Valproic acid

Identification

Summary

Valproic acid is an anticonvulsant used to control complex partial seizures and both simple and complex absence seizures.

Brand Names

Depakene, Depakote, Epival

Generic Name

Valproic acid

DrugBank Accession Number

DB00313

Background

Valproic acid, or valproate, is an fatty acid derivative and anticonvulsant originally synthesized in 1881 by Beverly S. Burton.²⁶ It enjoyed use as a popular organic solvent in industry and pharmaceutical manufacturing for nearly a century. In 1963, a serendipitous discovery was made by George Carraz during his investigations into the anticonvulsant effects of khelline when he found that all of his samples, dissolved in valproic acid, exerted a similar degree of anticonvulsive activity. It first received approval on February 28, 1978 from the FDA under the trade name Depakene.²⁹

Since then, it has been investigated for neuroprotective, anti-manic, and anti-migraine effects. It is currently a compound of interest in the field of oncology for its anti-proliferative effects and is the subject of many clinical trials in a variety of cancer types.

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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Similar Structures

Structure for Valproic acid (DB00313)

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Weight

Average: 144.2114
Monoisotopic: 144.115029756

Chemical Formula

C₈H₁₆O₂

Synonyms

• 2-n-propyl-n-valeric acid
• 2-propyl-pentanoic acid
• 2-Propylpentanoic Acid
• 2-Propylvaleric Acid
• 4-heptanecarboxylic acid
• acide valproïque
• ácido valproico
• acidum valproicum
• di-n-propylacetic acid
• Di-n-propylessigsäure
• Dipropylacetic acid
• DPA
• n-DPA
• Valproate
• Valproic acid
• Valproinsäure
• VPA

External IDs

• 44089

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Pharmacology

Indication

Indicated for:^Label

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.⁷

2) Treatment for acute bipolar depression.^8,9,10

3) Emergency treatment of status epilepticus.¹¹

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Management of	Absence seizures		••••••••••••			•••••••• ••••••• •••••••• •••••••• ••••••• ••••••• •••••••• •••••••••• •••••• ••••••• ••••••• •••••••• ••••••• •••••••• •••••••
Management of	Bipolar disorder (bd)		••• •••••	•••••		•••••••• ••••••• •••••••• ••••••• ••••••• •••••••• ••••••• •••••••• •••••••
Management of	Complex partial seizures		••••••••••••	•••••• •••••••••		•••••••• ••••••• •••••••• •••••••• ••••••• ••••••• •••••••• •••••••••• •••••• ••••••• ••••••• •••••••• ••••••• •••••••• •••••••
Management of	Depressive episode		••• •••••	•••••		•••••••• ••••••• ••••••• •••••••• ••••••• ••••••• •••••••• ••••••• •••••••• •••••••
Management of	Manic episode		••••••••••••			•••••••• ••••••• •••••••• •••••••• ••••••• ••••••• •••••••• •••••• ••••••• ••••••• •••••••• ••••••• •••••••• •••••••• ••••••• •••• ••••••• •••••••• •••••••

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Pharmacodynamics

Valproate has been shown to reduce the incidence of complex partial seizures and migraine headaches.^Label,5 It also improves symptom control in bipolar mania.²³ 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.¹

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.^2,6 The FDA labeling contains a warning regarding HIV reactivation during valproate use.^Label.

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.¹² 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.¹ 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).¹ 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 GABA_A receptors which contribute further to increased GABAergic activity.¹³

Valproate exerts a non-competitive indirect inhibitory effect on myo-inosital-1-phophate synthetase.¹⁴ 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.¹⁵ 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.¹⁶ The inhibition of the PKC pathway may also be a contributor to migraine prophylaxis.¹⁷ 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.¹⁸

Valproate also appears to impact fatty acid metabolism.¹ 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.¹⁹ Valproate has been found to be a non-competitive direct inhibitor of brain microsomal long-chain fatty acyl-CoA synthetase.²⁰ 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.²² 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.²¹ 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.²³ 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.²⁴ H3 hyperacetylation is associated with a reduction in glyceraldehyde-3-phosphate dehydrogenase, a pro-apoptotic enzyme, contributing further to valproate's neuroprotective effects.²⁵

Target	Actions	Organism
AHistone deacetylase 9	inhibitor	Humans
UShort/branched chain specific acyl-CoA dehydrogenase, mitochondrial	inhibitor	Humans
U2-oxoglutarate dehydrogenase, mitochondrial	inhibitor	Humans
USuccinate-semialdehyde dehydrogenase, mitochondrial	inhibitor	Humans
USodium channel protein	inhibitor	Humans
UHistone deacetylase 2	inhibitor	Humans
UPeroxisome proliferator-activated receptor alpha	Not Available	Humans
UPeroxisome proliferator-activated receptor delta	Not Available	Humans
UPeroxisome proliferator-activated receptor gamma	Not Available	Humans
UHistone deacetylase	inhibitor	Humans
UCyclin-dependent kinase inhibitor 1	regulator	Humans
UHepatocyte growth factor	inhibitor	Humans
UOrnithine decarboxylase	downregulator	Humans
UProgrammed cell death 1 ligand 1	downregulator	Humans

Absorption

The intravenous and oral forms of valproic acid are expected to produce the same AUC, Cmax, and Cmin at steady-state.^Label 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.³⁰ 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%.²⁷

Volume of distribution

11 L/1.73m².^Label

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.^Label This may be due to binding at separate high and low-affinity sites on albumin proteins.²⁷ Binding is expected to decrease in the elderly and patients with hepatic dysfunction.

Metabolism

Most drug is metabolized to glucuronide conjugates (30-50%) of the parent drug or of metabolites.^Label,27 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, ω₁, and ω₂ positions resulting in the formation of hydroxyls, ketones, carboxyls, a lactone metabolite, double bonds, and combinations.

Hover over products below to view reaction partners

• Valproic acid
  • 4-ene-Valproic acid
    • 2,4-Diene-VPA
  • 5-Hydroxyvalproic acid
    • 2-Propylglutaric acid
  • 3-Hydroxyvalproic acid
    • 3-Oxovalproic acid
    • 3-Oxovalproic acid
  • 4-Hydroxyvalproic acid
    • 2-n-Propyl-4-oxopentanoic acid
      • 2-Propylsuccinic acid
  • Valproic acid β-O-glucuronide
  • 2-ene-Valproic acid
    • 3-Hydroxyvalproic acid
  • (3Z)-2-Propylpent-3-enoic acid (3Z-Ene-VPA)
  • (3E)-2-Propylpent-3-enoic acid (3E-Ene-VPA)
  • Valproic acid CoA

Route of elimination

Most drug is eliminated through hepatic metabolism, about 30-50%.^Label 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.

Half-life

13-19 hours.^Label

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.

Clearance

0.56 L/hr/m^2Label

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.^Label

Adverse Effects

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Toxicity

LD₅₀ Values

Oral, mouse: 1098 mg/kg

Oral, rat: 670 mg/kg

Overdose

Symptoms of overdose include somnolence, heart block, deep coma, and hypernatremia. Fatalities have been reported, however patients have recovered from valproate serum concentrations as high as 2120 mcg/mL. The unbound fraction may be removed by hemodialysis. Naloxone has been demonstrated to reverse the CNS depressant effects of overdose but may also reverse the anti-epileptic effects.^Label

Reproductive Toxicity

Valproate use in pregnancy is known to increase the risk of neural tube defects and other structural abnormalities.^Label The risk of spina bifida increases from 0.06-0.07% in the normal population to 1-2% in valproate users. The North American Antiepileptic Drug (NAAED) Pregnancy Registry reports a major malformation rate of 9-11%, 5 times the baseline rate. These malformations include neural tube defects, cardiovascular malformations, craniofacial defects (e.g., oral clefts, craniosynostosis), hypospadias, limb malformations (e.g., clubfoot, polydactyly), and other malformations of varying severity involving other body systems. Other antiepileptic drugs, lamotrigine, carbemazepine, and phenytoin, have been found to reduce IQ in children exposed in utero. Valproate was also studied however the results did not achieve statistical significance (97 IQ (CI: 94-101)). Observational studies report an absolute risk increase of 2.9% (relative risk 2.9 times baseline) of autism spectrum disorder in children exposed to valproate in utero. There have been case reports of fatal hepatic failure in children of mothers who used valproate during pregnancy.

