Valproate (VPA) and its valproic acid, sodium valproate, and valproate semisodium forms are medications primarily used to treat

epilepsy Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrica ...

and

bipolar disorder Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that last from days to weeks each. If the elevated mood is severe or associated with ...

and prevent migraine headaches. They are useful for the prevention of seizures in those with absence seizures,

partial seizure Focal seizures (also called partial seizures and localized seizures) are seizures which affect initially only one hemisphere of the brain. The brain is divided into two hemispheres, each consisting of four lobes – the frontal, temporal, parie ...

s, and

generalized seizure Generalized epilepsy is a form of epilepsy characterised by generalised seizures with no apparent cause. Generalized seizures, as opposed to focal seizures, are a type of seizure that impairs consciousness and distorts the electrical activity of ...

s. They can be given intravenously or by mouth, and the tablet forms exist in both long- and short-acting formulations. Common side effects of valproate include nausea, vomiting,

somnolence Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling asleep ...

, and dry mouth. Serious side effects can include liver failure, and regular monitoring of liver function tests is therefore recommended. Other serious risks include

pancreatitis Pancreatitis is a condition characterized by inflammation of the pancreas. The pancreas is a large organ behind the stomach that produces digestive enzymes and a number of hormones. There are two main types: acute pancreatitis, and chronic pancr ...

and an increased suicide risk. Valproate is known to cause serious abnormalities in fetuses if taken during

pregnancy Pregnancy is the time during which one or more offspring develops (gestation, gestates) inside a woman, woman's uterus (womb). A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occur ...

, and is contra-indicated for women of childbearing age unless the drug is essential to their medical condition. As of 2022 the drug was still prescribed in the UK to potentially pregnant women, but use declined by 51% from 2018–19 to 2020–21. Valproate's precise mechanism of action is unclear. Proposed mechanisms include affecting GABA levels, blocking

voltage-gated sodium channel Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's membrane. They belong to the superfamily of cation channels and can be classified according to the trigger that opens the channel ...

s, and inhibiting histone deacetylases. Valproic acid is a branched

short-chain fatty acid Short-chain fatty acids (SCFAs) are fatty acids with fewer than six carbon atoms. Derived from intestinal microbial fermentation of indigestible foods, SCFAs are the main energy source of colonocytes, making them crucial to gastrointestinal healt ...

(SCFA) made from

valeric acid Valeric acid or pentanoic acid is a straight-chain alkyl carboxylic acid with the chemical formula . Like other low-molecular-weight carboxylic acids, it has an unpleasant odor. It is found in the perennial flowering plant ''Valeriana officin ...

. Valproate was first made in 1881 and came into medical use in 1962. It is on the

World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...

and is available as a generic medication. In 2020, it was the 109th most commonly prescribed medication in the United States, with more than 6million prescriptions.

Terminology

Valproic acid (VPA) is an organic weak acid. The

conjugate base A conjugate acid, within the Brønsted–Lowry acid–base theory, is a chemical compound formed when an acid donates a proton () to a base—in other words, it is a base with a hydrogen ion added to it, as in the reverse reaction it loses a ...

is valproate. The sodium

salt Salt is a mineral composed primarily of sodium chloride (NaCl), a chemical compound belonging to the larger class of salts; salt in the form of a natural crystalline mineral is known as rock salt or halite. Salt is present in vast quant ...

of the acid is sodium valproate and a

coordination complex A coordination complex consists of a central atom or ion, which is usually metallic and is called the ''coordination centre'', and a surrounding array of bound molecules or ions, that are in turn known as '' ligands'' or complexing agents. ...

of the two is known as valproate semisodium.

Medical uses

It is used primarily to treat

and

. It is also used to prevent migraine headaches.

Epilepsy

Valproate has a broad spectrum of anticonvulsant activity, although it is primarily used as a first-line treatment for tonic–clonic seizures,

absence seizures Absence seizures are one of several kinds of generalized seizures. These seizures are sometimes referred to as petit mal seizures (from the French for "little illness", a term dated in the late 18th century). Absence seizures are characterized b ...

and myoclonic seizures and as a second-line treatment for partial seizures and infantile spasms. It has also been successfully given

intravenously Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...

to treat status epilepticus.

