA is a known folate antagonist, which can cause neural tube defects in developing fetuses. Thus, folic acid supplements in pregnant women may alleviate teratogenic problems associated with VPA use. VPA and its metabolites inhibit the biosynthesis of carnitine by decreasing the concentration of alpha-ketoglutarate (through direct inhibition of alpha-ketoglutarate dehydrogenase) and may contribute to carnitine deficiency. It is postulated that carnitine supplementation may increase the beta-oxidation of VPA, thereby limiting cytosolic omega-oxidation and the production of toxic metabolites that are involved in liver toxicity and ammonia accumulation. VPA-induced hepatotoxicity and hyperammonemic encephalopathy may be promoted either by a pre-existing carnitine deficiency or by deficiency induced by VPA per se. VPA has been shown to downregulate levels of superoxide dismutase (SOD), glutathione (GSH), histone deacetylase (HDAC) and folate. It has also been shown to upregulate H2O2 and homocysteine. Elevated levels of H2O2 negatively affect the NADPH reducing system for dihydrofolate reductase (DHFR) and methylene tetrahydrofolate reductase (MTHFR) (A15079).
A15078: Jafarian I, Eskandari MR, Mashayekhi V, Ahadpour M, Hosseini MJ: Toxicity of valproic acid in isolated rat liver mitochondria. Toxicol Mech Methods. 2013 Oct;23(8):617-23. doi: 10.3109/15376516.2013.821567. Epub 2013 Aug 1. PMID:23819490
A15079: Hsieh CL, Wang HE, Tsai WJ, Peng CC, Peng RY: Multiple point action mechanism of valproic acid-teratogenicity alleviated by folic acid, vitamin C, and N-acetylcysteine in chicken embryo model. Toxicology. 2012 Jan 27;291(1-3):32-42. doi: 10.1016/j.tox.2011.10.015. Epub 2011 Oct 25. PMID:22051200

12.1.2 Hepatotoxicity

Prospective studies suggest that 5% to 10% of persons develop ALT elevations during long term valproate therapy, but these abnormalities are usually asymptomatic and can resolve even with continuation of drug. Unlike phenytoin and carbamazepine, valproate does not induce elevations in serum GGT levels. More importantly and not uncommonly, valproate can cause several forms of clinically apparent hepatotoxicity. Indeed, more than 100 fatal cases of acute or chronic liver injury due to valproate have been reported in the literature. Three clinically distinguishable forms of hepatotoxicity (besides simple aminotransferase elevations) can occur with valproate.

The first syndrome is hyperammonemia with minimal or no evidence of hepatic injury. This syndrome typically presents with progressive and episodic confusion followed by obtundation and coma. The time to onset is often within a few weeks of starting valproate or increasing the dose, but it can present months or even years after starting the medication (Case 1). The diagnosis is made by the finding of elevations in serum ammonia with normal (or near normal) serum aminotransferase and bilirubin levels. Valproate levels are usually normal or minimally high. The syndrome resolves within a few days of stopping valproate, but may reverse more rapidly with carnitine supplementation or renal hemodialysis.

The second form of injury from valproate is an acute hepatocellular injury with jaundice, typically accompanied by hepatocellular or mixed pattern of enzyme elevations (Case 2). This acute liver injury pattern usually has its onset within 1 to 6 months of starting valproate. The pattern of serum enzyme elevations can be hepatocellular or mixed; sometimes the serum aminotransferase levels are not markedly elevated, despite the severity of injury.

Immunoallergic features (fever, rash, eosinophilia) are usually absent, but rare cases with prominent features of hypersensitivity have been reported (Case 3). Multiple instances of fatal acute hepatic failure due to valproate have been published and valproate is regularly listed as a cause of drug induced acute liver failure. Liver histology is distinctive and reveals a microvesicular steatosis with central lobular necrosis, mild to moderate inflammation and cholestasis. In cases with a prolonged course, fibrosis, bile duct proliferation and regenerative nodules may be present. Prospective studies using historical controls suggest that carnitine (particularly intravenously) may be beneficial if given soon after presentation.

The third form of hepatic injury due to valproate is a Reye-like syndrome described in children on valproate who develop fever and lethargy (suggestive of a viral infection) followed by confusion, stupor and coma, with raised ammonia levels and marked ALT elevations but normal or minimally elevated bilirubin levels. Metabolic acidosis is also common and the syndrome can be rapidly fatal. Valproate may simply be an aspirin-like agent capable of triggering Reye syndrome if it is being taken when the child develops either influenza or varicella infection.

All three forms of valproate hepatotoxicity have features of mitochondrial injury, and liver histology usually demonstrates microvesicular steatosis with variable amounts of inflammation and cholestasis. Young age (

Likelihood score: A (well known cause of several forms of clinically apparent liver injury).

12.1.3 Drug Induced Liver Injury

Compound
valproic acid
DILI Annotation
Most-DILI-Concern
Severity Grade
8
Label Section
Box warning
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 Health Effects

Valproic acid causes hyperammonemia, which can lead to brain damage. Rarely, it can cause blood dyscrasia, impaired liver function, jaundice, thrombocytopenia, and prolonged coagulation times. In about 5% of pregnant users, valproic acid will cross the placenta and cause congenital anomalies. Valproic acid may also cause acute hematological toxicities, especially in children, including rare reports of myelodysplasia and acute leukemia-like syndrome (L1132). May cause a potentially dangerous rash that may develop into Stevens Johnson syndrome, an extremely rare but potentially fatal skin disease. Acute overdoses of VPA can lead to hypo/hyperthermia, tachycardia, hypotension, respiratory depression, coma, confusion, somnolence, dizziness, headaches and cerebral edema. Extended use of VPA can cause hepatotoxicity. Allopecia, anorexia, renal failure, tremors and miosis are also associated with chronic toxicity. VPA is a known teratogen (due to folate antagonism). The teratogenicity of VPA is mostly found at genetic and somatic levels, causing teratogenesis involving neural tube defects (NTDs), anencephaly, lumbosacral meningomyelocele, and leg dysfunction due to spina bifida aperta.
L1132: Wikipedia. Valproic Acid. Last Updated 30 July 2009. http://en.wikipedia.org/wiki/Valproic_acid

12.1.6 Effects During Pregnancy and Lactation

◉ Summary of Use during Lactation

Valproic acid levels in breastmilk are low and infant serum levels range from undetectable to low. Breastfeeding during valproic acid monotherapy does not appear to adversely affect infant growth or development; however, and breastfed infants had higher IQs and enhanced verbal abilities than nonbreastfed infants at 6 years of age in one study. A safety scoring system finds valproic acid possible to use during breastfeeding, and a computer model predicted a relatively low infant exposure, consistent with literature reports. If valproic acid is required by the mother, it is not a reason to discontinue breastfeeding.

No definite adverse reactions to valproic acid in breastfed infants have been reported. Theoretically, breastfed infants are at risk for valproic acid-induced hepatotoxicity, so infants should be monitored for jaundice and other signs of liver damage during maternal therapy. A questionable case of thrombocytopenia has been reported, so monitor the infant for unusual bruising or bleeding. A rare case of infant baldness might have been caused by valproate in milk. Observe the infant for jaundice and unusual bruising or bleeding. Combination therapy with sedating anticonvulsants or psychotropics may result in infant sedation or withdrawal reactions.