There have been reports of male infertility when taking valproate.^Label

Lactation

Valproate is excreted in human milk.^Label Data in the published literature describe the presence of valproate in human milk (range: 0.4 mcg/mL to 3.9 mcg/mL), corresponding to 1% to 10% of maternal serum levels. Valproate serum concentrations collected from breastfed infants aged 3 days postnatal to 12 weeks following delivery ranged from 0.7 mcg/mL to 4 mcg/mL, which were 1% to 6% of maternal serum valproate levels. A published study in children up to six years of age did not report adverse developmental or cognitive effects following exposure to valproate via breast milk.

Other Toxicity Considerations

Use in pediatrics under 2 years of age increases the risk of fatal hepatotoxicity.^Label

Pathways

Pathway	Category
Valproic Acid Metabolism Pathway	Drug metabolism

Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">

Interacting Gene/Enzyme	Allele name	Genotype(s)	Defining Change(s)	Type(s)	Description	Details
DNA polymerase subunit gamma-1	A467T	(A;A) / (A;G)	G > A	ADR Directly Studied	The presence of this polymorphism in POLG may indicate an increased risk of liver failure and death when treated with valproic acid.	Details
DNA polymerase subunit gamma-1	W748S	(C;C) / (C;G)	G > C	ADR Directly Studied	The presence of this polymorphism in POLG may indicate an increased risk of liver failure and death when treated with valproic acid.	Details

Interactions

Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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1,2-Benzodiazepine	The risk or severity of CNS depression can be increased when Valproic acid is combined with 1,2-Benzodiazepine.
Abacavir	The metabolism of Abacavir can be decreased when combined with Valproic acid.
Abametapir	The serum concentration of Valproic acid can be increased when it is combined with Abametapir.
Abatacept	The metabolism of Valproic acid can be increased when combined with Abatacept.
Abemaciclib	The serum concentration of Abemaciclib can be increased when it is combined with Valproic acid.

Food Interactions

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

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Divalproex sodium	644VL95AO6	76584-70-8	MSRILKIQRXUYCT-UHFFFAOYSA-M
Magnesium Valproate	Q400352CM2	62959-43-7	LKLLHOIUJVEAGU-UHFFFAOYSA-L
Valproate sodium	5VOM6GYJ0D	1069-66-5	AEQFSUDEHCCHBT-UHFFFAOYSA-M

Product Images

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International/Other Brands

Convulex / Depakine / Deprakine / Encorate / Epilim / Valcote / Valparin

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Depacon	Injection	100 mg/1mL	Intravenous	AbbVie Inc.	1996-12-30	2019-11-01
Depakene	Capsule, liquid filled	250 mg/1	Oral	REMEDYREPACK INC.	2018-10-03	2020-05-21
Depakene	Capsule, liquid filled	250 mg/1	Oral	AbbVie Inc.	1978-02-28	2019-10-11
Depakene	Capsule, liquid filled	250 mg/1	Oral	REMEDYREPACK INC.	2016-09-02	2018-08-17
Depakene	Solution	250 mg / 5 mL	Oral	Bgp Pharma Ulc	1978-12-31	Not applicable

Generic Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Apo-divalproex	Tablet, delayed release	500 mg / ect	Oral	Apotex Corporation	1999-03-24	Not applicable
Apo-divalproex	Tablet, delayed release	250 mg / ect	Oral	Apotex Corporation	1999-03-24	Not applicable
Apo-divalproex	Tablet, delayed release	125 mg	Oral	Apotex Corporation	1999-03-24	Not applicable
Apo-valproic Acid	Capsule	250 mg	Oral	Apotex Corporation	1998-06-01	Not applicable
Apo-valproic Acid Oral Solution	Solution	250 mg / 5 mL	Oral	Apotex Corporation	1998-07-15	Not applicable

Mixture Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End	Region	Image
DEPAKIN	Valproic acid (72.61 MG) + Valproate sodium (166.76 mg)	Granule, delayed release	Oral	Sanofi S.R.L.	2014-07-08	Not applicable
DEPAKIN	Valproic acid (290.27 MG) + Valproate sodium (666.6 mg)	Granule, delayed release	Oral	Sanofi S.R.L.	2014-07-08	Not applicable
DEPAKIN	Valproic acid (145 MG) + Valproate sodium (333 mg)	Tablet, extended release	Oral	Sanofi S.R.L.	2014-07-08	Not applicable
DEPAKIN	Valproic acid (87 MG) + Valproate sodium (199.8 mg)	Tablet, extended release	Oral	Sanofi S.R.L.	2014-07-08	Not applicable
DEPAKIN	Valproic acid (145.14 MG) + Valproate sodium (333.3 mg)	Granule, delayed release	Oral	Sanofi S.R.L.	2014-07-08	Not applicable

Categories

ATC Codes

N03AG01 — Valproic acid

• N03AG — Fatty acid derivatives
• N03A — ANTIEPILEPTICS
• N03 — ANTIEPILEPTICS
• N — NERVOUS SYSTEM

Drug Categories

• Acids, Acyclic
• Anti-epileptic Agent
• Anticonvulsants
• Antimanic Agents
• Antineoplastic Agents
• Central Nervous System Agents
• Central Nervous System Depressants
• Cytochrome P-450 CYP1A2 Inhibitors
• Cytochrome P-450 CYP1A2 Inhibitors (strength unknown)
• Cytochrome P-450 CYP2A6 Substrates
• Cytochrome P-450 CYP2A6 Substrates with a Narrow Therapeutic Index
• Cytochrome P-450 CYP2B6 Substrates
• Cytochrome P-450 CYP2B6 Substrates with a Narrow Therapeutic Index
• Cytochrome P-450 CYP2C19 Inhibitors
• Cytochrome P-450 CYP2C19 Inhibitors (weak)
• Cytochrome P-450 CYP2C19 Substrates
• Cytochrome P-450 CYP2C19 Substrates with a Narrow Therapeutic Index
• Cytochrome P-450 CYP2C8 Inhibitors
• Cytochrome P-450 CYP2C9 Inhibitors
• Cytochrome P-450 CYP2C9 Inhibitors (moderate)
• Cytochrome P-450 CYP2C9 Substrates
• Cytochrome P-450 CYP2C9 Substrates with a Narrow Therapeutic Index
• Cytochrome P-450 CYP3A Inhibitors
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Inhibitors
• Cytochrome P-450 CYP3A4 Inhibitors (strength unknown)
• Cytochrome P-450 CYP3A5 Substrates
• Cytochrome P-450 CYP3A5 Substrates with a Narrow Therapeutic Index
• Cytochrome P-450 Enzyme Inhibitors
• Cytochrome P-450 Substrates
• Decreased Central Nervous System Disorganized Electrical Activity
• Drugs causing inadvertant photosensitivity
• Enzyme Inhibitors
• Fatty Acid Derivatives
• Fatty Acids
• Fatty Acids, Volatile
• GABA Agents
• Hepatotoxic Agents
• Highest Risk QTc-Prolonging Agents
• Histone Deacetylase Inhibitors
• Lipids
• Methemoglobinemia Associated Agents
• Miscellaneous Anticonvulsants
• Mood Stabilizer
• Narrow Therapeutic Index Drugs
• Nervous System
• Neurotransmitter Agents
• OAT1/SLC22A6 inhibitors
• OAT3/SLC22A8 Inhibitors
• OAT3/SLC22A8 Substrates
• OAT3/SLC22A8 Substrates with a Narrow Therapeutic Index
• Organic Anion Transporting Polypeptide 2B1 Inhibitors
• Pentanoic Acids
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• Serotonergic Drugs Shown to Increase Risk of Serotonin Syndrome
• Tranquilizing Agents
• UGT1A1 Inhibitors
• UGT1A1 Substrates
• UGT1A1 Substrates with a Narrow Therapeutic Index
• UGT1A3 substrates
• UGT1A3 Substrates with a Narrow Therapeutic Index
• UGT1A4 substrates
• UGT1A6 substrate
• UGT1A6 Substrates with a Narrow Therapeutic Index
• UGT1A9 Substrates
• UGT1A9 Substrates with a Narrow Therapeutic Index
• UGT2B7 substrates
• UGT2B7 Substrates with a Narrow Therapeutic Index
• Valerates

