Identification

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Name
Valproic acid
Accession Number
DB00313  (APRD00256, DB00510, APRD00066)
Type
Small Molecule
Groups
Approved, Investigational
Description

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.

Structure
Thumb
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
Product Ingredients
IngredientUNIICASInChI Key
Divalproex sodium644VL95AO676584-70-8MSRILKIQRXUYCT-UHFFFAOYSA-M
Valproate sodium5VOM6GYJ0D1069-66-5AEQFSUDEHCCHBT-UHFFFAOYSA-M
Product Images
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
DepaconInjection100 mg/1mLIntravenousAbbVie Inc.1996-12-302019-11-01Us
DepakeneCapsule250 mgOralBgp Pharma Ulc1978-12-312017-05-16Canada
DepakeneCapsule, liquid filled250 mg/1OralRemedy Repack2016-09-022018-10-11Us
DepakeneCapsule, liquid filled250 mg/1OralAbbVie Inc.1978-02-282019-10-11Us
DepakeneSolution250 mg/5mLOralAbbVie Inc.1978-02-282019-07-17Us
DepakeneSolution250 mgOralBgp Pharma Ulc1978-12-31Not applicableCanada
DepakeneCapsule, liquid filled250 mg/1OralREMEDYREPACK INC.2018-10-03Not applicableUs
Depakene Cap 500mgCapsule, delayed releaseOralAbbott1981-12-312007-05-11Canada
DepakoteTablet, delayed release500 mg/1OralREMEDYREPACK INC.2014-07-112018-10-11Us00074 6215 13 nlmimage10 00210038
DepakoteTablet, delayed release500 mg/1OralRemedy Repack2008-08-072018-10-24Us
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Apo-divalproexTablet, delayed releaseOralApotex Corporation1999-03-24Not applicableCanada
Apo-divalproexTablet, delayed releaseOralApotex Corporation1999-03-24Not applicableCanada
Apo-divalproexTablet, delayed releaseOralApotex Corporation1999-03-24Not applicableCanada
Apo-valproicCapsuleOralApotex Corporation1998-06-01Not applicableCanada
Apo-valproicSolutionOralApotex Corporation1998-07-15Not applicableCanada
Divalproex SodiumTablet, film coated, extended release250 mg/1OralNcs Health Care Of Ky, Inc Dba Vangard Labs2010-02-08Not applicableUs
Divalproex SodiumTablet, extended release500 mg/1OralContract Pharmacy Services Pa2017-09-21Not applicableUs
Divalproex SodiumTablet, film coated, extended release250 mg/1OralAphena Pharma Solutions Tennessee, Inc.2009-01-29Not applicableUs
Divalproex SodiumTablet, film coated, extended release500 mg/1OralAmerican Health Packaging2013-11-14Not applicableUs
Divalproex SodiumTablet, delayed release125 mg/1OralREMEDYREPACK INC.2017-04-07Not applicableUs
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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International/Other Brands
Convulex / Depakine / Deprakine / Encorate / Epilim / Valcote / Valparin
Categories
UNII
614OI1Z5WI
CAS number
99-66-1
Weight
Average: 144.2114
Monoisotopic: 144.115029756
Chemical Formula
C8H16O2
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

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

Associated Conditions
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 GABAA 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

TargetActionsOrganism
UShort/branched chain specific acyl-CoA dehydrogenase, mitochondrial
inhibitor
Humans
AHistone deacetylase 9
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 alphaNot AvailableHumans
UPeroxisome proliferator-activated receptor deltaNot AvailableHumans
UPeroxisome proliferator-activated receptor gammaNot AvailableHumans
Additional Data Available
Adverse Effects

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Contraindications

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Blackbox Warnings

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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, 10% bound at 4 mcg/mL, but becomes non-linear at higher concentrations, increasing up to 18.5% bound 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.

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/m2Label

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

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

Affected organisms
  • Humans and other mammals
Pathways
PathwayCategory
Valproic Acid Metabolism PathwayDrug metabolism
Pharmacogenomic Effects/ADRs
Interacting Gene/EnzymeAllele nameGenotype(s)Defining Change(s)Type(s)DescriptionDetails
DNA polymerase subunit gamma-1A467T(A;A) / (A;G)G > AADR Directly StudiedThe 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-1W748S(C;C) / (C;G)G > CADR Directly StudiedThe 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
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.
DrugInteraction
(6R)-Folinic acidThe serum concentration of (6R)-Folinic acid can be decreased when it is combined with Valproic Acid.
(6S)-5,6,7,8-tetrahydrofolateThe serum concentration of (6S)-5,6,7,8-tetrahydrofolate can be decreased when it is combined with Valproic Acid.
(R)-warfarinThe serum concentration of (R)-warfarin can be increased when it is combined with Valproic acid.
(S)-WarfarinThe serum concentration of (S)-Warfarin can be increased when it is combined with Valproic acid.
2,5-Dimethoxy-4-ethylamphetamineThe risk or severity of serotonin syndrome can be increased when Valproic Acid is combined with 2,5-Dimethoxy-4-ethylamphetamine.
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of adverse effects can be increased when Valproic acid is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
3-isobutyl-1-methyl-7H-xanthineValproic Acid may increase the excretion rate of 3-isobutyl-1-methyl-7H-xanthine which could result in a lower serum level and potentially a reduction in efficacy.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Valproic acid.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of adverse effects can be increased when Valproic Acid is combined with 4-Bromo-2,5-dimethoxyamphetamine.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Valproic acid.
Additional Data Available
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    Extended Description

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  • Severity
    Severity

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Food Interactions
  • Avoid alcohol.
  • Do not take with milk.
  • Take with food.