◉ Effects in Breastfed Infants

A mother with epilepsy was taking valproic acid 2.4 grams daily and primidone 250 mg 3 times daily during pregnancy and postpartum. During the second week postpartum, her breastfed infant was sedated. Breastfeeding was stopped and the drowsiness cleared. The sedation was possibly caused by primidone in breastmilk although valproic acid might have contributed by increasing primidone levels.

Petechiae, thrombocytopenia, anemia, and mild hematuria occurred in a 2.5-month-old breastfed infant whose mother was taking valproic acid 600 mg twice daily. Blood hemoglobin and reticulocytes normalized between 12 and 19 days after discontinuing breastfeeding. The petechiae resolved 35 days after discontinuing breastfeeding and the infant's platelet count had almost reached the normal range by this time. By day 83, the infant's platelet count was well within the normal range. The authors believed the adverse effect to be caused by valproic acid in breastmilk. However, other authors believe that these symptoms were more likely caused by idiopathic thrombocytopenic purpura following a viral infection.

Two breastfed infants aged 1 and 3 months whose mothers were taking valproic acid monotherapy 750 and 500 mg daily developed normally and had no abnormal laboratory values. Their plasma levels were 6% and 1.5% or their mother's serum levels, respectively.

Six breastfed infants whose mothers were taking valproic acid 750 or 1000 mg daily had no adverse reactions to valproic acid in breastmilk.

An exclusively breastfed infants whose mother was taking valproate 1.8 g, topiramate 300 mg, and levetiracetam 2 g, daily during pregnancy and lactation appeared healthy to the investigators throughout the 6- to 8-week study period.

In a long-term study on infants exposed to anticonvulsants during breastfeeding, no difference in average intelligence quotient at 3 years of age was found between infants who were breastfed (n = 11) a median of 6 months and those not breastfed (n = 24) when their mothers were taking valproate monotherapy. At 6 years of age, extensive psychological and intelligence testing found that the breastfed infants had higher IQ values than the nonbreastfed infants.

A prospective cohort study in Norway followed infants of mothers who took antiepileptic drugs during pregnancy and lactation and compared them to infants of mothers with untreated epilepsy and infants with fathers who took antiepileptics as control groups. Of the 223 mothers studied, 27 were taking valproate monotherapy. Infants were assessed at 6, 18 and 36 months of age. Continuous breastfeeding in children of women using antiepileptic drugs was associated with no greater impaired development than those with no breastfeeding or breastfeeding for less than 6 months.

A woman with bipolar disorder who delivered twins and was taking sodium valproate in a therapeutic dosage was started on quetiapine 200 mg and olanzapine 15 mg at 11 pm daily after 20 days postpartum. She withheld breastfeeding during the night and discarded milk pumped at 7 am. She then breastfed her infants until 11 pm. The mother continued feeding the infants on this schedule for 15 months. Monthly follow-up of the infants indicated normal growth and neither the pediatricians nor the parents noted any adverse effects in the infants.

The 4-month-old breastfed infant of a mother taking divalproex for bipolar disorder developed patchy hair loss. The extent of nursing and dosage of divalproex were not stated. Divalproex was discontinued and 2 months later, the infant’s hair was normal. The hair loss was possibly caused by valproate.

◉ Effects on Lactation and Breastmilk

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

◉ Summary of Use during Lactation

Very little information is available on the clinical use of divalproex during breastfeeding. However, divalproex is rapidly metabolized in the body to the active drug valproic acid. Valproic acid levels in breastmilk are low and infant serum levels range from undetectable to low. Breastfeeding during valproic acid monotherapy does not appear to adversely affect infant growth or development, and breastfed infants had higher IQs and enhanced verbal abilities than nonbreastfed infants at 6 years of age in one study. A safety scoring system finds valproic acid possible to use during breastfeeding. If valproic acid is required by the mother, it is not necessarily a reason to discontinue breastfeeding.

No definite adverse reactions to valproic acid in breastfed infants have been reported. Theoretically, breastfed infants are at risk for valproic acid-induced hepatotoxicity, so infants should be monitored for jaundice and other signs of liver damage during maternal therapy. A questionable case of thrombocytopenia has been reported, so monitor the infant for unusual bruising or bleeding. A rare case of infant baldness might have been caused by valproate in milk. Observe the infant for jaundice and unusual bruising or bleeding. Combination therapy with sedating anticonvulsants or psychotropics may result in infant sedation or withdrawal reactions.

◉ Effects in Breastfed Infants

A mother with epilepsy was taking valproic acid 2.4 grams daily and primidone 250 mg 3 times daily during pregnancy and postpartum. During the second week postpartum, her breastfed infant was sedated. Breastfeeding was stopped and the drowsiness cleared. The sedation was possibly caused by primidone in breastmilk although valproic acid might have contributed by increasing primidone levels.

Petechiae, thrombocytopenia, anemia, and mild hematuria occurred in a 2.5-month-old breastfed infant whose mother was taking valproic acid 600 mg twice daily. Blood hemoglobin and reticulocytes normalized between 12 and 19 days after discontinuing breastfeeding. The petechiae resolved 35 days after discontinuing breastfeeding and the infant's platelet count had almost reached the normal range by this time. By day 83, the infant's platelet count was well within the normal range. The authors believed the adverse effect to be caused by valproic acid in breastmilk. However, other authors believe that these symptoms were more likely caused by idiopathic thrombocytopenic purpura following a viral infection.

Two breastfed infants aged 1 and 3 months whose mothers were taking valproic acid monotherapy 750 and 500 mg daily developed normally and had no abnormal laboratory values. Their plasma levels were 6% and 1.5% or their mother's serum levels, respectively.

Six breastfed infants whose mothers were taking valproic acid 750 or 1000 mg daily had no adverse reactions to valproic acid in breastmilk.

An exclusively breastfed infants whose mother was taking valproate 1.8 g, topiramate 300 mg, and levetiracetam 2 g, daily during pregnancy and lactation appeared healthy to the investigators throughout the 6- to 8-week study period.

In a long-term study on infants exposed to anticonvulsants during breastfeeding, no difference in average intelligence quotient at 3 years of age was found between infants who were breastfed (n = 11) a median of 6 months and those not breastfed (n = 24) when their mothers were taking valproate monotherapy. At 6 years of age, extensive psychological and intelligence testing found that the breastfed infants had higher IQ values than the nonbreastfed infants.

A prospective cohort study in Norway followed infants of mothers who took antiepileptic drugs during pregnancy and lactation and compared them to infants of mothers with untreated epilepsy and infants with fathers who took antiepileptics as control groups. Of the 223 mothers studied, 27 were taking valproate monotherapy. Infants were assessed at 6, 18 and 36 months of age. Continuous breastfeeding in children of women using antiepileptic drugs was associated with no greater impaired development than those with no breastfeeding or breastfeeding for less than 6 months.

A woman with bipolar disorder who delivered twins and was taking sodium valproate in a therapeutic dosage was started on quetiapine 200 mg and olanzapine 15 mg at 11 pm daily after 20 days postpartum. She withheld breastfeeding during the night and discarded milk pumped at 7 am. She then breastfed her infants until 11 pm. The mother continued feeding the infants on this schedule for 15 months. Monthly follow-up of the infants indicated normal growth and neither the pediatricians nor the parents noted any adverse effects in the infants.