Chemical TaxonomyProvided by Classyfire

Description

This compound belongs to the class of organic compounds known as methyl-branched fatty acids. These are fatty acids with an acyl chain that has a methyl branch. Usually, they are saturated and contain only one or more methyl group. However, branches other than methyl may be present.

Kingdom

Organic compounds

Super Class

Lipids and lipid-like molecules

Class

Fatty Acyls

Sub Class

Fatty acids and conjugates

Direct Parent

Methyl-branched fatty acids

Alternative Parents

Monocarboxylic acids and derivatives / Carboxylic acids / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds

Substituents

Aliphatic acyclic compound / Carbonyl group / Carboxylic acid / Carboxylic acid derivative / Hydrocarbon derivative / Methyl-branched fatty acid / Monocarboxylic acid or derivatives / Organic oxide / Organic oxygen compound / Organooxygen compound

Molecular Framework

Aliphatic acyclic compounds

External Descriptors

branched-chain fatty acid, branched-chain saturated fatty acid (CHEBI:39867) / Branched fatty acids (LMFA01020291)

Affected organisms

• Humans and other mammals

Chemical Identifiers

UNII

614OI1Z5WI

CAS number

99-66-1

InChI Key

NIJJYAXOARWZEE-UHFFFAOYSA-N

InChI

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

IUPAC Name

2-propylpentanoic acid

SMILES

CCCC(CCC)C(O)=O

References

Synthesis Reference

Daniel Aubert, Francis Blanc, Henri Desmolin, Michel Morre, Lucette Sindely, "Valproic acid preparations." U.S. Patent US5017613, issued January, 1965.

US5017613

General References

1. Rosenberg G: The mechanisms of action of valproate in neuropsychiatric disorders: can we see the forest for the trees? Cell Mol Life Sci. 2007 Aug;64(16):2090-103. [Article]
2. Lehrman G, Hogue IB, Palmer S, Jennings C, Spina CA, Wiegand A, Landay AL, Coombs RW, Richman DD, Mellors JW, Coffin JM, Bosch RJ, Margolis DM: Depletion of latent HIV-1 infection in vivo: a proof-of-concept study. Lancet. 2005 Aug 13-19;366(9485):549-55. [Article]
3. Schwartz C, Palissot V, Aouali N, Wack S, Brons NH, Leners B, Bosseler M, Berchem G: Valproic acid induces non-apoptotic cell death mechanisms in multiple myeloma cell lines. Int J Oncol. 2007 Mar;30(3):573-82. [Article]
4. Valentini A, Gravina P, Federici G, Bernardini S: Valproic acid induces apoptosis, p16INK4A upregulation and sensitization to chemotherapy in human melanoma cells. Cancer Biol Ther. 2007 Feb;6(2):185-91. Epub 2007 Feb 5. [Article]
5. Linde M, Mulleners WM, Chronicle EP, McCrory DC: Valproate (valproic acid or sodium valproate or a combination of the two) for the prophylaxis of episodic migraine in adults. Cochrane Database Syst Rev. 2013 Jun 24;(6):CD010611. doi: 10.1002/14651858.CD010611. [Article]
6. Routy JP, Tremblay CL, Angel JB, Trottier B, Rouleau D, Baril JG, Harris M, Trottier S, Singer J, Chomont N, Sekaly RP, Boulassel MR: Valproic acid in association with highly active antiretroviral therapy for reducing systemic HIV-1 reservoirs: results from a multicentre randomized clinical study. HIV Med. 2012 May;13(5):291-6. doi: 10.1111/j.1468-1293.2011.00975.x. Epub 2012 Jan 26. [Article]
7. Cipriani A, Reid K, Young AH, Macritchie K, Geddes J: Valproic acid, valproate and divalproex in the maintenance treatment of bipolar disorder. Cochrane Database Syst Rev. 2013 Oct 17;(10):CD003196. doi: 10.1002/14651858.CD003196.pub2. [Article]
8. Ghaemi SN, Gilmer WS, Goldberg JF, Zablotsky B, Kemp DE, Kelley ME, Bauer AD, Fleck J, Filkowski MM, Stan VA, Dunn RT: Divalproex in the treatment of acute bipolar depression: a preliminary double-blind, randomized, placebo-controlled pilot study. J Clin Psychiatry. 2007 Dec;68(12):1840-4. [Article]
9. Davis LL, Bartolucci A, Petty F: Divalproex in the treatment of bipolar depression: a placebo-controlled study. J Affect Disord. 2005 Apr;85(3):259-66. doi: 10.1016/j.jad.2004.09.009. [Article]
10. Muzina DJ, Gao K, Kemp DE, Khalife S, Ganocy SJ, Chan PK, Serrano MB, Conroy CM, Calabrese JR: Acute efficacy of divalproex sodium versus placebo in mood stabilizer-naive bipolar I or II depression: a double-blind, randomized, placebo-controlled trial. J Clin Psychiatry. 2011 Jun;72(6):813-9. doi: 10.4088/JCP.09m05570gre. Epub 2010 Aug 24. [Article]
11. Prasad M, Krishnan PR, Sequeira R, Al-Roomi K: Anticonvulsant therapy for status epilepticus. Cochrane Database Syst Rev. 2014 Sep 10;(9):CD003723. doi: 10.1002/14651858.CD003723.pub3. [Article]
12. El-Habr EA, Dubois LG, Burel-Vandenbos F, Bogeas A, Lipecka J, Turchi L, Lejeune FX, Coehlo PL, Yamaki T, Wittmann BM, Fareh M, Mahfoudhi E, Janin M, Narayanan A, Morvan-Dubois G, Schmitt C, Verreault M, Oliver L, Sharif A, Pallud J, Devaux B, Puget S, Korkolopoulou P, Varlet P, Ottolenghi C, Plo I, Moura-Neto V, Virolle T, Chneiweiss H, Junier MP: A driver role for GABA metabolism in controlling stem and proliferative cell state through GHB production in glioma. Acta Neuropathol. 2017 Apr;133(4):645-660. doi: 10.1007/s00401-016-1659-5. Epub 2016 Dec 28. [Article]
13. Yamada MK, Nakanishi K, Ohba S, Nakamura T, Ikegaya Y, Nishiyama N, Matsuki N: Brain-derived neurotrophic factor promotes the maturation of GABAergic mechanisms in cultured hippocampal neurons. J Neurosci. 2002 Sep 1;22(17):7580-5. [Article]
14. Shaltiel G, Shamir A, Shapiro J, Ding D, Dalton E, Bialer M, Harwood AJ, Belmaker RH, Greenberg ML, Agam G: Valproate decreases inositol biosynthesis. Biol Psychiatry. 2004 Dec 1;56(11):868-74. doi: 10.1016/j.biopsych.2004.08.027. [Article]
15. Yu W, Greenberg ML: Inositol depletion, GSK3 inhibition and bipolar disorder. Future Neurol. 2016 May;11(2):135-148. doi: 10.2217/fnl-2016-0003. Epub 2016 Apr 26. [Article]
16. Manji HK, Etcheberrigaray R, Chen G, Olds JL: Lithium decreases membrane-associated protein kinase C in hippocampus: selectivity for the alpha isozyme. J Neurochem. 1993 Dec;61(6):2303-10. [Article]
17. Yi L, Wu Q, Chen N, Song G, Wang C, Zou Q, Zhang Z: Valproate Plays a Protective Role against Migraine by Inhibiting Protein Kinase C Signalling in Nitroglycerin-treated Mice. Basic Clin Pharmacol Toxicol. 2018 Mar;122(3):310-316. doi: 10.1111/bcpt.12915. Epub 2017 Nov 12. [Article]
18. Watterson JM, Watson DG, Meyer EM, Lenox RH: A role for protein kinase C and its substrates in the action of valproic acid in the brain: implications for neural plasticity. Brain Res. 2002 Apr 26;934(1):69-80. [Article]
19. Bolanos JP, Medina JM: Effect of valproate on the metabolism of the central nervous system. Life Sci. 1997;60(22):1933-42. [Article]
20. Bazinet RP, Weis MT, Rapoport SI, Rosenberger TA: Valproic acid selectively inhibits conversion of arachidonic acid to arachidonoyl-CoA by brain microsomal long-chain fatty acyl-CoA synthetases: relevance to bipolar disorder. Psychopharmacology (Berl). 2006 Jan;184(1):122-9. Epub 2005 Dec 13. [Article]
21. Tang Y, Glauser TA, Gilbert DL, Hershey AD, Privitera MD, Ficker DM, Szaflarski JP, Sharp FR: Valproic acid blood genomic expression patterns in children with epilepsy - a pilot study. Acta Neurol Scand. 2004 Mar;109(3):159-68. [Article]
22. Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS: Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem. 2001 Sep 28;276(39):36734-41. doi: 10.1074/jbc.M101287200. Epub 2001 Jul 25. [Article]
23. Sharma RP, Rosen C, Kartan S, Guidotti A, Costa E, Grayson DR, Chase K: Valproic acid and chromatin remodeling in schizophrenia and bipolar disorder: preliminary results from a clinical population. Schizophr Res. 2006 Dec;88(1-3):227-31. doi: 10.1016/j.schres.2006.07.015. Epub 2006 Sep 25. [Article]
24. Huang Y, Doherty JJ, Dingledine R: Altered histone acetylation at glutamate receptor 2 and brain-derived neurotrophic factor genes is an early event triggered by status epilepticus. J Neurosci. 2002 Oct 1;22(19):8422-8. [Article]
25. Kanai H, Sawa A, Chen RW, Leeds P, Chuang DM: Valproic acid inhibits histone deacetylase activity and suppresses excitotoxicity-induced GAPDH nuclear accumulation and apoptotic death in neurons. Pharmacogenomics J. 2004;4(5):336-44. [Article]
26. Lopez-Munoz F, Baumeister AA, Hawkins MF, Alamo C: The role of serendipity in the discovery of the clinical effects of psychotropic drugs: beyond of the myth. Actas Esp Psiquiatr. 2012 Jan-Feb;40(1):34-42. Epub 2012 Jan 1. [Article]
27. Zaccara G, Messori A, Moroni F: Clinical pharmacokinetics of valproic acid--1988. Clin Pharmacokinet. 1988 Dec;15(6):367-89. doi: 10.2165/00003088-198815060-00002. [Article]
28. Depacon FDA Label (2006) [Link]
29. Depakene FDA [Link]
30. Depakene FDA Label (2019) [Link]
31. FDA Approved Drug Products: Stavzor (valproic acid) delayed-release capsules for oral use [Link]