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. [PubMed:17514356]
  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. [PubMed:16099290]
  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. [PubMed:17273758]
  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. [PubMed:17218782]
  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. [PubMed:23797677]
  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. [PubMed:22276680]
  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. [PubMed:24132760]
  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. [PubMed:18162014]
  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. [PubMed:15780695]
  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. [PubMed:20816041]
  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. [PubMed:25207925]
  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. [PubMed:28032215]
  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. [PubMed:12196581]
  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. [PubMed:15576064]
  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. [PubMed:29339929]
  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. [PubMed:8245981]
  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. [PubMed:28990289]
  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. [PubMed:11937071]
  19. Bolanos JP, Medina JM: Effect of valproate on the metabolism of the central nervous system. Life Sci. 1997;60(22):1933-42. [PubMed:9180347]
  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. [PubMed:16344985]
  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. [PubMed:14763951]
  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. [PubMed:11473107]
  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. [PubMed:16996718]
  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. [PubMed:12351716]
  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. [PubMed:15289798]
  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. [PubMed:22344494]
  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. [PubMed:3149565]
  28. Depacon FDA Label (2006) [Link]
  29. Depakene FDA [Link]
  30. Depakene FDA Label (2019) [Link]
External Links
Human Metabolome Database
HMDB0001877
KEGG Drug
D00399
KEGG Compound
C07185
PubChem Compound
3121
PubChem Substance
46505925
ChemSpider
3009
BindingDB
50003616
ChEBI
39867
ChEMBL
CHEMBL109
Therapeutic Targets Database
DNC001659
PharmGKB
PA451846
HET
2PP
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
PDRhealth
PDRhealth Drug Page
Wikipedia
Valproic_Acid
ATC Codes
N03AG01 — Valproic acid
AHFS Codes
  • 28:12.92 — Miscellaneous Anticonvulsants
PDB Entries
1dit
FDA label
Download (316 KB)
MSDS
Download (77.9 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0CompletedBasic ScienceAlzheimer's Disease (AD)1
0CompletedPreventionHead and Neck Squamous Cell Carcinoma (HNSCC)1
0CompletedTreatmentChronic Lymphocytic Leukaemia (CLL)1
0RecruitingPreventionTumors, Solid1
0Unknown StatusBasic ScienceBladder Cancers / Hematuria1
1CompletedNot AvailableBipolar Disorder (BD) / Psychotic Disorder NOS / Schizophrenic Disorders1
1CompletedNot AvailableEpilepsies / Schizophrenic Disorders1
1CompletedNot AvailableHealthy Volunteers9
1CompletedHealth Services ResearchHealthy Volunteers1
1CompletedPreventionContraception1
1CompletedTreatmentAcute Myelogenous Leukaemia (AML) / Myelodysplastic Syndrome1
1CompletedTreatmentAdnexal Masses / Borderline Ovarian Epithelial Tumor / Neoplasms, Ovarian / Ovarian Clear Cell Tumor / Ovarian Endometrioid Tumor / Ovarian Serous Tumor / Recurrent Ovarian Carcinoma1
1CompletedTreatmentAdult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities / Adult Acute Myeloid Leukemia With Del(5q) / Adult Acute Myeloid Leukemia With Inv(16)(p13;q22) / Adult Acute Myeloid Leukemia With T(15;17)(q22;q12) / Adult Acute Myeloid Leukemia With T(16;16)(p13;q22) / Adult Acute Myeloid Leukemia With T(8;21)(q22;q22) / Chronic Lymphocytic Leukemia (CLL) - Refractory / Recurrent Adult Acute Myeloid Leukemia / Recurrent Small Lymphocytic Lymphoma / Untreated Adult Acute Myeloid Leukemia1
1CompletedTreatmentAdvanced Cancers1
1CompletedTreatmentBipolar Disorder (BD)1
1CompletedTreatmentBipolar Disorder (BD) / Epilepsies2
1CompletedTreatmentBrain and Central Nervous System Tumors / Unspecified Childhood Solid Tumor, Protocol Specific1
1CompletedTreatmentCancer, Advanced1
1CompletedTreatmentCancer, Advanced / Metastatic Brain Tumors / Neuroectodermal Tumors1
1CompletedTreatmentDrug Drug Interaction (DDI)1
1CompletedTreatmentEpilepsies1
1CompletedTreatmentHealthy Volunteers7
1CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections1
1CompletedTreatmentLocally Advanced Sarcoma / Metastatic Sarcoma / Sarcomas / Soft Tissue Sarcoma (STS) / Unresectable Sarcoma1
1CompletedTreatmentLung Cancers1
1CompletedTreatmentNeoplams, Advanced / Neoplasms, Advanced1
1CompletedTreatmentNon-Small Cell Lung Cancer Recurrent / Stage IV Non-Small Cell Lung Cancer1
1CompletedTreatmentRecurrent Adult Burkitt Lymphoma / Recurrent Adult Diffuse Large Cell Lymphoma / Recurrent Mantle Cell Lymphoma1
1CompletedTreatmentSeizures1
1CompletedTreatmentShock, Hemorrhagic1
1CompletedTreatmentSpinal Muscular Atrophy (SMA)1
1CompletedTreatmentTumors, Solid2
1CompletedTreatmentThrombotic events1
1RecruitingTreatmentAcute Leukemia in Remission / Acute Lymphoblastic Leukemia in Remission / Haematological Malignancies / Lymphoma, Hodgkins / Myelodysplastic Syndromes / Non-Hodgkin's Lymphoma (NHL)1
1RecruitingTreatmentAdvanced Cancers / Advanced Malignant Neoplasm / Castleman's Disease / Digestive System Carcinoma / Erdheim-Chester Disease (ECD) / Lip and Oral Cavity Carcinoma / Lymphangioleiomyomatosis / Malignant Endocrine Neoplasm / Malignant Female Reproductive System Neoplasm / Malignant Male Reproductive System Neoplasm / Malignant respiratory tract neoplasm / Malignant Thoracic Neoplasm / Malignant Urinary System Neoplasm / Mesothelial Neoplasm / Metastatic Malignant Neoplasm / Neoplasms, Malignant / Neurofibromatosis Type 2 / Recurrent Adult Soft Tissue Sarcoma / Recurrent Breast Carcinoma / Recurrent Childhood Soft Tissue Sarcoma / Recurrent Digestive System Carcinoma / Recurrent Female Reproductive System Carcinoma / Recurrent Male Reproductive System Carcinoma / Recurrent Malignant Neoplasm / Recurrent Pharyngeal Carcinoma / Recurrent Thyroid Gland Carcinoma / Refractory Malignant Neoplasm / Soft Tissue Neoplasms / Stage III Breast Cancer AJCC V7 / Stage III Pharyngeal Cancer / Stage IIIA Breast Cancer AJCC v7 / Stage IIIB Breast Cancer AJCC v7 / Stage IIIC Breast Cancer AJCC v7 / Stage IV Breast Cancer AJCC v6 and v7 / Stage IV Pharyngeal Cancer / Stage IVA Pharyngeal Cancer / Stage IVB Pharyngeal Cancer / Stage IVC Pharyngeal Cancer / Thyroid Gland Neoplasm / Urothelial carcinoma ureter metastatic1