The 4-month-old breastfed infant of a mother taking divalproex for bipolar disorder developed patchy hair loss. The extent of nursing and dosage of divalproex were not stated. Divalproex was discontinued and 2 months later, the infant’s hair was normal. The hair loss was possibly caused by valproate.

◉ Effects on Lactation and Breastmilk

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

◈ What is valproic acid?

Valproic acid is a medication that has been used to control seizures in the treatment of epilepsy, and to treat bipolar disorder and migraines. Valproic acid is sometimes also called sodium valproate or valproate sodium. Some brand names for valproic acid are Depakene®, Stavzor®, and Depacon®. A similar medication, divalproex (Depakote®), breaks down into valproic acid in the body.The Food and Drug Administration recommends that people who are pregnant do not take valproate sodium and related products, valproic acid and divalproex sodium to prevent migraine headaches. For epilepsy or bipolar disorder, valproate products should only be prescribed during pregnancy if other medications are not effective in treating the condition or cannot be used for another reason.Sometimes when people find out they are pregnant, they think about changing how they take their medication, or stopping their medication altogether. However, it is important to talk with your healthcare providers before making any changes to how you take your medication. Your healthcare providers can talk with you about the benefits of treating your condition and the risks of untreated illness during pregnancy.

◈ I am taking valproic acid, but I would like to stop taking it before getting pregnant. How long does the drug stay in my body?

People eliminate medications at different rates. In healthy adults, it takes 2-4 days, on average, for most of the valproic acid to be gone from the body.

◈ What might happen if I stopped taking my valproic acid and then had a seizure during my pregnancy?

Having a seizure while pregnant might be harmful to the fetus. Complications depend on many things, such as the type of seizure, how long the seizure lasts, and the number of seizures that happen. Epileptic seizures might cause periods of time when the fetus is not getting enough oxygen, which could lead to problems with development. These seizures could also be life-threatening for both the person who is pregnant and the fetus. A seizure could cause a person who is pregnant to fall or have an accident that could injure themselves or the fetus.

◈ What might happen if I stopped taking my valproic acid and then had a relapse of bipolar disorder during my pregnancy?

People who are pregnant and have bipolar disorder who stop taking their medication during pregnancy might have a higher chance for symptoms of depression or mania that could be harmful to both the person who is pregnant and the fetus. Episodes of depression or mania are very stressful for a person who is pregnant. During manic or depressive episodes, the person who is pregnant might have more trouble taking care of themselves and keeping themselves safe.

◈ I take valproic acid. Can it make it harder for me to get pregnant?

Some studies suggest that people on valproic acid might have a higher chance of developing polycystic ovary syndrome (PCOS), a condition associated with trouble getting pregnant. Studies have found that people with seizure disorders and people with bipolar disorder might have problems with their periods and trouble getting pregnant. This possible increase might be due to the conditions that the people have, rather than the use of medication.

◈ Does taking valproic acid increase the chance of miscarriage?

Miscarriage is common and can occur in any pregnancy for many different reasons. It is not known if valproic acid increases the chance of miscarriage.

◈ Does taking valproic acid increase the chance of birth defects?

Every pregnancy starts out with a 3-5% chance of having a birth defect. This is called the background risk. Studies have found that taking valproic acid in pregnancy is associated with a chance of having a baby with fetal valproate spectrum disorder which includes minor and major birth defects. Birth defects are typically classified as major if they need surgery to be repaired. Some of the birth defects that are more likely to happen include heart defects, cleft lip (when the lip does not form correctly and needs surgery to repair after birth), or neural tube defects (an opening in the baby’s spine or skull). Some babies exposed to valproic acid might also have more minor birth defects like facial differences, such as a thin upper lip. The chance of a birth defect seems to be greater with higher doses of valproic acid or with taking it with another seizure medication.The most common neural tube defect linked to valproic acid use is spina bifida (opening in the spine). The chance of a neural tube defect when taking valproic acid is approximately 1 in 50 to 1 in 100 (1-2%). Taking extra folic acid before trying to get pregnant and in early pregnancy might help lower the chance of some birth defects in pregnancies exposed to valproic acid. Talk to your healthcare provider about how much folic acid you should take. For more information on folic acid, please see the MotherToBaby fact sheet at: https://mothertobaby.org/fact-sheets/folic-acid/.

◈ Does taking valproic in pregnancy increase the chance of other pregnancy-related problems?

Valproic acid might increase the chance of low birth weight (weighing less than 5 pounds, 8 ounces [2500 grams] at birth). There have been reports of temporary low blood sugar levels (hypoglycemia) in newborns.

◈ Does taking valproic in pregnancy affect future behavior or learning for the child?

Prenatal exposure to valproic acid can increase the chance of problems with learning and development. Different studies have shown an increased chance of intellectual disability, developmental delay, autism spectrum disorder, other developmental disorders, attention deficit/hyperactivity disorder, attachment disorder, decreased language and memory skills, and decreased social and adaptive behavior skills. Not all studies have shown the same results. Some of the long-term problems in the exposed children might be due to how severe the seizure disorder is in the person who is pregnant.

◈ What screenings or tests are available to see if my pregnancy has birth defects or other issues?

There are ways to screen for neural tube defects in pregnancy. A blood test can be done to measure the amount of a protein called alpha fetoprotein (AFP) in the blood of the person who is pregnant. Babies with spina bifida have higher levels of AFP. If the AFP is higher than usual in the blood test, more testing or screenings might be offered to you to get more information.An ultrasound that looks at the fetal spine can be used to screen for spina bifida. Ultrasounds can also screen for some other birth defects, such as a heart defect or cleft lip. Talk with your healthcare provider about any prenatal screenings or testing that are available to you. There are no tests available during pregnancy that can tell how much effect there could be on future behavior or learning.

◈ Breastfeeding while taking valproic acid:

The amount of valproic acid that passes into breast milk is low and blood levels from exposed infants are low to undetectable. There is a theoretical (not proven) concern that infants exposed to valproic acid through breastmilk could develop liver toxicity, so infants should be monitored for any changes or problems. If you suspect the baby has symptoms such as jaundice (yellowing of the skin or eyes), rash, or fever, contact the child’s healthcare provider. Be sure to talk to your healthcare provider about all your breastfeeding questions.

◈ If a male takes valproic acid, could it affect fertility or increase the chance of birth defects?

It is not known if valproic acid could affect male fertility (ability to get partner pregnant) or increase the chance of birth defects above the background risk. In general, exposures that sperm donors or fathers have are unlikely to increase risks to a pregnancy. For more information, please see the MotherToBaby fact sheet Paternal Exposures at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.Available pregnancy registries include:US: North American Antiepileptic Drug (AED) Pregnancy Registry: 1-888-233-2334 or http://www.aedpregnancyregistry.org/Europe and other continents: the EURAP Registry (International Registry of Antiepileptic Drugs and Pregnancy) http://eurapinternational.org/index.Psychiatric medications: https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.

12.1.7 Exposure Routes

Inhalation. Rapid absorption from gastrointestinal tract. Although the rate of valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle), conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences should be of minor clinical importance under the steady state conditions achieved in chronic use in the treatment of epilepsy. Food has a greater influence on the rate of absorption of the Depakote tablet (increases Tmax from 4 to 8 hours) than on the absorption of Depakote sprinkle capsules (increase Tmax from 3.3 to 4.8 hours). Furthermore, studies suggest that total daily systemic bioavailability (extent of absorption) is the primary determinant of seizure control.