External Links

Human Metabolome Database

HMDB0001877

KEGG Drug

D00399

KEGG Compound

C07185

PubChem Compound

3121

PubChem Substance

46505925

ChemSpider

3009

BindingDB

50003616

RxNav

11118

ChEBI

39867

ChEMBL

CHEMBL109

ZINC

ZINC000003008621

Therapeutic Targets Database

DNC001659

PharmGKB

PA451846

PDBe Ligand

2PP

RxList

RxList Drug Page

Drugs.com

Drugs.com Drug Page

PDRhealth

PDRhealth Drug Page

Wikipedia

Valproate

PDB Entries

1dit

FDA label

Download (316 KB)

MSDS

Download (77.9 KB)

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
4	Active Not Recruiting	Other	Epilepsy	1
4	Completed	Not Available	Healthy Subjects (HS)	1
4	Completed	Prevention	Post Cerebral Hemorrhage	1
4	Completed	Treatment	Acute Migraine	1
4	Completed	Treatment	Alcohol Withdrawal Syndrome	1

Pharmacoeconomics

Manufacturers

• Banner pharmacaps inc
• Abbott laboratories pharmaceutical products div
• Catalent pharma solutions llc
• Par pharmaceutical inc
• Rp scherer north america div rp scherer corp
• Usl pharma inc
• Alpharma uspd inc
• Apotex inc richmond hill
• High technology pharmacal co inc
• Pharmaceutical assoc inc div beach products
• Sun pharmaceutical industries inc
• Teva pharmaceuticals usa
• Vintage pharmaceuticals llc
• Wockhardt eu operations (swiss) ag

Packagers

• Abbott Laboratories Ltd.
• Apothecon
• Atlantic Biologicals Corporation
• Banner Pharmacaps Inc.
• Bedford Labs
• Ben Venue Laboratories Inc.
• Caraco Pharmaceutical Labs
• Cardinal Health
• Catalent Pharma Solutions
• Coupler Enterprises Inc.
• Global Pharmaceuticals
• Heartland Repack Services LLC
• Hi Tech Pharmacal Co. Inc.
• Impax Laboratories Inc.
• Ivax Pharmaceuticals
• Kaiser Foundation Hospital
• Lake Erie Medical and Surgical Supply
• Major Pharmaceuticals
• Mckesson Corp.
• Murfreesboro Pharmaceutical Nursing Supply
• Noven Pharmaceuticals Inc.
• Nucare Pharmaceuticals Inc.
• Pharmaceutical Association
• Pharmaceutical Utilization Management Program VA Inc.
• Physicians Total Care Inc.
• Pliva Inc.
• Precision Dose Inc.
• Prepackage Specialists
• Prepak Systems Inc.
• Professional Co.
• Qualitest
• Rebel Distributors Corp.
• Remedy Repack
• Sandoz
• Teva Pharmaceutical Industries Ltd.
• Tya Pharmaceuticals
• UDL Laboratories
• USL Pharma Inc.
• Vangard Labs Inc.
• Vintage Pharmaceuticals Inc.
• Watson Pharmaceuticals
• Wockhardt Ltd.
• Xactdose Inc.