1RecruitingTreatmentGlioblastomas1
1RecruitingTreatmentNasopharyngeal Carcinoma2
1TerminatedTreatmentBrain and Central Nervous System Tumors / Neuroblastomas / Sarcomas / Unspecified Childhood Solid Tumor, Protocol Specific1
1TerminatedTreatmentHigh Grade Sarcoma1
1TerminatedTreatmentHuman Immunodeficiency Virus (HIV) Infections1
1TerminatedTreatmentMalignancies1
1TerminatedTreatmentMetastatic Brain Tumors1
1TerminatedTreatmentShock, Hemorrhagic / Traumas1
1TerminatedTreatmentSolid Tumor Malignancies1
1Unknown StatusDiagnosticEpilepsies1
1Unknown StatusPreventionTraumatic Brain Injury (TBI)1
1Unknown StatusTreatmentDementias1
1WithdrawnTreatmentAnaplastic Astrocytoma (AA) / Glioblastomas / Gliomas / Medulloblastomas / Pediatric Brain Tumor1
1, 2CompletedTreatmentALPS / Hypersplenism / Lymphadenopathy1
1, 2CompletedTreatmentAcute Myelogenous Leukaemia (AML)2
1, 2CompletedTreatmentAlcohol Dependence / Bipolar Disorder (BD)1
1, 2CompletedTreatmentBipolar Disorder (BD) / Dependence, Cocaine1
1, 2CompletedTreatmentLeukemias / Myelodysplastic Syndromes1
1, 2CompletedTreatmentLymphoma, Large B-Cell, Diffuse (DLBCL)1
1, 2CompletedTreatmentSpinal Muscular Atrophy Type I1
1, 2RecruitingTreatmentCardiac Valve Disease / Coronary Artery Disease / Organ Failure, Multiple1
1, 2RecruitingTreatmentColorectal Cancers1
1, 2RecruitingTreatmentEpilepsies1
1, 2RecruitingTreatmentHIV-1-infection1
1, 2RecruitingTreatmentLeukemia Acute Myeloid Leukemia (AML)1
1, 2RecruitingTreatmentSolid Tumor, Adult1
1, 2TerminatedTreatmentMalignant Melanoma1
1, 2Unknown StatusTreatmentChronic Lymphocytic Leukaemia (CLL)1
1, 2Unknown StatusTreatmentLocally Advanced Inoperable Non-small-lung Cancer1
1, 2WithdrawnTreatmentScleroderma / Sclerosis, Progressive Systemic1
2Active Not RecruitingTreatmentAnaplastic Astrocytoma (AA) / Brain Stem Gliomas / Glial Cell Tumors / Glioblastoma Multiforme (GBM) / Gliomatosis Cerebri / Gliosarcoma / Malignant Gliomas1
2Active Not RecruitingTreatmentSmith-Magenis Syndrome1
2CompletedPreventionPain, Neuropathic / Phantom Pain1
2CompletedTreatmentAcute Myelogenous Leukaemia (AML) / Leukemias / Myelodysplastic Syndrome1
2CompletedTreatmentAcute Myelogenous Leukaemia (AML) / Myelodysplastic Syndrome2
2CompletedTreatmentAcute Myelogenous Leukaemia (AML) / Myelodysplastic Syndromes (MDS)1
2CompletedTreatmentAlcohol Dependence / Bipolar Disorder (BD)1
2CompletedTreatmentAlzheimer's Disease (AD)1
2CompletedTreatmentAndrogenetic Alopecia1
2CompletedTreatmentAutism, Early Infantile1
2CompletedTreatmentCancer, Breast1
2CompletedTreatmentEpilepsies / Infantile Spasms (IS)1
2CompletedTreatmentEye Disease, Hereditary / Eye Diseases / Retinal Degenerations / Retinal Diseases / Retinitis Pigmentosa (RP)1
2CompletedTreatmentGlycogen Storage Disease Type V1
2CompletedTreatmentGrand Mal Status Epilepticus1
2CompletedTreatmentHead and Neck Carcinoma / Oral Cavity Cancer / Oropharyngeal Cancers1
2CompletedTreatmentHigh Grade Gliomas / Neoplasms, Brain1
2CompletedTreatmentHuntington's Disease (HD)1
2CompletedTreatmentIntermittent Explosive Disorder1
2CompletedTreatmentLeukemia Acute Myeloid Leukemia (AML)1
2CompletedTreatmentMesothelioma, Malignant1
2CompletedTreatmentMixed Mania Bipolar Disorder1
2CompletedTreatmentMoods Disorders1
2CompletedTreatmentMyelodysplastic Syndromes1
2CompletedTreatmentNeoplasms, Thyroid1
2CompletedTreatmentPediatric Epilepsy1
2CompletedTreatmentProgressive Supranuclear Palsy (PSP)1
2CompletedTreatmentRetinitis Pigmentosa (RP)1
2CompletedTreatmentRubinstein-Taybi Syndrome1
2CompletedTreatmentSchizophrenic Disorders1
2CompletedTreatmentSmall Cell Lung Carcinoma1
2CompletedTreatmentSpecific Phobias1
2CompletedTreatmentSpinal Muscular Atrophy (SMA)2
2RecruitingOtherWolfram Syndrome1
2RecruitingTreatmentAcute Myelogenous Leukemia AML / Myelodysplastic Syndrome MDS1
2RecruitingTreatmentBrain and Nervous System / Glioblastomas / Gliomas / Malignant Gliomas / Recurrent Adult Brain Neoplasm / WHO Grade III Glioma1
2RecruitingTreatmentCancer That is Associated With a Chronic Viral Infection / EBER Positive Hodgkins and Non-hodgkins Lymphona / EBER Positive NPC / P16 Positive SCCHN / P16 Positive Squamous Cell Carcinoma of the Anus or Anal Canal / P16 Positive Squamous Cell Carcinoma of the Penis / P16 Positive Squamous Cell Carcinoma of the Vagina or Vulva / Squamous Cell Carcinoma of the Cervix1
2RecruitingTreatmentCiliary Body and Choroid Melanoma, Medium/Large Size / Ciliary Body and Choroid Melanoma, Small Size / Iris Melanoma / Stage I Intraocular Melanoma / Stage IIA Intraocular Melanoma / Stage IIB Intraocular Melanoma / Stage IIIA Intraocular Melanoma / Stage IIIB Intraocular Melanoma / Stage IIIC Intraocular Melanoma1
2RecruitingTreatmentGeneralized Convulsive Status Epilepticus1
2RecruitingTreatmentGraft Versus Host Disease, Acute / Peripheral Blood Stem Cell Transplantation1
2RecruitingTreatmentMigraine in Children1
2RecruitingTreatmentSquamous Cell Carcinoma of the Head and Neck (SCCHN)1
2TerminatedTreatmentBipolar 1 Disorder1
2TerminatedTreatmentCancer, Breast1
2TerminatedTreatmentChronic Lymphocytic Leukaemia (CLL)1
2TerminatedTreatmentHead and Neck Carcinoma1
2TerminatedTreatmentHuman Immunodeficiency Virus (HIV) Infections1
2TerminatedTreatmentMyelodysplastic Syndrome MDS1
2TerminatedTreatmentProstate Cancer1
2Unknown StatusTreatmentHuman Immunodeficiency Virus (HIV) Infections1
2Unknown StatusTreatmentLeukemias / Malignant Lymphomas1
2Unknown StatusTreatmentMalignant Neoplasm of Pancreas1
2Unknown StatusTreatmentMyelodysplastic Syndrome1
2Unknown StatusTreatmentNodding Syndrome1
2WithdrawnTreatmentAutism Spectrum Conditions/Disorders / Autism, Early Infantile1
2WithdrawnTreatmentAutism, Early Infantile1
2WithdrawnTreatmentBipolar Disorder (BD) / Depression, Bipolar1
2WithdrawnTreatmentBipolar I or II Depression and Alcohol Abuse or Dependence1
2WithdrawnTreatmentDepression, Bipolar1
2WithdrawnTreatmentChronic Chronic myelogenous leukemia1
2, 3CompletedTreatmentAlcohol Dependence / Alcohol Related Disorders / Moods Disorders1
2, 3CompletedTreatmentBipolar Disorder (BD)1
2, 3CompletedTreatmentBipolar Disorder (BD) / Depression, Bipolar1
2, 3Not Yet RecruitingTreatmentGlomerulonephritis minimal lesion / Glomerulosclerosis, Focal Segmental / Idiopathic Nephrotic Syndrome1
2, 3RecruitingTreatmentChildhood Ependymoma1
2, 3TerminatedTreatmentNeurocostal neuralgia / Neuropathic Peripheral Pain1
3Active Not RecruitingTreatmentBenzodiazepine Refractory Status Epilepticus1