12.1.8 Symptoms

Acute toxicity symptoms include hypo/hyperthermia, tachycardia, hepatic toxicity, hypotension, respiratory depression, coma, confusion, somnolence, dizziness, headaches and cerebral edema. Allopecia, anorexia, liver toxicity, renal failure, tremors and miosis are also associated with chronic toxicity.

12.1.9 Acute Effects

12.1.10 Toxicity Data

Oral, mouse: LD50 = 1098 mg/kg; Oral, rat: LD50 = 670 mg/kg. In general, serum or plasma valproic acid concentrations are in a range of 20–100 mg/l during controlled therapy, but may reach 150–1500 mg/l following acute poisoning.

12.1.11 Treatment

In case of acute oral exposure, administer charcoal as a slurry. Consider gastric lavage after ingestion of a potentially life-threatening amount of the compound if it can be performed soon after ingestion (generally within 1 hour). Protect the patient’s airway by placement in Trendelenburg position (head down) and on their left side (left lateral decubitus position) or by endotracheal intubation. Control any seizures first. Some experimental and clinical data suggest that early intravenous supplementation with l-carnitine could improve survival in severe VPA-induced hepatotoxicity. Carnitine administration has been shown to speed the decrease of ammonemia in patients with VPA-induced encephalopathy. As it does not appear to be harmful, l-carnitine is commonly recommended in severe VPA poisoning, especially in children (A15080). In case of inhalation, move patient to fresh air, monitor for respiratory distress. If the exposure occurred via eye contact, irrigate exposed eyes with copious amounts of room temperature water for at least 15 minutes. Remove contaminated clothing and wash exposed area thoroughly with soap and water if the exposure occurred via dermal contact. (T36).
A15080: Lheureux PE, Hantson P: Carnitine in the treatment of valproic acid-induced toxicity. Clin Toxicol (Phila). 2009 Feb;47(2):101-11. doi: 10.1080/15563650902752376. PMID:19280426
T36: Rumack BH (2009). POISINDEX(R) Information System. Englewood, CO: Micromedex, Inc. CCIS Volume 141, edition expires Aug, 2009.

12.1.12 Interactions

Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely been associated with toxicity. Monitoring of amitriptyline levels should be considered for patients taking valproate concomitantly with amitriptyline. Consideration should be given to lowering the dose of amitriptyline/nortriptyline in the presence of valproate.
NIH; DailyMed. Current Medication Information for Depakene (Valproic Acid) Capsule, liquid filled (Revised: July 2014). Available from, as of November 20, 2014: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6b4331f5-4475-417a-6a9d-09c2f8334235
A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) and may result in loss of seizure control. The mechanism of this interaction is not well understood. Serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or seizure control deteriorates...
NIH; DailyMed. Current Medication Information for Depakene (Valproic Acid) Capsule, liquid filled (Revised: July 2014). Available from, as of November 20, 2014: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6b4331f5-4475-417a-6a9d-09c2f8334235
Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11-epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic patients.
NIH; DailyMed. Current Medication Information for Depakene (Valproic Acid) Capsule, liquid filled (Revised: July 2014). Available from, as of November 20, 2014: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6b4331f5-4475-417a-6a9d-09c2f8334235
A study involving the co-administration of 1200 mg/day of felbamate with valproate to patients with epilepsy (n = 10) revealed an increase in mean valproate peak concentration by 35% (from 86 to 115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2400 mg/day increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A decrease in valproate dosage may be necessary when felbamate therapy is initiated.
NIH; DailyMed. Current Medication Information for Depakene (Valproic Acid) Capsule, liquid filled (Revised: July 2014). Available from, as of November 20, 2014: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6b4331f5-4475-417a-6a9d-09c2f8334235
For more Interactions (Complete) data for VALPROIC ACID (61 total), please visit the HSDB record page.

12.1.13 Antidote and Emergency Treatment

Administration of high-dose naloxone has been reported to reverse valproate-induced CNS depression. Theories regarding the reversal of sedation by naloxone include reversal of the release of endogenous opioids and reversal of valproate blockade of GABA uptake by cells. Serum glucose, calcium, phosphate, and platelets must be frequently measured and treated accordingly.
Dart, R.C. (ed). Medical Toxicology. Third Edition, Lippincott Williams & Wilkins. Philadelphia, PA. 2004., p. 800
There is no evidence that either gastric lavage or administration of activated charcoal changes outcome. Whole bowel irrigation should be considered if the patient ingests Depakote or an extended release preparation and presents within 6 hours of ingestion.
Dart, R.C. (ed). Medical Toxicology. Third Edition, Lippincott Williams & Wilkins. Philadelphia, PA. 2004., p. 799
Hemoperfusion and hemodiafiltration without hemoperfusion have been performed to treated severe valproate overdose. Although the high degree of protein binding should not make it amenable to dialysis, the hypothesis is that unbound drug is markedly increased in overdose. None of the means of extracorporeal detoxification has been compared to supportive care to determine if these measures improve outcome.
Dart, R.C. (ed). Medical Toxicology. Third Edition, Lippincott Williams & Wilkins. Philadelphia, PA. 2004., p. 799
A healthy, nonepileptic 16 mo old child ingested a massive overdose (approximately 4000 mg) of valproic acid. /Therapeutic range is 40 to 100 ug/mL./ Upon admission to the hospital, he was in a deep coma and had generalized hypotonicity and no response to pain. His serum and urinary concentrations of VPA were 1316.2 and 3289.5 ug/mL, respectively. Urinary concn of the beta-oxidation metabolites of valproic acid were low, whereas concn of omega- and omega l-oxidation metabolites were high. Moreover, 4-en-valproate (a potential hepatotoxin) was detected in the urine. Gastric lavage and general supportive measures were undertaken, including intravenous infusion to increase urine output and oral L-carnitine to correct hypocarnitinemia. Subsequently, the beta-oxidation metabolites incr, the omega- and omega 1-oxidation metabolites decr, and 4-en-valproate was no longer detected. The patient recovered completely and was discharged on the eighth hospital day without any sequelae.
Ishikura H, et al; J Anal Toxicol 20 (1):55-8 (1996)
For more Antidote and Emergency Treatment (Complete) data for VALPROIC ACID (13 total), please visit the HSDB record page.