Dosage Forms

Form	Route	Strength
Injection	Intravenous	500 mg
Tablet, delayed release	Oral	125 mg
Tablet, delayed release	Oral	250 mg / ect
Tablet, delayed release	Oral	500 mg / ect
Solution	Oral	10.000 g
Tablet	Oral	100.000 mg
Granule	Oral	200 mg
Granule	Oral	400 mg
Granule	Oral	400.000 mg
Tablet	Oral	300.00 mg
Solution	Oral	200 mg
Syrup	Oral	5 g
Injection, solution	Parenteral	100 mg/ml
Capsule	Oral	150 mg
Capsule, delayed release	Oral	300 mg/1
Capsule	Oral	300 mg
Capsule, delayed release	Oral	300 MG
Syrup	Oral	50 mg/ml
Capsule	Oral	500 mg
Tablet	Oral	300 mg
Tablet	Oral
Tablet	Oral	500 mg
Solution	Oral	20.000 g
Suspension	Oral	4.000 g
Tablet	Oral	400.0000 mg
Capsule	Oral	250.000 mg
Syrup	Oral	5.000 g
Capsule, liquid filled	Oral	250 mg
Granule	Oral	100 MG
Granule	Oral	1000 MG
Granule	Oral	250 MG
Granule	Oral	50 MG
Granule	Oral	500 MG
Granule	Oral	750 MG
Granule, delayed release	Oral
Powder, for solution	Intravenous	400 MG/4ML
Solution	Oral	200 MG/ML
Tablet, coated	Oral	300 MG
Tablet, coated	Oral	500 MG
Tablet, extended release	Oral
Syrup	Oral	57.64 mg/ml
Solution / drops	Oral	300 mg/ml
Tablet, film coated	Oral	500 mg
Injection, powder, for solution	Parenteral	400 mg
Tablet, delayed release	Oral
Tablet, extended release	Oral	250 mg/1
Tablet, extended release	Oral	500 mg/1
Tablet, extended release	Oral
Tablet, film coated, extended release	Oral
Solution	Oral
Syrup	Oral	250 mg / 5 mL
Tablet, extended release	Oral	250 mg
Capsule	Oral	125 mg/1
Capsule, coated pellets	Oral	125 mg/1
Tablet, delayed release	Oral	125 mg/1
Tablet, delayed release	Oral	250 mg/1
Tablet, delayed release	Oral	500 mg/1
Tablet, extended release	Oral	500 1/1
Tablet, extended release	Oral	583159 Mg
Tablet, film coated, extended release	Oral	250 mg/1
Tablet, film coated, extended release	Oral	500 mg/1
Tablet, film coated	Oral	125 mg/1
Tablet, film coated	Oral	250 mg/1
Tablet, film coated	Oral	500 mg/1
Tablet, delayed release particles	Oral	500 mg/1
Tablet	Oral	600.000 mg
Tablet, delayed release	Oral	300 mg
Liquid	Intravenous	500 mg / 5 mL
Tablet, delayed release	Oral	269.1 MG
Tablet, coated	Oral	200.00 mg
Tablet, film coated	Oral	199.8 mg
Injection, solution	Intravenous	400 mg/mL
Syrup	Oral	200 mg/5ml
Injection, powder, for solution	Intravenous	400 mg
Tablet	Oral	250.000 mg
Solution	Oral	300 mg
Syrup	Oral
Solution	Oral	37.5 g
Capsule, coated	Oral	250 mg
Capsule	Oral	250 mg / cap
Solution	Oral	200 mg/5mL
Tablet, extended release	Oral	270 Mg
Tablet, extended release	Oral	540 Mg
Tablet	Oral	200.000 mg
Tablet	Oral	500.00 mg
Tablet	Oral	538.00 mg
Solution	Oral	5.760 g
Capsule, extended release	Oral
Granule	Oral
Tablet, sugar coated	Oral	150 mg
Tablet, sugar coated	Oral	300 mg
Solution	Oral	60 MG/ML
Tablet, sugar coated	Oral	600 mg
Tablet, extended release	Oral	300 MG
Tablet, extended release	Oral	1000 MG
Capsule, extended release	Oral	150 MG
Capsule, extended release	Oral	300 MG
Capsule	Oral	250 mg
Solution	Oral	250 mg / 5 mL
Capsule, delayed release	Oral	500 mg
Tablet, film coated	Oral
Solution	Intravenous	500 mg
Syrup	Oral	50 mg / mL
Syrup	Oral	250 mg/5ml
Injection, solution		400 mg/4ml
Injection, solution	Intravenous	400 mg/4ml
Injection, solution	Intravenous	100.0 mg/ml
Capsule, delayed release	Oral	125 mg/1
Capsule, delayed release	Oral	250 mg/1
Capsule, delayed release	Oral	500 mg/1
Tablet	Oral	83.000 mg
Tablet, film coated	Oral	538.1 mg
Capsule, coated	Oral	125 mg
Tablet, delayed release	Oral	250 mg
Tablet, extended release	Oral	50000000 mg
Tablet, film coated, extended release	Oral
Tablet, film coated	Oral
Tablet, delayed release	Oral	200 mg
Tablet, delayed release	Oral	500 mg
Tablet, delayed release	Oral	600 MG
Solution	Oral	300 MG/G
Solution	Oral	300 MG/ML
Tablet, delayed release	Oral	150 MG
Injection	Intravenous	100 mg/1mL
Injection	Intravenous	500 mg/5mL
Injection, solution	Intravenous	100 mg/1mL
Solution / drops	Oral
Capsule, liquid filled	Oral	250 mg/1
Capsule	Oral	250 mg/1
Solution	Oral	250 mg/5mL
Solution	Oral	500 mg/10mL
Tablet	Oral	250 mg/1
Tablet	Oral	260.6 mg
Solution	Intravenous	400 mg
Tablet	Oral	400.000 mg
Tablet	Oral	269.070 mg
Tablet	Oral	269.07 mg
Tablet, delayed release	Oral	478 mg
Powder		400 mg/4ml
Syrup	Oral	200 mg/1ml
Solution		200 mg/1ml
Solution	Oral	200 mg/1ml
Tablet, extended release	Oral	500 mg

Prices

Unit description	Cost	Unit
Valproic acid liquid	10.2USD	g
Depakene 250 mg capsule	2.21USD	capsule
Valproic acid 250 mg capsule	0.79USD	capsule
Depakene 250 mg/5ml Syrup	0.66USD	ml
Novo-Valproic 500 mg Enteric-Coated Capsule	0.54USD	capsule
Pms-Valproic Acid E.C. 500 mg Enteric-Coated Capsule	0.54USD	capsule
Apo-Valproic 250 mg Capsule	0.27USD	capsule
Mylan-Valproic 250 mg Capsule	0.27USD	capsule
Novo-Valproic 250 mg Capsule	0.27USD	capsule
Nu-Valproic 250 mg Capsule	0.27USD	capsule
Pms-Valproic Acid 250 mg Capsule	0.27USD	capsule
Ratio-Valproic 250 mg Capsule	0.27USD	capsule
Sandoz Valproic 250 mg Capsule	0.27USD	capsule
Valproic Acid 250 mg/5ml Syrup	0.16USD	ml
Valproic acid 250 mg/5 ml syr	0.15USD	ml
Depakene 50 mg/ml Syrup	0.11USD	ml
Apo-Valproic 50 mg/ml Syrup	0.06USD	ml
Pms-Valproic Acid 50 mg/ml Syrup	0.06USD	ml
Ratio-Valproic 50 mg/ml Syrup	0.06USD	ml

DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US6713086	Yes	2004-03-30	2019-06-18
US6720004	Yes	2004-04-13	2019-06-18
US6511678	Yes	2003-01-28	2019-06-18
US6528090	Yes	2003-03-04	2019-06-18
US6528091	Yes	2003-03-04	2019-06-18
US6419953	Yes	2002-07-16	2019-06-18

Properties

State

Solid

Experimental Properties

Property	Value	Source
boiling point (°C)	222	ChemIDplus
water solubility	1.3 mg/mL	FDA label (2006)
logP	2.75	ChemIDplus
logS	-1.86	ADME Research, USCD
pKa	4.8	FDA label (2006)