3CompletedDiagnosticBipolar Disorder (BD)1
3CompletedPreventionBipolar Disorder (BD)1
3CompletedPreventionBipolar I Disorder1
3CompletedTreatmentAlcohol Dependence1
3CompletedTreatmentAlcohol Dependence / Bipolar I Disorder1
3CompletedTreatmentAlzheimer's Disease (AD)1
3CompletedTreatmentAmyotrophic Lateral Sclerosis (ALS)1
3CompletedTreatmentAttention Deficit and Disruptive Behavior Disorders / Marijuana Abuse1
3CompletedTreatmentBipolar Disorder (BD)10
3CompletedTreatmentBipolar Disorder (BD) / Schizophrenic Disorders1
3CompletedTreatmentBipolar Disorder Mania1
3CompletedTreatmentBipolar I Disorder2
3CompletedTreatmentBipolar I Disorder, Manic or Mixed1
3CompletedTreatmentBipolar Spectrum Disorder With Moderate-to- Severe Hypomania or Mild Mania1
3CompletedTreatmentChildhood Absence Epilepsy / Epilepsies / Petit Mal Epilepsy / Seizures1
3CompletedTreatmentCraniocerebral Injuries / Post-Traumatic Seizure Disorder1
3CompletedTreatmentDepression, Bipolar1
3CompletedTreatmentEpilepsies1
3CompletedTreatmentEpilepsies / Seizures1
3CompletedTreatmentGrand Mal Status Epilepticus / Non-convulsive Status Epilepticus1
3CompletedTreatmentManic or Mixed Episode Associated With Bipolar I Disorder1
3CompletedTreatmentMigraine3
3CompletedTreatmentParaparesis Spastic Tropical1
3CompletedTreatmentPost Traumatic Stress Disorder (PTSD)1
3CompletedTreatmentPsychomotor Agitation1
3CompletedTreatmentPartial onset seizure Epilepsy1
3Enrolling by InvitationTreatmentBipolar Disorder II1
3RecruitingTreatmentAnaplastic Astrocytoma WHO Grade III / Diffuse Intrinsic Pontine Glioma (DIPG) / Diffuse Midline Glioma Histone 3 K27M WHO Grade IV / Glioblastoma WHO Grade IV / Gliomatosis Cerebri1
3RecruitingTreatmentSpinal Muscular Atrophy (SMA)1
3TerminatedTreatmentAcute Agitation / Dementias1
3TerminatedTreatmentAnxiety Disorders / Dementias / Depression / Psychosomatic Disorders / Schizophrenic Disorders1
3TerminatedTreatmentBipolar Disorder (BD)1
3TerminatedTreatmentSeizure Disorder, Partial1
3Unknown StatusTreatmentAutism, Early Infantile1
3Unknown StatusTreatmentBipolar Disorder (BD)1
3WithdrawnTreatmentMigraine Disorders1
4Active Not RecruitingTreatmentEpilepsy, Idiopathic Generalized1
4CompletedNot AvailableConvulsions / Epilepsies / Osteopenia / Osteoporosis / Seizures1
4CompletedNot AvailableHealthy Volunteers1
4CompletedPreventionPost Cerebral Hemorrhage1
4CompletedTreatmentAcute Migraine1
4CompletedTreatmentAlzheimer's Disease (AD) / Dementia, Alzheimer Type / Dementias / Senile Dementia, Alzheimer Type1
4CompletedTreatmentAttention Deficit Disorder With Hyperactivity / Oppositional Defiant Disorder1
4CompletedTreatmentBipolar Disorder (BD)14
4CompletedTreatmentBipolar Disorder (BD) / Depression1
4CompletedTreatmentBipolar Disorder (BD) / Mania2
4CompletedTreatmentBipolar Disorder (BD) / Mania / Substance Abuse / Substance Dependence1
4CompletedTreatmentBipolar I Disorder2
4CompletedTreatmentBipolar I Disorder / Bipolar II Disorder1
4CompletedTreatmentBronchial Asthma1
4CompletedTreatmentDepression, Bipolar1
4CompletedTreatmentDepression, Bipolar / Substance Abuse1
4CompletedTreatmentEpilepsies4
4CompletedTreatmentHealthy Volunteers1
4CompletedTreatmentIrritable Aggression1
4CompletedTreatmentMania / Mixed Mania1
4CompletedTreatmentMoods Disorders1
4CompletedTreatmentOpiate Dependence / Substance Withdrawal Syndrome / Substance, Addiction1
4CompletedTreatmentSchizoaffective Disorders / Schizophrenic Disorders1
4CompletedTreatmentSchizophrenic Disorders2
4CompletedTreatmentSchizophrenic Disorders / Toxoplasmosis1
4Not Yet RecruitingBasic ScienceBariatric Surgery Candidate1
4Not Yet RecruitingTreatmentBenign Childhood Epilepsy With Centrotemporal Spikes1
4Not Yet RecruitingTreatmentEpilepsy, Localization Related1
4RecruitingPreventionAlcohol Dependence / Alcohol Use Disorder (AUD) / Alcohol Withdrawal Syndrome(AWS) / Heavy Drinking / Traumas1
4RecruitingTreatmentAcute Kidney Injury (AKI) / Impaired Renal Function / Pharmacokinetics / Renal Failure1
4RecruitingTreatmentAlcohol Withdrawal Syndrome(AWS)1
4RecruitingTreatmentBipolar Disorder (BD)1
4RecruitingTreatmentEpilepsies1
4RecruitingTreatmentGliomas1
4TerminatedTreatmentBMI >30 kg/m2 / Healthy Volunteers / Pharmacokinetics1
4TerminatedTreatmentBipolar Disorder (BD)2
4TerminatedTreatmentHyperactive Delirium / Mixed Delirium1
4TerminatedTreatmentMalignant Lymphomas / Precancerous/Nonmalignant Condition1
4TerminatedTreatmentPost Traumatic Stress Disorder (PTSD)1
4Unknown StatusNot AvailableBipolar Affective Disorders1
4Unknown StatusTreatmentAttention Deficit Disorder With Hyperactivity1
4Unknown StatusTreatmentAutism, Early Infantile1
4Unknown StatusTreatmentBipolar Disorder (BD) / Generalized Anxiety Disorder (GAD) / Panic Disorders1
4Unknown StatusTreatmentCardiac Arrest1
4Unknown StatusTreatmentEpilepsies1
4WithdrawnTreatmentAlzheimer's Disease (AD) / Behavioral Symptoms / Dementias1
4WithdrawnTreatmentBipolar Disorder (BD)2
4WithdrawnTreatmentDepression, Bipolar1
Not AvailableCompletedNot AvailableBipolar Disorder (BD)2
Not AvailableCompletedNot AvailableBipolar Disorder (BD) / Epilepsies1
Not AvailableCompletedNot AvailableEpilepsies3
Not AvailableCompletedTreatmentAlcohol Dependence / Traumatic Brain Injury (TBI)1
Not AvailableCompletedTreatmentBipolar Disorder (BD)1
Not AvailableCompletedTreatmentBody Composition / Insulin Resistance1
Not AvailableCompletedTreatmentBorderline Personality Disorder (BPD)1
Not AvailableCompletedTreatmentCluster Headache1
Not AvailableCompletedTreatmentElderly / Epilepsies / Seizures1
Not AvailableCompletedTreatmentEpilepsies1
Not AvailableCompletedTreatmentGeneralized Convulsive Status Epilepticus / Intensive Care Units1
Not AvailableCompletedTreatmentPhotosensitive Epilepsy1
Not AvailableCompletedTreatmentSarcomas1
Not AvailableCompletedTreatmentSubstance Withdrawal Syndrome1
Not AvailableEnrolling by InvitationNot AvailableBipolar Disorder (BD)1
Not AvailableEnrolling by InvitationTreatmentSchizophrenic Disorders1
Not AvailableRecruitingNot AvailableEpilepsies1
Not AvailableRecruitingTreatmentAnoxic Encephalopathy / Cardiac Arrest / Refractory seizure disorders1
Not AvailableRecruitingTreatmentSchizophrenic Disorders1
Not AvailableTerminatedTreatmentSubarachnoid Hemorrhage1
Not AvailableTerminatedTreatmentTropical Spastic Paraparesis1
Not AvailableUnknown StatusNot AvailableAdverse Effects / Epilepsies1
Not AvailableUnknown StatusNot AvailableRefractory seizure disorders1
Not AvailableUnknown StatusTreatmentBipolar Disorder (BD)1
Not AvailableUnknown StatusTreatmentChronic Lymphocytic Leukaemia (CLL)1
Not AvailableUnknown StatusTreatmentSchizophrenic Disorders1