12.1.14 Human Toxicity Excerpts

/HUMAN EXPOSURE STUDIES/ The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. In a clinical trial of /valproate/ (divalproex sodium) as monotherapy in patients with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of platelets /= 110 ug/mL (females) or >/= 135 ug/mL (males). The therapeutic benefit which may accompany the higher doses should therefore be weighed against the possibility of a greater incidence of adverse effects. Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet aggregation, and abnormal coagulation parameters, (e.g., low fibrinogen), platelet counts and coagulation tests are recommended before initiating therapy and at periodic intervals. It is recommended that patients receiving Depakene (valproic acid) be monitored for platelet count and coagulation parameters prior to planned surgery. Evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy.
NIH; DailyMed. Current Medication Information for Depakene (Valproic Acid) Capsule, liquid filled (Revised: July 2014). Available from, as of November 20, 2014: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6b4331f5-4475-417a-6a9d-09c2f8334235
/ALTERNATIVE and IN VITRO TESTS/ Human studies of neurodevelopment suggest that children exposed in utero to certain antiepileptic drugs (AEDs) suffer a variety of brain-behavior sequelae, such as neural tube defects, developmental delays, cognitive deficits, etc. Valproic acid (VPA), a commonly used AED, has greater risk for these side effects compared with other AEDs. However, the detailed molecular mechanisms underlying this developmental neurotoxicity of VPA is unclear despite previous research demonstrating that VPA could induce widespread apoptotic neurodegeneration in developing brains of animal models. This study characterizes the role of astrocytes in VPA-induced neurodegeneration. In developing brains, /this study/ evaluated the developmental neurotoxicity of VPA on differentiating neurons and astrocytes from neural progenitor cells cultured from the hippocampus of human fetuses. Exposure of a neuron-enriched culture to VPA at 250uM or 500uM did not cause neuronal apoptosis, but at 1mM and 7 days exposure, a slight increase in the percentage of apoptotic cells was observed. In contrast, VPA at 250 uM to 1mM, selectively induced neuronal apoptosis in a neuron-astrocyte mixed cell culture model. The VPA-treated astrocytes showed morphological changes, and the level of tumor necrosis factor-alpha (TNF-alpha) was elevated in the supernatant. Both neuronal apoptosis and TNF-alpha release from astrocytes increased with concentration and exposure time to VPA, suggesting a synergism between the two cell types. Treatment of the neuron-astrocyte mixed culture exposed to VPA with TNF-alpha antibody partly prevented neuronal apoptosis, while the addition of exogenous TNF-alpha induced apoptosis in both cultures. Moreover, this pro-apoptotic effect was specific to VPA, as another AED, valpromide, failed to mimic this pro-apoptotic effect, nor did an inhibitor of histone deacetylase (iHDAC), sodium butyrate (NaB). /This reports/ a novel finding that astrocytes participate in VPA induced neurodegeneration by releasing TNF-alpha.
Wang C et al; Neurosci Lett 497 (2): 122-7 (2011)
/HUMAN EXPOSURE STUDIES/ Valproic acid (VPA) inhibits histone deacetylase and has been reported to induce apoptosis in glioma. /This study reports on/ 44 heavily pretreated pediatric patients with high-grade glioma or diffuse intrinsic pontine glioma who received VPA as oral continues maintenance treatment with individual dose adaptation. The tumor status when starting the drug was: no measurable disease in 12, measurable but stable disease in 12, and measurable progressive disease in 22 patients. Average trough blood levels of VPA were 99 mg/L. The most frequent complaint was somnolence (three patients), but no severe toxicity was reported. One relapse patient responded, early progression of disease was observed in three frontline patients and in six relapsed patients. Median overall survival duration for all patients was 1.33 years, with large differences between first-line (5-year overall survival, 44%) and relapse therapy (5-year overall survival, 14%). This shows that valproate is safe in this patient population. The moderate tumor efficacy encourages studying the drug further as an element of multi-agent protocols.
Wolff JE et al; J Neurooncol 90 (3): 309-14 (2008)
/ALTERNATIVE and IN VITRO TESTS/ Valproic acid (VPA) is a widely used antiepileptic drug and also prescribed to treat migraine, chronic headache and bipolar disorder. Although it is usually well tolerated, a severe hepatotoxic reaction has been repeatedly reported after VPA administration. A profound toxic reaction on administration of VPA has been observed in several patients carrying POLG mutations, and heterozygous genetic variation in POLG has been strongly associated with VPA-induced liver toxicity. /This research studied/ the effect of VPA in fibroblasts of five patients carrying pathogenic mutations in the POLG gene. VPA administration caused a significant increase in the expression of POLG and several regulators of mitochondrial biogenesis. It was further supported by elevated mtDNA copy numbers. The effect of VPA on mitochondrial biogenesis was observed in both control and patient cell lines, but the capacity of mutant POLG to increase the expression of mitochondrial genes and to increase mtDNA copy numbers was less effective. No evidence of substantive differences in DNA methylation across the genome was observed between POLG mutated patients and controls. Given the marked perturbation of gene expression observed in the cell lines studied, we conclude that altered DNA methylation is unlikely to make a major contribution to POLG-mediated VPA toxicity. /This/ data provide experimental evidence that VPA triggers increased mitochondrial biogenesis by altering the expression of several mitochondrial genes; however, the capacity of POLG-deficient liver cells to address the increased metabolic rate caused by VPA administration is significantly impaired.
Sitarz KS et al; Mol Genet Metab 112 (1): 57-63 (2014)
For more Human Toxicity Excerpts (Complete) data for VALPROIC ACID (68 total), please visit the HSDB record page.