Predicted Properties

Property	Value	Source
Water Solubility	2.36 mg/mL	ALOGPS
logP	2.54	ALOGPS
logP	2.8	Chemaxon
logS	-1.8	ALOGPS
pKa (Strongest Acidic)	5.14	Chemaxon
Physiological Charge	-1	Chemaxon
Hydrogen Acceptor Count	2	Chemaxon
Hydrogen Donor Count	1	Chemaxon
Polar Surface Area	37.3 Å2	Chemaxon
Rotatable Bond Count	5	Chemaxon
Refractivity	40.25 m3·mol-1	Chemaxon
Polarizability	17 Å3	Chemaxon
Number of Rings	0	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	No	Chemaxon
Veber's Rule	Yes	Chemaxon
MDDR-like Rule	No	Chemaxon

Predicted ADMET Features

Property	Value	Probability
Human Intestinal Absorption	+	0.9828
Blood Brain Barrier	+	0.9626
Caco-2 permeable	+	0.8866
P-glycoprotein substrate	Non-substrate	0.7345
P-glycoprotein inhibitor I	Non-inhibitor	0.9695
P-glycoprotein inhibitor II	Non-inhibitor	0.7405
Renal organic cation transporter	Non-inhibitor	0.9277
CYP450 2C9 substrate	Non-substrate	0.8247
CYP450 2D6 substrate	Non-substrate	0.9115
CYP450 3A4 substrate	Non-substrate	0.7033
CYP450 1A2 substrate	Non-inhibitor	0.5447
CYP450 2C9 inhibitor	Non-inhibitor	0.8174
CYP450 2D6 inhibitor	Non-inhibitor	0.9397
CYP450 2C19 inhibitor	Non-inhibitor	0.957
CYP450 3A4 inhibitor	Non-inhibitor	0.9583
CYP450 inhibitory promiscuity	Low CYP Inhibitory Promiscuity	0.9364
Ames test	Non AMES toxic	0.9805
Carcinogenicity	Non-carcinogens	0.5266
Biodegradation	Ready biodegradable	0.8523
Rat acute toxicity	1.8543 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Weak inhibitor	0.9357
hERG inhibition (predictor II)	Non-inhibitor	0.9249

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)

Download (8.07 KB)

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted GC-MS Spectrum - GC-MS	Predicted GC-MS	splash10-004m-9300000000-e66da5fefd079f7426a4
Mass Spectrum (Electron Ionization)	MS	splash10-0fk9-9300000000-1a0314ea63d5a3c9bba1
MS/MS Spectrum - Quattro_QQQ 10V, N/A (Annotated)	LC-MS/MS	splash10-0udi-2900000000-156413e81733a6236c1f
MS/MS Spectrum - Quattro_QQQ 25V, N/A (Annotated)	LC-MS/MS	splash10-0f6y-2900000000-a769cafb885b78532cac
MS/MS Spectrum - Quattro_QQQ 40V, N/A (Annotated)	LC-MS/MS	splash10-0gbj-7900000000-46a522b9a26459334f5a
LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 10V, Negative	LC-MS/MS	splash10-0006-0900000000-39a45d4e3201082d9d89
LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 20V, Negative	LC-MS/MS	splash10-0002-9000000000-4ddd957d8c8dc2b1de03
LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 10V, Negative	LC-MS/MS	splash10-0006-0900000000-6ba582ae102c4721034d
LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 20V, Negative	LC-MS/MS	splash10-0006-0900000000-58d9ba88010f1b370c58
LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 30V, Negative	LC-MS/MS	splash10-0006-3900000000-2d1032d7e8ac58235b4f
LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 40V, Negative	LC-MS/MS	splash10-0a4j-9000000000-0d39870bc4521a42c50a
LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 50V, Negative	LC-MS/MS	splash10-00di-9000000000-3c4e21b69b8877d6df3e
LC-MS/MS Spectrum - LC-ESI-QQ , negative	LC-MS/MS	splash10-0006-0900000000-39a45d4e3201082d9d89
LC-MS/MS Spectrum - LC-ESI-QQ , negative	LC-MS/MS	splash10-0002-9000000000-4ddd957d8c8dc2b1de03
LC-MS/MS Spectrum - LC-ESI-QQ , negative	LC-MS/MS	splash10-0006-0900000000-6ba582ae102c4721034d
LC-MS/MS Spectrum - LC-ESI-QQ , negative	LC-MS/MS	splash10-0006-0900000000-58d9ba88010f1b370c58
LC-MS/MS Spectrum - LC-ESI-QQ , negative	LC-MS/MS	splash10-0006-3900000000-2d1032d7e8ac58235b4f
LC-MS/MS Spectrum - LC-ESI-QQ , negative	LC-MS/MS	splash10-0a4j-9000000000-0d39870bc4521a42c50a
LC-MS/MS Spectrum - LC-ESI-QQ , negative	LC-MS/MS	splash10-00di-9000000000-3c4e21b69b8877d6df3e
MS/MS Spectrum - Linear Ion Trap , negative	LC-MS/MS	splash10-0006-0900000000-5b83f0d6c36f8249285a
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-05mn-9100000000-1296c85264d729ebdd60
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0006-0900000000-41f1697912c937aa72fe
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0002-9100000000-b0decd8eb32a392ef900
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0a4u-9000000000-dca6f0202defe9675c4d
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0a4i-9000000000-4e09e902a4b7ea32569b
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-052f-9000000000-2c2d7ecfe9ea944eeaf4
1H NMR Spectrum	1D NMR	Not Applicable
1H NMR Spectrum	1D NMR	Not Applicable
13C NMR Spectrum	1D NMR	Not Applicable
Predicted 1H NMR Spectrum	1D NMR	Not Applicable
Predicted 13C NMR Spectrum	1D NMR	Not Applicable
[1H,13C] 2D NMR Spectrum	2D NMR	Not Applicable

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å2)	Source type	Source
[M-H]-	134.9790161	predicted	DarkChem Lite v0.1.0
[M-H]-	135.0536161	predicted	DarkChem Lite v0.1.0
[M-H]-	134.65881	predicted	DeepCCS 1.0 (2019)
[M+H]+	137.54492	predicted	DeepCCS 1.0 (2019)
[M+Na]+	146.34946	predicted	DeepCCS 1.0 (2019)

Targets

Build, predict & validate machine-learning models

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insights and accelerate drug research.

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Binding Properties

×

Property	Measurement	pH	Temperature (°C)	References
IC 50 (nM)	>2000000	N/A	N/A	A27732

Details

Binding Properties1. Histone deacetylase 9

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Inhibitor

General Function

Transcription factor binding

Specific Function

Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an impo...