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
FormRouteStrength
Tablet, delayed releaseOral
CapsuleOral250 mg
SolutionOral250 mg
Tablet, extended releaseOral250 mg/1
Tablet, extended releaseOral500 mg/1
SyrupOral
CapsuleNot applicable125 mg/1
CapsuleOral125 mg/1
Capsule, coated pelletsOral125 mg/1
Tablet, delayed releaseOral125 mg/1
Tablet, delayed releaseOral250 mg/1
Tablet, delayed releaseOral500 mg/1
Tablet, film coated, extended releaseOral250 mg/1
Tablet, film coated, extended releaseOral500 mg/1
Tablet, film coatedOral125 mg/1
Tablet, film coatedOral250 mg/1
Tablet, film coatedOral500 mg/1
Tablet, delayed release particlesOral500 mg/1
LiquidIntravenous
Tablet, extended releaseOral
CapsuleOral
SolutionOral
Capsule, delayed releaseOral
Capsule, delayed releaseOral125 mg/1
Capsule, delayed releaseOral250 mg/1
Capsule, delayed releaseOral500 mg/1
InjectionIntravenous100 mg/1mL
InjectionIntravenous500 mg/5mL
Injection, solutionIntravenous100 mg/1mL
Capsule, liquid filledOral250 mg/1
CapsuleOral250 mg/1
SolutionOral250 mg/5mL
SolutionOral500 mg/10mL
TabletOral250 mg/1
Prices
Unit descriptionCostUnit
Valproic acid liquid10.2USD g
Depakene 250 mg capsule2.21USD capsule
Valproic acid 250 mg capsule0.79USD capsule
Depakene 250 mg/5ml Syrup0.66USD ml
Novo-Valproic 500 mg Enteric-Coated Capsule0.54USD capsule
Pms-Valproic Acid E.C. 500 mg Enteric-Coated Capsule0.54USD capsule
Apo-Valproic 250 mg Capsule0.27USD capsule
Mylan-Valproic 250 mg Capsule0.27USD capsule
Novo-Valproic 250 mg Capsule0.27USD capsule
Nu-Valproic 250 mg Capsule0.27USD capsule
Pms-Valproic Acid 250 mg Capsule0.27USD capsule
Ratio-Valproic 250 mg Capsule0.27USD capsule
Sandoz Valproic 250 mg Capsule0.27USD capsule
Valproic Acid 250 mg/5ml Syrup0.16USD ml
Valproic acid 250 mg/5 ml syr0.15USD ml
Depakene 50 mg/ml Syrup0.11USD ml
Apo-Valproic 50 mg/ml Syrup0.06USD ml
Pms-Valproic Acid 50 mg/ml Syrup0.06USD ml
Ratio-Valproic 50 mg/ml Syrup0.06USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US6713086Yes2004-03-302019-06-18Us
US6720004Yes2004-04-132019-06-18Us
US6511678Yes2003-01-282019-06-18Us
US6528090Yes2003-03-042019-06-18Us
US6528091Yes2003-03-042019-06-18Us
US6419953Yes2002-07-162019-06-18Us
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