12.1.15 Non-Human Toxicity Excerpts

/ALTERNATIVE and IN VITRO TESTS/ Valproic acid (VPA), a major antiepileptic drug, induces neural tube defects (NTDs) in humans and mice. Many candidate molecules for its teratogenicity have been suggested by recent molecular biological studies. Wnt signal pathways, which are involved in various developmental events in the embryo, consist of many transcription factors such as Dishevelled (Dvl), Frizzled, Axin, and so on. Cxxc finger 4 (Cxxc4) has been identified as a negative regulator of Dvl, and is required for the development of anterior neural tissues in Xenopus. Since defects in Wnt cascade molecules are known to cause mouse NTDs, /it is/ hypothesized that Cxxc4 is one of the target molecules for VPA teratogenicity in the mouse neural tube. /A previous study/ measured the mRNA level of Cxxc4 in the cephalic regions of NMRI mice embryos injected once with VPA (800 mg/kg) on gestation day 8.5 in GeneChip analysis. One, three and six hours after VPA treatment, the Cxxc4 mRNA level was enhanced to 171%, 203% and 141%, respectively, compared to the vehicle control. In this study, whole mount in situ hybridization (WISH) was carried out to determine the spatiotemporal expression pattern of Cxxc4 mRNA in the mouse embryo. Cxxc4 expression was detected at the mesencephalic and dorsal midline, where neural tube closure occurs. This pattern was not changed by VPA treatment. These results, taken together, indicate that VPA may up-regulate Cxxc4 and disrupt the Dvl-mediated Wnt signal pathway.
Hisamori M et al; Congenit Anom (Kyoto) 47 (4): A27 (2007)
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Exposure to the anticonvulsant drug valproic acid (VPA) in utero is associated with a 1-2% increase in neural tube defects (NTDs), however the molecular mechanisms by which VPA induces teratogenesis are unknown. Previous studies demonstrated that VPA, a direct inhibitor of histone deacetylase, can induce histone hyperacetylation and other epigenetic changes such as histone methylation and DNA demethylation. The objective of this study was to determine if maternal exposure to VPA in mice has the ability to cause these epigenetic alterations in the embryo and thus contribute to its mechanism of teratogenesis. Pregnant CD-1 mice (GD 9.0) were administered a teratogenic dose of VPA (400mg/kg, s.c.) and embryos extracted 1, 3, 6, and 24h after injection. To assess embryonic histone acetylation and histone methylation, Western blotting was performed on whole embryo homogenates, as well as immunohistochemical staining on embryonic sections. To measure DNA methylation changes, the cytosine extension assay was performed. Results demonstrated that a significant increase in histone acetylation that peaked 3h after VPA exposure was accompanied by an increase in histone methylation at histone H3 lysine 4 (H3K4) and a decrease in histone methylation at histone H3 lysine 9 (H3K9). Immunohistochemical staining revealed increased histone acetylation in the neuroepithelium, heart, and somites. A decrease in methylated histone H3K9 staining was observed in the neuroepithelium and somites, METHYLATED histone H3K4 staining was observed in the neuroepithelium. No significant differences in global or CpG island DNA methylation were observed in embryo homogenates. These results support the possibility that epigenetic modifications caused by VPA during early mouse organogenesis results in congenital malformations.
Tung EW and Winn LM. Toxicol Appl Pharmacol 248 (3): 201-9 (2010)
/GENOTOXICITY/ Valproic acid (VPA) has been used as anticonvulsants, however, it induces hepatotoxicity such as microvesicular steatosis and necrosis in the liver. To explore the mechanisms of VPA-induced steatosis, /this study/ profiled the gene expression patterns of the mouse liver that were altered by treatment with VPA using microarray analysis. VPA was orally administered as a single dose of 100 mg/kg (low-dose) or 1000 mg/kg (high-dose) to ICR mice and the animals were killed at 6, 24, or 72 hr after treatment. Serum alanine aminotransferase and aspartate aminotransferase levels were not significantly altered in the experimental animals. However, symptoms of steatosis were observed at 72 hr with low-dose and at 24 hr and 72 hr with high-dose. After microarray data analysis, 1910 genes were selected by two-way ANOVA (P<0.05) as VPA-responsive genes. Hierarchical clustering revealed that gene expression changes depended on the time rather than the dose of VPA treatment. Gene profiling data showed striking changes in the expression of genes associated with lipid, fatty acid, and steroid metabolism, oncogenesis, signal transduction, and development. Functional categorization of 1156 characteristically up- and down-regulated genes (cutoff >1.5-fold) revealed that 60 genes were involved in lipid metabolism that was interconnected with biological pathways for biosynthesis of triglyceride and cholesterol, catabolism of fatty acid, and lipid transport. This gene expression profile may be associated with the known steatogenic hepatotoxicity of VPA and it may provide useful information for prediction of hepatotoxicity of unknown chemicals or new drug candidates through pattern recognition.
Lee MH et al; Toxicol Appl Pharmacol 220 (1): 45-59 (2007)
/GENOTOXICITY/ Valproic acid (VPA) is used clinically to treat epilepsy, however it induces hepatotoxicity such as microvesicular steatosis. Acute hepatotoxicity of VPA has been well documented by biochemical studies and microarray analysis, but little is known about the chronic effects of VPA in the liver. /The present investigation/ profiled gene expression patterns in the mouse liver after subchronic treatment with VPA. VPA was administered orally at a dose of 100 mg/kg/day or 500 mg/kg/day to ICR mice, and the livers were obtained after 1, 2, or 4 weeks. The activities of serum liver enzymes did not change, whereas triglyceride concentration increased significantly. Microarray analysis revealed that 1325 genes of a set of 32,996 individual genes were VPA responsive when examined by two-way ANOVA (P<0.05) and fold change (>1.5). Consistent with our previous results obtained using an acute VPA exposure model (Lee et al., Toxicol Appl Pharmacol. 220:45-59, 2007), the most significantly over-represented biological terms for these genes included lipid, fatty acid, and steroid metabolism. Biological pathway analysis suggests that the genes responsible for increased biosynthesis of cholesterol and triglyceride, and for decreased fatty acid beta-oxidation contribute to the abnormalities in lipid metabolism induced by subchronic VPA treatment. A comparison of the VPA-responsive genes in the acute and subchronic models extracted 15 commonly altered genes, such as Cyp4a14 and Adpn, which may have predictive power to distinguish the mode of action of hepatotoxicants. /This/ data /provides/ a better understanding of the molecular mechanisms of VPA-induced hepatotoxicity and useful information to predict steatogenic hepatotoxicity.
Lee MH et al; Toxicol Appl Pharmacol 226 (3): 271-84 (2008)
For more Non-Human Toxicity Excerpts (Complete) data for VALPROIC ACID (69 total), please visit the HSDB record page.

12.1.16 Non-Human Toxicity Values

LD50 Guinea pig oral 824 mg/kg
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 3087
LD50 Mouse sc 860 mg/kg
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 3087
LD50 Mouse ip 470 mg/kg
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 3087
LD50 Mouse oral 1098 mg/kg
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 3087
For more Non-Human Toxicity Values (Complete) data for VALPROIC ACID (7 total), please visit the HSDB record page.

12.1.17 Ongoing Test Status

The following link will take the user to the National Toxicology Program (NTP) Test Agent Search Results page, which tabulates all of the "Standard Toxicology & Carcinogenesis Studies", "Developmental Studies", and "Genetic Toxicity Studies" performed with this chemical. Clicking on the "Testing Status" link will take the user to the status (i.e., in review, in progress, in preparation, on test, completed, etc.) and results of all the studies that the NTP has done on this chemical.[Available from, as of November 12, 2014: http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=ntpsearch.searchresults&searchterm=99-66-1]
EPA has released the first beta version (version 0.5) of the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. The beta version of the iCSS Dashboard provides an interactive tool to explore rapid, automated (or in vitro high-throughput) chemical screening data generated by the Toxicity Forecaster (ToxCast) project and the federal Toxicity Testing in the 21st century (Tox21) collaboration. /The title compound was tested by ToxCast and/or Tox21 assays; Click on the "Chemical Explorer" button on the tool bar to see the data./[USEPA; ICSS Dashboard Application; Available from, as of June 27, 2014: http://actor.epa.gov/dashboard/]

12.1.18 Populations at Special Risk

Valproic acid (VPA) is a known human teratogen. Exposure in pregnancy is associated with approximately three-fold increase in the rate of major anomalies, mainly spina bifida and only rarely anencephaly (NTD), cardiac, craniofacial, skeletal and limb defects and a possible set of dysmorphic features, the "valproate syndrome" with decreased intrauterine growth ... . There is also, mainly in the children with the "valproate syndrome", a significant increase in the rate of developmental problems, manifested by decreased verbal intelligence often with communication problems of the autistic spectrum disorder (ASD). VPA is teratogenic in most animal species tested, but the human embryo seems to be the most susceptible. A daily dose of 1000 mg or more and/or polytherapy are associated with a higher teratogenic risk ...
Ornoy A. Reprod Toxicol 28 (1): 1-10 (2009)
Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data show that maternal valproate use can cause neural tube defects and other structural abnormalities (e.g., craniofacial defects, cardiovascular malformations and malformations involving various body systems). The rate of congenital malformations among babies born to mothers using valproate is about four times higher than the rate among babies born to epileptic mothers using other anti-seizure monotherapies. Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population... Women with epilepsy who are pregnant or who plan to become pregnant should not be treated with valproate unless other treatments have failed to provide adequate symptom control or are otherwise unacceptable. In such women, the benefits of treatment with valproate during pregnancy may still outweigh the risks.
NIH; DailyMed. Current Medication Information for DEPAKENE- valproic acid capsule, liquid filled (Revised: July 2014). Available from, as of November 20, 2014: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6b4331f5-4475-417a-6a9d-09c2f8334235
Experience has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions. When /valproic acid capsule/ products are used in this patient group, they should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks.
NIH; DailyMed. Current Medication Information for DEPAKENE- valproic acid capsule, liquid filled (Revised: July 2014). Available from, as of November 20, 2014: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6b4331f5-4475-417a-6a9d-09c2f8334235
/Valproate/ is contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorder. Valproate-induced acute liver failure and liver-related deaths have been reported in patients with hereditary neurometabolic syndromes caused by mutations in the gene for mitochondrial DNA polymerase gamma (POLG) (e.g., Alpers-Huttenlocher Syndrome) at a higher rate than those without these syndromes. Most of the reported cases of liver failure in patients with these syndromes have been identified in children and adolescents.
NIH; DailyMed. Current Medication Information for DEPAKENE- valproic acid capsule, liquid filled (Revised: July 2014). Available from, as of November 20, 2014: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6b4331f5-4475-417a-6a9d-09c2f8334235
For more Populations at Special Risk (Complete) data for VALPROIC ACID (13 total), please visit the HSDB record page.