Gene Name

HDAC9

Uniprot ID

Q9UKV0

Uniprot Name

Histone deacetylase 9

Molecular Weight

111296.29 Da

References

1. Ylisastigui L, Archin NM, Lehrman G, Bosch RJ, Margolis DM: Coaxing HIV-1 from resting CD4 T cells: histone deacetylase inhibition allows latent viral expression. AIDS. 2004 May 21;18(8):1101-8. [Article]
2. Michaelis M, Kohler N, Reinisch A, Eikel D, Gravemann U, Doerr HW, Nau H, Cinatl J Jr: Increased human cytomegalovirus replication in fibroblasts after treatment with therapeutical plasma concentrations of valproic acid. Biochem Pharmacol. 2004 Aug 1;68(3):531-8. [Article]
3. Kanai H, Sawa A, Chen RW, Leeds P, Chuang DM: Valproic acid inhibits histone deacetylase activity and suppresses excitotoxicity-induced GAPDH nuclear accumulation and apoptotic death in neurons. Pharmacogenomics J. 2004;4(5):336-44. [Article]
4. Stockhausen MT, Sjolund J, Manetopoulos C, Axelson H: Effects of the histone deacetylase inhibitor valproic acid on Notch signalling in human neuroblastoma cells. Br J Cancer. 2005 Feb 28;92(4):751-9. [Article]
5. Beutler AS, Li S, Nicol R, Walsh MJ: Carbamazepine is an inhibitor of histone deacetylases. Life Sci. 2005 May 13;76(26):3107-15. [Article]
6. Rosenberg G: The mechanisms of action of valproate in neuropsychiatric disorders: can we see the forest for the trees? Cell Mol Life Sci. 2007 Aug;64(16):2090-103. [Article]
7. Kawano T, Akiyama M, Agawa-Ohta M, Mikami-Terao Y, Iwase S, Yanagisawa T, Ida H, Agata N, Yamada H: Histone deacetylase inhibitors valproic acid and depsipeptide sensitize retinoblastoma cells to radiotherapy by increasing H2AX phosphorylation and p53 acetylation-phosphorylation. Int J Oncol. 2010 Oct;37(4):787-95. [Article]

Details2. Short/branched chain specific acyl-CoA dehydrogenase, mitochondrial

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Inhibitor

General Function

Oxidoreductase activity, acting on the ch-ch group of donors, with a flavin as acceptor

Specific Function

Has greatest activity toward short branched chain acyl-CoA derivative such as (s)-2-methylbutyryl-CoA, isobutyryl-CoA, and 2-methylhexanoyl-CoA as well as toward short straight chain acyl-CoAs such...

Gene Name

ACADSB

Uniprot ID

P45954

Uniprot Name

Short/branched chain specific acyl-CoA dehydrogenase, mitochondrial

Molecular Weight

47485.035 Da

References

1. Ito M, Ikeda Y, Arnez JG, Finocchiaro G, Tanaka K: The enzymatic basis for the metabolism and inhibitory effects of valproic acid: dehydrogenation of valproyl-CoA by 2-methyl-branched-chain acyl-CoA dehydrogenase. Biochim Biophys Acta. 1990 May 16;1034(2):213-8. [Article]
2. Bazinet RP, Weis MT, Rapoport SI, Rosenberger TA: Valproic acid selectively inhibits conversion of arachidonic acid to arachidonoyl-CoA by brain microsomal long-chain fatty acyl-CoA synthetases: relevance to bipolar disorder. Psychopharmacology (Berl). 2006 Jan;184(1):122-9. Epub 2005 Dec 13. [Article]

Details3. 2-oxoglutarate dehydrogenase, mitochondrial

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Inhibitor

General Function

Thiamine pyrophosphate binding

Specific Function

The 2-oxoglutarate dehydrogenase complex catalyzes the overall conversion of 2-oxoglutarate to succinyl-CoA and CO(2). It contains multiple copies of three enzymatic components: 2-oxoglutarate dehy...

Gene Name

OGDH

Uniprot ID

Q02218

Uniprot Name

2-oxoglutarate dehydrogenase, mitochondrial

Molecular Weight

115934.37 Da

References

1. Johannessen CU, Johannessen SI: Valproate: past, present, and future. CNS Drug Rev. 2003 Summer;9(2):199-216. [Article]

Details4. Succinate-semialdehyde dehydrogenase, mitochondrial

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Inhibitor

General Function

Succinate-semialdehyde dehydrogenase [nad(p)+] activity

Specific Function

Catalyzes one step in the degradation of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA).

Gene Name

ALDH5A1

Uniprot ID

P51649

Uniprot Name

Succinate-semialdehyde dehydrogenase, mitochondrial

Molecular Weight

57214.23 Da

References

1. Johannessen CU, Johannessen SI: Valproate: past, present, and future. CNS Drug Rev. 2003 Summer;9(2):199-216. [Article]

Details5. Sodium channel protein (Protein Group)

Kind

Protein group

Organism

Humans

Pharmacological action

Unknown

Actions

Inhibitor

General Function

Voltage-gated sodium channel activity

Specific Function

Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a...

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Components:

Name	UniProt ID
Sodium channel protein type 1 subunit alpha	P35498
Sodium channel protein type 10 subunit alpha	Q9Y5Y9
Sodium channel protein type 11 subunit alpha	Q9UI33
Sodium channel protein type 2 subunit alpha	Q99250
Sodium channel protein type 3 subunit alpha	Q9NY46
Sodium channel protein type 4 subunit alpha	P35499
Sodium channel protein type 5 subunit alpha	Q14524
Sodium channel protein type 7 subunit alpha	Q01118
Sodium channel protein type 8 subunit alpha	Q9UQD0
Sodium channel protein type 9 subunit alpha	Q15858
Sodium channel subunit beta-1	Q07699
Sodium channel subunit beta-2	O60939
Sodium channel subunit beta-3	Q9NY72
Sodium channel subunit beta-4	Q8IWT1

References

1. Farber NB, Jiang XP, Heinkel C, Nemmers B: Antiepileptic drugs and agents that inhibit voltage-gated sodium channels prevent NMDA antagonist neurotoxicity. Mol Psychiatry. 2002;7(7):726-33. [Article]

Binding Properties

×

Property	Measurement	pH	Temperature (°C)	References
IC 50 (nM)	62000	N/A	N/A	A27732

Details

Binding Properties6. Histone deacetylase 2

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Inhibitor

General Function

Transcription factor binding

Specific Function

Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an impo...

Gene Name

HDAC2

Uniprot ID

Q92769

Uniprot Name

Histone deacetylase 2

Molecular Weight

55363.855 Da

References

1. Kramer OH, Zhu P, Ostendorff HP, Golebiewski M, Tiefenbach J, Peters MA, Brill B, Groner B, Bach I, Heinzel T, Gottlicher M: The histone deacetylase inhibitor valproic acid selectively induces proteasomal degradation of HDAC2. EMBO J. 2003 Jul 1;22(13):3411-20. [Article]
2. Gottlicher M: Valproic acid: an old drug newly discovered as inhibitor of histone deacetylases. Ann Hematol. 2004;83 Suppl 1:S91-2. [Article]

Details7. Peroxisome proliferator-activated receptor alpha

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

General Function

Zinc ion binding

Specific Function

Ligand-activated transcription factor. Key regulator of lipid metabolism. Activated by the endogenous ligand 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16:0/18:1-GPC). Activated by oleyleth...

Gene Name

PPARA

Uniprot ID

Q07869

Uniprot Name

Peroxisome proliferator-activated receptor alpha

Molecular Weight

52224.595 Da

References

1. Szalowska E, van der Burg B, Man HY, Hendriksen PJ, Peijnenburg AA: Model steatogenic compounds (amiodarone, valproic acid, and tetracycline) alter lipid metabolism by different mechanisms in mouse liver slices. PLoS One. 2014 Jan 29;9(1):e86795. doi: 10.1371/journal.pone.0086795. eCollection 2014. [Article]

Details8. Peroxisome proliferator-activated receptor delta

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

General Function

Zinc ion binding

Specific Function

Ligand-activated transcription factor. Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Has a preference for poly-unsaturated fatty acids, such as gamma-lin...

Gene Name

PPARD

Uniprot ID

Q03181

Uniprot Name

Peroxisome proliferator-activated receptor delta

Molecular Weight

49902.99 Da

References

1. Szalowska E, van der Burg B, Man HY, Hendriksen PJ, Peijnenburg AA: Model steatogenic compounds (amiodarone, valproic acid, and tetracycline) alter lipid metabolism by different mechanisms in mouse liver slices. PLoS One. 2014 Jan 29;9(1):e86795. doi: 10.1371/journal.pone.0086795. eCollection 2014. [Article]

Details9. Peroxisome proliferator-activated receptor gamma

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

General Function

Zinc ion binding

Specific Function

Nuclear receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the nuclear receptor binds to DNA specific PPAR response elements (PPRE...