    Learn more

Properties

State
Solid
Experimental Properties
PropertyValueSource
boiling point (°C)222ChemIDplus
water solubility1.3 mg/mLFDA label (2006)
logP2.75ChemIDplus
logS-1.86ADME Research, USCD
pKa4.8FDA label (2006)
Predicted Properties
PropertyValueSource
Water Solubility2.36 mg/mLALOGPS
logP2.54ALOGPS
logP2.8ChemAxon
logS-1.8ALOGPS
pKa (Strongest Acidic)5.14ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area37.3 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity40.25 m3·mol-1ChemAxon
Polarizability17 Å3ChemAxon
Number of Rings0ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9828
Blood Brain Barrier+0.9626
Caco-2 permeable+0.8866
P-glycoprotein substrateNon-substrate0.7345
P-glycoprotein inhibitor INon-inhibitor0.9695
P-glycoprotein inhibitor IINon-inhibitor0.7405
Renal organic cation transporterNon-inhibitor0.9277
CYP450 2C9 substrateNon-substrate0.8247
CYP450 2D6 substrateNon-substrate0.9115
CYP450 3A4 substrateNon-substrate0.7033
CYP450 1A2 substrateNon-inhibitor0.5447
CYP450 2C9 inhibitorNon-inhibitor0.8174
CYP450 2D6 inhibitorNon-inhibitor0.9397
CYP450 2C19 inhibitorNon-inhibitor0.957
CYP450 3A4 inhibitorNon-inhibitor0.9583
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9364
Ames testNon AMES toxic0.9805
CarcinogenicityNon-carcinogens0.5266
BiodegradationReady biodegradable0.8523
Rat acute toxicity1.8543 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9357
hERG inhibition (predictor II)Non-inhibitor0.9249
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Download (8.07 KB)
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Mass Spectrum (Electron Ionization)MSsplash10-0fk9-9300000000-1a0314ea63d5a3c9bba1
MS/MS Spectrum - Quattro_QQQ 10V, N/A (Annotated)LC-MS/MSsplash10-0udi-2900000000-156413e81733a6236c1f
MS/MS Spectrum - Quattro_QQQ 25V, N/A (Annotated)LC-MS/MSsplash10-0f6y-2900000000-a769cafb885b78532cac
MS/MS Spectrum - Quattro_QQQ 40V, N/A (Annotated)LC-MS/MSsplash10-0gbj-7900000000-46a522b9a26459334f5a
LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 10V, NegativeLC-MS/MSsplash10-0006-0900000000-39a45d4e3201082d9d89
LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 20V, NegativeLC-MS/MSsplash10-0002-9000000000-4ddd957d8c8dc2b1de03
LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 10V, NegativeLC-MS/MSsplash10-0006-0900000000-6ba582ae102c4721034d
LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 20V, NegativeLC-MS/MSsplash10-0006-0900000000-58d9ba88010f1b370c58
LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 30V, NegativeLC-MS/MSsplash10-0006-3900000000-2d1032d7e8ac58235b4f
LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 40V, NegativeLC-MS/MSsplash10-0a4j-9000000000-0d39870bc4521a42c50a
LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 50V, NegativeLC-MS/MSsplash10-00di-9000000000-3c4e21b69b8877d6df3e
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-QQ , negativeLC-MS/MSsplash10-0006-0900000000-39a45d4e3201082d9d89
LC-MS/MS Spectrum - LC-ESI-QQ , negativeLC-MS/MSsplash10-0002-9000000000-4ddd957d8c8dc2b1de03
LC-MS/MS Spectrum - LC-ESI-QQ , negativeLC-MS/MSsplash10-0006-0900000000-6ba582ae102c4721034d
LC-MS/MS Spectrum - LC-ESI-QQ , negativeLC-MS/MSsplash10-0006-0900000000-58d9ba88010f1b370c58
LC-MS/MS Spectrum - LC-ESI-QQ , negativeLC-MS/MSsplash10-0006-3900000000-2d1032d7e8ac58235b4f
LC-MS/MS Spectrum - LC-ESI-QQ , negativeLC-MS/MSsplash10-0a4j-9000000000-0d39870bc4521a42c50a
LC-MS/MS Spectrum - LC-ESI-QQ , negativeLC-MS/MSsplash10-00di-9000000000-3c4e21b69b8877d6df3e
MS/MS Spectrum - Linear Ion Trap , negativeLC-MS/MSsplash10-0006-0900000000-5b83f0d6c36f8249285a
1H NMR Spectrum1D NMRNot Applicable
1H NMR Spectrum1D NMRNot Applicable
13C NMR Spectrum1D NMRNot Applicable
[1H,13C] 2D NMR Spectrum2D NMRNot Applicable

Taxonomy

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
Methyl-branched fatty acid / Monocarboxylic acid or derivatives / Carboxylic acid / Carboxylic acid derivative / Organic oxygen compound / Organic oxide / Hydrocarbon derivative / Organooxygen compound / Carbonyl group / Aliphatic acyclic compound
Molecular Framework
Aliphatic acyclic compounds
External Descriptors
branched-chain fatty acid, branched-chain saturated fatty acid (CHEBI:39867) / Branched fatty acids (LMFA01020291)

Targets

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. [PubMed:2112956]
  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. [PubMed:16344985]
Details
2. 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. [PubMed:15166525]
  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. [PubMed:15242819]
  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. [PubMed:15289798]
  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. [PubMed:15685243]
  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. [PubMed:15850602]
  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. [PubMed:17514356]
  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. [PubMed:20811699]
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. [PubMed:12847559]
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. [PubMed:12847559]
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...