12.1.19 Protein Binding

Protein binding is linear at low concentrations with a free fraction of approximately 10% at 40 mcg/mL but becomes non-linear at higher concentrations with a free fraction of 18.5% at 135 mcg/mL. This may be due to binding at separate high and low-affinity sites on albumin proteins. Binding is expected to decrease in the elderly and patients with hepatic dysfunction.

12.2 Ecological Information

12.2.1 Ecotoxicity Values

EC50; Species: Xenopus laevis (African clawed frog, embryo); Conditions: freshwater, renewal, pH 7.0-7.8; Concentration: 30500 ug/L for 96 hr (95% confidence interval: 28000-33000 ug/L); Effect: general developmental changes, craniofacial defects, abnormal gut coiling /> or =98% purity/
Dawson DA et al; Teratog Carcinog Mutagen 16 (2): 109-124 (1996) Available from, as of June 25, 2007
LC50; Species: Xenopus laevis (African clawed frog, embryo); Conditions: freshwater, renewal, pH 7.0-7.8; Concentration: 851700 ug/L for 96 hr (95% confidence interval: 818000-882000 ug/L) /> or =98% purity/
Dawson DA et al; Teratog Carcinog Mutagen 16 (2): 109-124 (1996) Available from, as of June 25, 2007

12.2.2 Environmental Fate / Exposure Summary

Valproic acid's production and administration as an anticonvulsant, anti-bipolar disorder and antimigraine drug may result in its release to the environment through various waste streams. If released to air, an estimated vapor pressure of 8.5X10-2 mm Hg at 25 °C indicates valproic acid will exist solely as a vapor in the atmosphere. Vapor-phase valproic acid will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 17 hours. Valproic acid does not contain chromophores that absorb at wavelengths >290 nm and, therefore, is not expected to be susceptible to direct photolysis by sunlight. If released to soil, valproic acid is expected to have high mobility based upon an estimated Koc of 47. The pKa of valproic acid is 4.6, indicating that this compound will exist almost entirely in the anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts. Volatilization from moist soil is not expected because the compound exists as an anion and anions do not volatilize. Biodegradation data in soil or water were not available. If released into water, valproic acid is not expected to adsorb to suspended solids and sediment based upon the estimated Koc. The pKa indicates valproic acid will exist almost entirely in the anion form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process. An estimated BCF of 3 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions (pH 5 to 9). Occupational exposure to valproic acid may occur through inhalation and dermal contact with this compound at workplaces where valproic acid is produced or used. Exposure to valproic acid among the general population may be limited to those administered the drug. (SRC)

12.2.3 Artificial Pollution Sources

Valproic acid's production and administration as an anticonvulsant, anti-bipolar disorder and antimigraine drug(1) may result in its release to the environment through various waste streams(SRC).
(1) O'Neil MJ, ed; The Merck Index. 15th ed. Whitehouse Station, NJ: Merck and Co., Inc. p. 1839 (2013)

12.2.4 Environmental Fate

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 47(SRC), determined from a log Kow of 2.75(2) and a regression-derived equation(3), indicates that valproic acid is expected to have very high mobility in soil(SRC). The pKa of valproic acid is 4.60(4), indicating that this compound will exist almost entirely in the anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(5). Volatilization from moist soil is not expected because the compound exists as an anion and anions do not volatilize. Valproic acid is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 8.5X10-2 mm Hg at 25 °C(SRC), determined from a fragment constant method(3). Biodegradation data in soil were not available(SRC, 2014).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) Sangster J; LOGKOW Databank. A databank of evaluated octanol-water partition coefficients (Log P) on microcomputer diskette. Montreal, Quebec, Canada: Sangster Research Laboratories (1993)
(3) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Aug 26, 2014: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
(4) O'Neil MJ, ed; The Merck Index. 15th ed. Whitehouse Station, NJ: Merck and Co., Inc. p. 1839 (2013)
(5) Doucette WJ; pp. 141-188 in Handbook of Property Estimation Methods for Chemicals. Boethling RS, Mackay D, eds. Boca Raton, FL: Lewis Publ (2000)
AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 47(SRC), determined from a log Kow of 2.75(2) and a regression-derived equation(3), indicates that valproic acid is not expected to adsorb to suspended solids and sediment(SRC). A pKa of 4.60(4) indicates valproic acid will exist almost entirely in the anion form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process(SRC). According to a classification scheme(5), an estimated BCF of 3(SRC), from its log Kow(2) and a regression-derived equation(3), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC, 2014).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) Sangster J; LOGKOW Databank. A databank of evaluated octanol-water partition coefficients (Log P) on microcomputer diskette. Montreal, Quebec, Canada: Sangster Research Laboratories (1993)
(3) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Aug 26, 2014: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
(4) O'Neil MJ, ed; The Merck Index. 15th ed. Whitehouse Station, NJ: Merck and Co., Inc. p. 1839 (2013)
(5) Franke C et al; Chemosphere 29: 1501-14 (1994)
ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), valproic acid, which has an estimated vapor pressure of 8.5X10-2 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase valproic acid is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 17 hours(SRC), calculated from its rate constant of 8.2X10-12 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Valproic acid does not contain chromophores that absorb at wavelengths >290 nm(4) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).
(1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Aug 26, 2014: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
(3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993)
(4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 8-12 (1990)

12.2.5 Environmental Abiotic Degradation

The rate constant for the vapor-phase reaction of valproic acid with photochemically-produced hydroxyl radicals has been estimated as 8.2X10-12 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 17 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Valproic acid is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(2). Valproic acid does not contain chromophores that absorb at wavelengths >290 nm(2) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).
(1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993)
(2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5, 8-12 (1990)

12.2.6 Environmental Bioconcentration

An estimated BCF of 3 was calculated in fish for valproic acid(SRC), using a log Kow of 2.75(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).
(1) Sangster J; LOGKOW Databank. A databank of evaluated octanol-water partition coefficients (Log P) on microcomputer diskette. Montreal, Quebec, Canada: Sangster Research Laboratories (1993)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Aug 26, 2014: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
(3) Franke C et al; Chemosphere 29: 1501-14 (1994)

12.2.7 Soil Adsorption / Mobility

The Koc of valproic acid is estimated as 47(SRC), using a log Kow of 2.75(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that valproic acid is expected to have very high mobility in soil. The pKa of valproic acid is 4.6(4), indicating that this compound will exist almost entirely in the anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(5).
(1) Sangster J; LOGKOW Databank. A databank of evaluated octanol-water partition coefficients (Log P) on microcomputer diskette. Montreal, Quebec, Canada: Sangster Research Laboratories (1993)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Aug 26, 2014: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
(3) Swann RL et al; Res Rev 85: 17-28 (1983)
(4) O'Neil MJ, ed; The Merck Index. 15th ed. Whitehouse Station, NJ: Merck and Co., Inc. p. 1839 (2013)
(5) Doucette WJ; pp. 141-188 in Handbook of Property Estimation Methods for Chemicals. Boethling RS, Mackay D, eds. Boca Raton, FL: Lewis Publ (2000)