Gene Name

PPARG

Uniprot ID

P37231

Uniprot Name

Peroxisome proliferator-activated receptor gamma

Molecular Weight

57619.58 Da

References

1. Szalowska E, van der Burg B, Man HY, Hendriksen PJ, Peijnenburg AA: Model steatogenic compounds (amiodarone, valproic acid, and tetracycline) alter lipid metabolism by different mechanisms in mouse liver slices. PLoS One. 2014 Jan 29;9(1):e86795. doi: 10.1371/journal.pone.0086795. eCollection 2014. [Article]

Details10. Histone deacetylase (Protein Group)

Kind

Protein group

Organism

Humans

Pharmacological action

Unknown

Actions

Inhibitor

General Function

Transcription regulatory region sequence-specific dna binding

Specific Function

Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an impo...

---

Components:

Name	UniProt ID
Histone deacetylase 1	Q13547
Histone deacetylase 10	Q969S8
Histone deacetylase 11	Q96DB2
Histone deacetylase 2	Q92769
Histone deacetylase 3	O15379
Histone deacetylase 4	P56524
Histone deacetylase 5	Q9UQL6
Histone deacetylase 6	Q9UBN7
Histone deacetylase 7	Q8WUI4
Histone deacetylase 8	Q9BY41
Histone deacetylase 9	Q9UKV0

References

1. Booth L, Roberts JL, Poklepovic A, Dent P: [pemetrexed + sildenafil], via autophagy-dependent HDAC downregulation, enhances the immunotherapy response of NSCLC cells. Cancer Biol Ther. 2017 Sep 2;18(9):705-714. doi: 10.1080/15384047.2017.1362511. [Article]
2. Nelson-DeGrave VL, Wickenheisser JK, Cockrell JE, Wood JR, Legro RS, Strauss JF 3rd, McAllister JM: Valproate potentiates androgen biosynthesis in human ovarian theca cells. Endocrinology. 2004 Feb;145(2):799-808. Epub 2003 Oct 23. [Article]
3. Chabane N, Li X, Fahmi H: HDAC4 contributes to IL-1-induced mPGES-1 expression in human synovial fibroblasts through up-regulation of Egr-1 transcriptional activity. J Cell Biochem. 2009 Feb 15;106(3):453-63. doi: 10.1002/jcb.22027. [Article]
4. Rocchi P, Tonelli R, Camerin C, Purgato S, Fronza R, Bianucci F, Guerra F, Pession A, Ferreri AM: p21Waf1/Cip1 is a common target induced by short-chain fatty acid HDAC inhibitors (valproic acid, tributyrin and sodium butyrate) in neuroblastoma cells. Oncol Rep. 2005 Jun;13(6):1139-44. [Article]
5. Kouraklis G, Theocharis S: Histone deacetylase inhibitors and anticancer therapy. Curr Med Chem Anticancer Agents. 2002 Jul;2(4):477-84. doi: 10.2174/1568011023353921. [Article]
6. Chang MC, Chen YJ, Lian YC, Chang BE, Huang CC, Huang WL, Pan YH, Jeng JH: Butyrate Stimulates Histone H3 Acetylation, 8-Isoprostane Production, RANKL Expression, and Regulated Osteoprotegerin Expression/Secretion in MG-63 Osteoblastic Cells. Int J Mol Sci. 2018 Dec 17;19(12). pii: ijms19124071. doi: 10.3390/ijms19124071. [Article]
7. Matsumoto Y, Motoki T, Kubota S, Takigawa M, Tsubouchi H, Gohda E: Inhibition of tumor-stromal interaction through HGF/Met signaling by valproic acid. Biochem Biophys Res Commun. 2008 Feb 1;366(1):110-6. doi: 10.1016/j.bbrc.2007.11.089. Epub 2007 Nov 29. [Article]

Details11. Cyclin-dependent kinase inhibitor 1

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Regulator

General Function

May be involved in p53/TP53 mediated inhibition of cellular proliferation in response to DNA damage. Binds to and inhibits cyclin-dependent kinase activity, preventing phosphorylation of critical cyclin-dependent kinase substrates and blocking cell cycle progression. Functions in the nuclear localization and assembly of cyclin D-CDK4 complex and promotes its kinase activity towards RB1. At higher stoichiometric ratios, inhibits the kinase activity of the cyclin D-CDK4 complex. Inhibits DNA synthesis by DNA polymerase delta by competing with POLD3 for PCNA binding (PubMed:11595739).

Specific Function

Cyclin binding

Gene Name

CDKN1A

Uniprot ID

P38936

Uniprot Name

Cyclin-dependent kinase inhibitor 1

Molecular Weight

18119.145 Da

References

1. Rocchi P, Tonelli R, Camerin C, Purgato S, Fronza R, Bianucci F, Guerra F, Pession A, Ferreri AM: p21Waf1/Cip1 is a common target induced by short-chain fatty acid HDAC inhibitors (valproic acid, tributyrin and sodium butyrate) in neuroblastoma cells. Oncol Rep. 2005 Jun;13(6):1139-44. [Article]

Details12. Hepatocyte growth factor

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Inhibitor

General Function

Serine-type endopeptidase activity

Specific Function

Potent mitogen for mature parenchymal hepatocyte cells, seems to be a hepatotrophic factor, and acts as a growth factor for a broad spectrum of tissues and cell types. Activating ligand for the rec...

Gene Name

HGF

Uniprot ID

P14210

Uniprot Name

Hepatocyte growth factor

Molecular Weight

83133.115 Da

References

1. Matsumoto Y, Motoki T, Kubota S, Takigawa M, Tsubouchi H, Gohda E: Inhibition of tumor-stromal interaction through HGF/Met signaling by valproic acid. Biochem Biophys Res Commun. 2008 Feb 1;366(1):110-6. doi: 10.1016/j.bbrc.2007.11.089. Epub 2007 Nov 29. [Article]

Details13. Ornithine decarboxylase

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Downregulator

General Function

Protein homodimerization activity

Specific Function

Key enzyme of polyamine biosynthesis that converts ornithine into putrescine, which is the precursor for the polyamines, spermidine and spermine.

Gene Name

ODC1

Uniprot ID

P11926

Uniprot Name

Ornithine decarboxylase

Molecular Weight

51147.73 Da

References

1. Booth L, Roberts JL, Poklepovic A, Dent P: [pemetrexed + sildenafil], via autophagy-dependent HDAC downregulation, enhances the immunotherapy response of NSCLC cells. Cancer Biol Ther. 2017 Sep 2;18(9):705-714. doi: 10.1080/15384047.2017.1362511. [Article]

Details14. Programmed cell death 1 ligand 1

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Downregulator

General Function

Not Available

Specific Function

Involved in the costimulatory signal, essential for T-cell proliferation and production of IL10 and IFNG, in an IL2-dependent and a PDCD1-independent manner. Interaction with PDCD1 inhibits T-cell ...

Gene Name

CD274

Uniprot ID

Q9NZQ7

Uniprot Name

Programmed cell death 1 ligand 1

Molecular Weight

33275.095 Da

References

1. Booth L, Roberts JL, Poklepovic A, Dent P: [pemetrexed + sildenafil], via autophagy-dependent HDAC downregulation, enhances the immunotherapy response of NSCLC cells. Cancer Biol Ther. 2017 Sep 2;18(9):705-714. doi: 10.1080/15384047.2017.1362511. [Article]

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Drug created at June 13, 2005 13:24 / Updated at February 20, 2024 23:55