Components:
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. [PubMed:12192617]
Details
6. 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. [PubMed:12840003]
  2. Gottlicher M: Valproic acid: an old drug newly discovered as inhibitor of histone deacetylases. Ann Hematol. 2004;83 Suppl 1:S91-2. [PubMed:15124690]
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. [PubMed:24489787]
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. [PubMed:24489787]
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. [PubMed:24489787]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inducer
General Function
Steroid hydroxylase activity
Specific Function
Exhibits a high coumarin 7-hydroxylase activity. Can act in the hydroxylation of the anti-cancer drugs cyclophosphamide and ifosphamide. Competent in the metabolic activation of aflatoxin B1. Const...
Gene Name
CYP2A6
Uniprot ID
P11509
Uniprot Name
Cytochrome P450 2A6
Molecular Weight
56501.005 Da
References
  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [PubMed:19515014]
  2. Raunio H, Rautio A, Gullsten H, Pelkonen O: Polymorphisms of CYP2A6 and its practical consequences. Br J Clin Pharmacol. 2001 Oct;52(4):357-63. [PubMed:11678779]
  3. Rendic S: Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448. [PubMed:11996015]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
References
  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [PubMed:19515014]
  2. Hedrich WD, Hassan HE, Wang H: Insights into CYP2B6-mediated drug-drug interactions. Acta Pharm Sin B. 2016 Sep;6(5):413-425. doi: 10.1016/j.apsb.2016.07.016. Epub 2016 Aug 9. [PubMed:27709010]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [PubMed:19515014]
  2. Amini-Shirazi N, Ghahremani MH, Ahmadkhaniha R, Mandegary A, Dadgar A, Abdollahi M, Shadnia S, Pakdaman H, Kebriaeezadeh A: Influence of CYP2C9 polymorphism on metabolism of valproate and its hepatotoxin metabolite in Iranian patients. Toxicol Mech Methods. 2010 Oct;20(8):452-7. doi: 10.3109/15376516.2010.497977. [PubMed:20602621]
  3. Gunes A, Bilir E, Zengil H, Babaoglu MO, Bozkurt A, Yasar U: Inhibitory effect of valproic acid on cytochrome P450 2C9 activity in epilepsy patients. Basic Clin Pharmacol Toxicol. 2007 Jun;100(6):383-6. doi: 10.1111/j.1742-7843.2007.00061.x. [PubMed:17516991]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxygen binding
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
References
  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [PubMed:19515014]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Prostaglandin-endoperoxide synthase activity
Specific Function
Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Involved in the constitutive production of prostanoids in particular in the stomach and platelets. In gas...
Gene Name
PTGS1
Uniprot ID
P23219
Uniprot Name
Prostaglandin G/H synthase 1
Molecular Weight
68685.82 Da
References
  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [PubMed:19515014]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Data supported only by in vitro studies.
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. Facciola G, Avenoso A, Scordo MG, Madia AG, Ventimiglia A, Perucca E, Spina E: Small effects of valproic acid on the plasma concentrations of clozapine and its major metabolites in patients with schizophrenic or affective disorders. Ther Drug Monit. 1999 Jun;21(3):341-5. [PubMed:10365650]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. Fleming J, Chetty M: Psychotropic drug interactions with valproate. Clin Neuropharmacol. 2005 Mar-Apr;28(2):96-101. [PubMed:15795555]
  2. Anderson GD: A mechanistic approach to antiepileptic drug interactions. Ann Pharmacother. 1998 May;32(5):554-63. doi: 10.1345/aph.17332. [PubMed:9606477]
  3. Gunes A, Bilir E, Zengil H, Babaoglu MO, Bozkurt A, Yasar U: Inhibitory effect of valproic acid on cytochrome P450 2C9 activity in epilepsy patients. Basic Clin Pharmacol Toxicol. 2007 Jun;100(6):383-6. doi: 10.1111/j.1742-7843.2007.00061.x. [PubMed:17516991]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Facciola G, Avenoso A, Scordo MG, Madia AG, Ventimiglia A, Perucca E, Spina E: Small effects of valproic acid on the plasma concentrations of clozapine and its major metabolites in patients with schizophrenic or affective disorders. Ther Drug Monit. 1999 Jun;21(3):341-5. [PubMed:10365650]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Protein homodimerization activity
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
Gene Name
UGT1A4
Uniprot ID
P22310
Uniprot Name
UDP-glucuronosyltransferase 1-4
Molecular Weight
60024.535 Da
References
  1. Argikar UA, Remmel RP: Effect of aging on glucuronidation of valproic acid in human liver microsomes and the role of UDP-glucuronosyltransferase UGT1A4, UGT1A8, and UGT1A10. Drug Metab Dispos. 2009 Jan;37(1):229-36. doi: 10.1124/dmd.108.022426. Epub 2008 Oct 6. [PubMed:18838507]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. Isoform 2 lacks transferase activity but acts as a negative reg...
Gene Name
UGT1A8
Uniprot ID
Q9HAW9
Uniprot Name
UDP-glucuronosyltransferase 1-8
Molecular Weight
59741.035 Da
References
  1. Krishnaswamy S, Hao Q, Al-Rohaimi A, Hesse LM, von Moltke LL, Greenblatt DJ, Court MH: UDP glucuronosyltransferase (UGT) 1A6 pharmacogenetics: II. Functional impact of the three most common nonsynonymous UGT1A6 polymorphisms (S7A, T181A, and R184S). J Pharmacol Exp Ther. 2005 Jun;313(3):1340-6. Epub 2005 Mar 10. [PubMed:15761113]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Protein kinase c binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. Isoform 2 lacks transferase activity but acts as a negative reg...
Gene Name
UGT1A10
Uniprot ID
Q9HAW8
Uniprot Name
UDP-glucuronosyltransferase 1-10
Molecular Weight
59809.075 Da
References
  1. Krishnaswamy S, Hao Q, Al-Rohaimi A, Hesse LM, von Moltke LL, Greenblatt DJ, Court MH: UDP glucuronosyltransferase (UGT) 1A6 pharmacogenetics: II. Functional impact of the three most common nonsynonymous UGT1A6 polymorphisms (S7A, T181A, and R184S). J Pharmacol Exp Ther. 2005 Jun;313(3):1340-6. Epub 2005 Mar 10. [PubMed:15761113]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Protein homodimerization activity
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform has specificity for phenols. Isoform 3 lacks trans...
Gene Name
UGT1A6
Uniprot ID
P19224
Uniprot Name
UDP-glucuronosyltransferase 1-6
Molecular Weight
60750.215 Da
References
  1. Krishnaswamy S, Hao Q, Al-Rohaimi A, Hesse LM, von Moltke LL, Greenblatt DJ, Court MH: UDP glucuronosyltransferase (UGT) 1A6 pharmacogenetics: II. Functional impact of the three most common nonsynonymous UGT1A6 polymorphisms (S7A, T181A, and R184S). J Pharmacol Exp Ther. 2005 Jun;313(3):1340-6. Epub 2005 Mar 10. [PubMed:15761113]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Retinoic acid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. Isoform 2 lacks transferase activity but acts as a negative reg...
Gene Name
UGT1A3
Uniprot ID
P35503
Uniprot Name
UDP-glucuronosyltransferase 1-3
Molecular Weight
60337.835 Da
References