12.2.8 Volatilization from Water / Soil

A pKa of 4.6(1) indicates valproic acid will exist almost entirely in the anion form at pH values of 5 to 9 and, therefore, volatilization from water or moist soil surfaces is not expected to be an important fate process(2). Valproic acid is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 8.5X10-2 mm Hg(SRC), determined from a fragment constant method(3).
(1) O'Neil MJ, ed; The Merck Index. 15th ed. Whitehouse Station, NJ: Merck and Co., Inc. p. 1839 (2013)
(2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990)
(3) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Aug 26, 2014: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm

12.2.9 Effluent Concentrations

Valproic acid has a predicted environmental concentration of 4.92 ng/L in wastewater effluent as a result of a nationwide survey conducted in Spain in 2009. Its occurrence in the aquatic environment was estimated at 229.80 kg/yr(1).
(1) Ortiz de Garcia S et al; Sci Total Environ 444: 451-465 (2003)

12.2.10 Milk Concentrations

Valproic acid and its salt, sodium valproate, are excreted into human milk in low concentrations. Milk concentrations up to 15% of the corresponding level in the mother's serum have been measured. In two infants, serum levels of valporate were 1.5% and 6.0% of maternal values.
Briggs, G.G., Freeman, R.K., Yaffee, S.J.; Drugs in Pregancy and Lactation Nineth Edition. Wolters Kluwer/Lippincott Williams & Wilkins, Philadelphia, PA. 2011, p. 1543
EXPERIMENTAL: Valproate is distributed into breast milk. Concentrations in breast milk have been reported to be 1 to 10% of the total maternal serum concentration. /Valproate/
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 2855

12.2.11 Probable Routes of Human Exposure

NIOSH (NOES Survey 1981-1983) has statistically estimated that 5,848 workers (3,255 of these are female) are potentially exposed to valproic acid in the US(1). Occupational exposure to valproic acid may occur through inhalation and dermal contact with this compound at workplaces where valproic acid is produced or used. Exposure to valproic acid among the general population may be limited to those administered the drug(SRC).
(1) NIOSH; NOES. National Occupational Exposure Survey conducted from 1981-1983. Estimated numbers of employees potentially exposed to specific agents by 2-digit standard industrial classification (SIC). Available from, as of Aug 25, 2014: https://www.cdc.gov/noes/

13 Associated Disorders and Diseases

14 Literature

14.1 Consolidated References

14.2 NLM Curated PubMed Citations

14.3 Springer Nature References

14.4 Thieme References

14.5 Nature Journal References

14.6 Chemical Co-Occurrences in Literature

14.7 Chemical-Gene Co-Occurrences in Literature

14.8 Chemical-Disease Co-Occurrences in Literature

15 Patents

15.1 Depositor-Supplied Patent Identifiers

15.2 WIPO PATENTSCOPE

15.3 Chemical Co-Occurrences in Patents

15.4 Chemical-Disease Co-Occurrences in Patents

15.5 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 alcohol.
  • Avoid milk and dairy products.
  • Take with food.

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

19 Classification

19.1 MeSH Tree

19.2 NCI Thesaurus Tree

19.3 ChEBI Ontology

19.4 LIPID MAPS Classification

19.5 KEGG: Lipid

19.6 KEGG: USP

19.7 KEGG: ATC

19.8 KEGG: Target-based Classification of Drugs

19.9 KEGG: Drug Groups

19.10 KEGG: Drug Classes

19.11 WHO ATC Classification System

19.12 FDA Pharm Classes

19.13 ChemIDplus

19.14 CAMEO Chemicals

19.15 IUPHAR / BPS Guide to PHARMACOLOGY Target Classification

19.16 ChEMBL Target Tree

19.17 UN GHS Classification

19.18 EPA CPDat Classification

19.19 NORMAN Suspect List Exchange Classification

19.20 CCSBase Classification

19.21 EPA DSSTox Classification

19.22 LOTUS Tree

19.23 EPA Substance Registry Services Tree

19.24 MolGenie Organic Chemistry Ontology

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  11. Human Metabolome Database (HMDB)
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    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
  12. New Zealand Environmental Protection Authority (EPA)
    LICENSE
    This work is licensed under the Creative Commons Attribution-ShareAlike 4.0 International licence.
    https://www.epa.govt.nz/about-this-site/general-copyright-statement/
  13. California Safe Cosmetics Program (CSCP) Product Database
  14. 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
  15. 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
  16. 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
  17. 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
  18. 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
  19. Therapeutic Target Database (TTD)
  20. 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
  21. California Office of Environmental Health Hazard Assessment (OEHHA)
  22. ChEBI
  23. 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
  24. LiverTox
  25. 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/
  26. 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
  27. Open Targets
    LICENSE
    Datasets generated by the Open Targets Platform are freely available for download.
    https://platform-docs.opentargets.org/licence
  28. CCSbase
    CCSbase Classification
    https://ccsbase.net/
  29. 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/
    VALPROIC ACID
    NORMAN Suspect List Exchange Classification
    https://www.norman-network.com/nds/SLE/
  30. 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
  31. DailyMed
  32. 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
  33. Drugs and Lactation Database (LactMed)
  34. Mother To Baby Fact Sheets
    LICENSE
    Copyright by OTIS. This work is available under the Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported license (CC BY-NC-ND 3.0).
    https://www.ncbi.nlm.nih.gov/books/about/copyright/
  35. 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
  36. EPA Chemical and Products Database (CPDat)
  37. EU Clinical Trials Register
  38. NITE-CMC
    2-Propan-1-ylpentanoic acid [Valproic acid] - FY2017 (New/original classication)
    https://www.chem-info.nite.go.jp/chem/english/ghs/17-mhlw-0004e.html
  39. FDA Medication Guides
    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
  40. 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
  41. 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
  42. SpectraBase
  43. Japan Chemical Substance Dictionary (Nikkaji)
  44. 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
    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
  45. LIPID MAPS
    Lipid Classification
    https://www.lipidmaps.org/
  46. Natural Product Activity and Species Source (NPASS)
  47. MassBank Europe
  48. MassBank of North America (MoNA)
    LICENSE
    The content of the MoNA database is licensed under CC BY 4.0.
    https://mona.fiehnlab.ucdavis.edu/documentation/license
  49. Metabolomics Workbench
  50. Nature Chemical Biology
  51. NIPH Clinical Trials Search of Japan
  52. 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
  53. NLM RxNorm Terminology
    LICENSE
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    https://www.nlm.nih.gov/research/umls/rxnorm/docs/termsofservice.html
  54. NMRShiftDB
  55. WHO Anatomical Therapeutic Chemical (ATC) Classification
    LICENSE
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    https://www.whocc.no/copyright_disclaimer/
  56. 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
  57. 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
  58. Protein Data Bank in Europe (PDBe)
  59. Springer Nature
  60. SpringerMaterials
  61. 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/
  62. Wikidata
  63. Wikipedia
  64. Medical Subject Headings (MeSH)
    LICENSE
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    https://www.nlm.nih.gov/copyright.html
  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