  1. Krishnaswamy S, Hao Q, Al-Rohaimi A, Hesse LM, von Moltke LL, Greenblatt DJ, Court MH: UDP glucuronosyltransferase (UGT) 1A6 pharmacogenetics: II. Functional impact of the three most common nonsynonymous UGT1A6 polymorphisms (S7A, T181A, and R184S). J Pharmacol Exp Ther. 2005 Jun;313(3):1340-6. Epub 2005 Mar 10. [PubMed:15761113]
  2. Argikar UA, Remmel RP: Effect of aging on glucuronidation of valproic acid in human liver microsomes and the role of UDP-glucuronosyltransferase UGT1A4, UGT1A8, and UGT1A10. Drug Metab Dispos. 2009 Jan;37(1):229-36. doi: 10.1124/dmd.108.022426. Epub 2008 Oct 6. [PubMed:18838507]
  3. Chung JY, Cho JY, Yu KS, Kim JR, Lim KS, Sohn DR, Shin SG, Jang IJ: Pharmacokinetic and pharmacodynamic interaction of lorazepam and valproic acid in relation to UGT2B7 genetic polymorphism in healthy subjects. Clin Pharmacol Ther. 2008 Apr;83(4):595-600. Epub 2007 Aug 8. [PubMed:17687269]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Glucuronosyltransferase activity
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds.Its unique specificity for 3,4-catechol estrogens and estriol su...
Gene Name
UGT2B7
Uniprot ID
P16662
Uniprot Name
UDP-glucuronosyltransferase 2B7
Molecular Weight
60694.12 Da
References
  1. Chung JY, Cho JY, Yu KS, Kim JR, Lim KS, Sohn DR, Shin SG, Jang IJ: Pharmacokinetic and pharmacodynamic interaction of lorazepam and valproic acid in relation to UGT2B7 genetic polymorphism in healthy subjects. Clin Pharmacol Ther. 2008 Apr;83(4):595-600. Epub 2007 Aug 8. [PubMed:17687269]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Glucuronosyltransferase activity
Specific Function
UDPGTs are of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isozyme displays activity toward several classes of xeno...
Gene Name
UGT2B15
Uniprot ID
P54855
Uniprot Name
UDP-glucuronosyltransferase 2B15
Molecular Weight
61035.815 Da
References
  1. Chung JY, Cho JY, Yu KS, Kim JR, Lim KS, Sohn DR, Shin SG, Jang IJ: Pharmacokinetic and pharmacodynamic interaction of lorazepam and valproic acid in relation to UGT2B7 genetic polymorphism in healthy subjects. Clin Pharmacol Ther. 2008 Apr;83(4):595-600. Epub 2007 Aug 8. [PubMed:17687269]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Retinoic acid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform has specificity for phenols. Isoform 2 lacks trans...
Gene Name
UGT1A9
Uniprot ID
O60656
Uniprot Name
UDP-glucuronosyltransferase 1-9
Molecular Weight
59940.495 Da
References
  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [PubMed:19515014]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
General Function
Steroid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
Gene Name
UGT1A1
Uniprot ID
P22309
Uniprot Name
UDP-glucuronosyltransferase 1-1
Molecular Weight
59590.91 Da
References
  1. Interactions [Link]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Dasgupta A, Emerson L: Interaction of valproic acid with nonsteroidal antiinflammatory drugs mefenamic acid and fenoprofen in normal and uremic sera: lack of interaction in uremic sera due to the presence of endogenous factors. Ther Drug Monit. 1996 Dec;18(6):654-9. [PubMed:8946661]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Involved in the renal elimination of endogenous and exogenous organic anions. Functions as organic anion exchanger when the uptake of one molecule of organic anion is coupled with an efflux of one ...
Gene Name
SLC22A6
Uniprot ID
Q4U2R8
Uniprot Name
Solute carrier family 22 member 6
Molecular Weight
61815.78 Da
References
  1. Sekine T, Watanabe N, Hosoyamada M, Kanai Y, Endou H: Expression cloning and characterization of a novel multispecific organic anion transporter. J Biol Chem. 1997 Jul 25;272(30):18526-9. [PubMed:9228014]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Symporter activity
Specific Function
Sodium-ion dependent, high affinity carnitine transporter. Involved in the active cellular uptake of carnitine. Transports one sodium ion with one molecule of carnitine. Also transports organic cat...
Gene Name
SLC22A5
Uniprot ID
O76082
Uniprot Name
Solute carrier family 22 member 5
Molecular Weight
62751.08 Da
References
  1. Ohashi R, Tamai I, Yabuuchi H, Nezu JI, Oku A, Sai Y, Shimane M, Tsuji A: Na(+)-dependent carnitine transport by organic cation transporter (OCTN2): its pharmacological and toxicological relevance. J Pharmacol Exp Ther. 1999 Nov;291(2):778-84. [PubMed:10525100]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Plays an important role in the excretion/detoxification of endogenous and exogenous organic anions, especially from the brain and kidney. Involved in the transport basolateral of steviol, fexofenad...
Gene Name
SLC22A8
Uniprot ID
Q8TCC7
Uniprot Name
Solute carrier family 22 member 8
Molecular Weight
59855.585 Da
References
  1. Ohtsuki S, Asaba H, Takanaga H, Deguchi T, Hosoya K, Otagiri M, Terasaki T: Role of blood-brain barrier organic anion transporter 3 (OAT3) in the efflux of indoxyl sulfate, a uremic toxin: its involvement in neurotransmitter metabolite clearance from the brain. J Neurochem. 2002 Oct;83(1):57-66. [PubMed:12358729]
  2. Cha SH, Sekine T, Fukushima JI, Kanai Y, Kobayashi Y, Goya T, Endou H: Identification and characterization of human organic anion transporter 3 expressing predominantly in the kidney. Mol Pharmacol. 2001 May;59(5):1277-86. [PubMed:11306713]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Symporter activity
Specific Function
Proton-coupled monocarboxylate transporter. Catalyzes the rapid transport across the plasma membrane of many monocarboxylates such as lactate, pyruvate, branched-chain oxo acids derived from leucin...
Gene Name
SLC16A1
Uniprot ID
P53985
Uniprot Name
Monocarboxylate transporter 1
Molecular Weight
53943.685 Da
References
  1. Tamai I, Sai Y, Ono A, Kido Y, Yabuuchi H, Takanaga H, Satoh E, Ogihara T, Amano O, Izeki S, Tsuji A: Immunohistochemical and functional characterization of pH-dependent intestinal absorption of weak organic acids by the monocarboxylic acid transporter MCT1. J Pharm Pharmacol. 1999 Oct;51(10):1113-21. [PubMed:10579682]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates sodium-independent multispecific organic anion transport. Transport of prostaglandin E2, prostaglandin F2, tetracycline, bumetanide, estrone sulfate, glutarate, dehydroepiandrosterone sulf...
Gene Name
SLC22A7
Uniprot ID
Q9Y694
Uniprot Name
Solute carrier family 22 member 7
Molecular Weight
60025.025 Da
References
  1. Kobayashi Y, Ohshiro N, Shibusawa A, Sasaki T, Tokuyama S, Sekine T, Endou H, Yamamoto T: Isolation, characterization and differential gene expression of multispecific organic anion transporter 2 in mice. Mol Pharmacol. 2002 Jul;62(1):7-14. [PubMed:12065749]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent transport of organic anions such as taurocholate, the prostaglandins PGD2, PGE1, PGE2, leukotriene C4, thromboxane B2 and iloprost.
Gene Name
SLCO2B1
Uniprot ID
O94956
Uniprot Name
Solute carrier organic anion transporter family member 2B1
Molecular Weight
76709.98 Da
References
  1. Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P: Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions. J Med Chem. 2012 May 24;55(10):4740-63. doi: 10.1021/jm300212s. Epub 2012 May 15. [PubMed:22541068]

Drug created on June 13, 2005 07:24 / Updated on October 18, 2019 21:36