Mental illness

Bipolar disorder

Valproate products are also used to treat manic or mixed episodes of

Schizophrenia

A 2016 systematic review compared the efficacy of valproate as an add-on for people with

schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social wit ...

Dopamine dysregulation syndrome

Based upon five case reports, valproic acid may have efficacy in controlling the symptoms of the

dopamine dysregulation syndrome Dopamine dysregulation syndrome (DDS) is a dysfunction of the reward system observed in some individuals taking dopaminergic medications for an extended length of time. It typically occurs in people with Parkinson's disease (PD) who have taken dop ...

that arise from the treatment of

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...

with levodopa.

Migraines

Valproate is also used to prevent

migraine headaches Migraine (, ) is a common neurological disorder characterized by recurrent headaches. Typically, the associated headache affects one side of the head, is pulsating in nature, may be moderate to severe in intensity, and could last from a few hou ...

Other

The medication has been tested in the treatment of AIDS and

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

, owing to its histone-deacetylase-inhibiting effects.

Contraindications

Contraindications include: * Pre-existing acute or chronic liver dysfunction or family history of severe liver inflammation (hepatitis), particularly medicine related. * Known

hypersensitivity Hypersensitivity (also called hypersensitivity reaction or intolerance) refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. They are usually referred to as an over-reaction of the immune ...

to valproate or any of the ingredients used in the preparation * Urea cycle disorders * Hepatic

porphyria Porphyria is a group of liver disorders in which substances called porphyrins build up in the body, negatively affecting the skin or nervous system. The types that affect the nervous system are also known as acute porphyria, as symptoms are ...

*Hepatotoxicity *

Mitochondrial disease Mitochondrial disease is a group of disorders caused by mitochondrial dysfunction. Mitochondria are the organelles that generate energy for the cell and are found in every cell of the human body except red blood cells. They convert the energy of ...

Pancreatitis Pancreatitis is a condition characterized by inflammation of the pancreas. The pancreas is a large organ behind the stomach that produces digestive enzymes and a number of hormones. There are two main types: acute pancreatitis, and chronic pancr ...

Porphyria Porphyria is a group of liver disorders in which substances called porphyrins build up in the body, negatively affecting the skin or nervous system. The types that affect the nervous system are also known as acute porphyria, as symptoms are ...

Pregnancy Pregnancy is the time during which one or more offspring develops (gestation, gestates) inside a woman, woman's uterus (womb). A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occur ...

(except when no other treatments are available for the treatment of epilepsy)

Adverse effects

Most common adverse effects include: * Nausea (22%) *

Drowsiness Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling asleep ...

(19%) * Dizziness (12%) * Vomiting (12%) *

Weakness Weakness is a symptom of a number of different conditions. The causes are many and can be divided into conditions that have true or perceived muscle weakness. True muscle weakness is a primary symptom of a variety of skeletal muscle diseases, i ...

(10%) Serious adverse effects include: * Bleeding * Low blood platelets *

Encephalopathy Encephalopathy (; from grc, ἐνκέφαλος "brain" + πάθος "suffering") means any disorder or disease of the brain, especially chronic degenerative conditions. In modern usage, encephalopathy does not refer to a single disease, but r ...

* Suicidal behavior and thoughts * Low body temperature Valproic acid has a

black box warning In the United States, a boxed warning (sometimes "black box warning", colloquially) is a type of warning that appears on the package insert for certain prescription drugs, so called because the U.S. Food and Drug Administration specifies that it ...

for

hepatotoxicity Hepatotoxicity (from ''hepatic toxicity'') implies chemical-driven liver damage. Drug-induced liver injury is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdrawn fr ...

, and fetal abnormalities. It is worthy of mentioning that some adverse effects related to valproic acid may be dose-dependent such as pancytopenia. There is evidence that valproic acid may cause premature growth plate

ossification Ossification (also called osteogenesis or bone mineralization) in bone remodeling is the process of laying down new bone material by cells named osteoblasts. It is synonymous with bone tissue formation. There are two processes resulting in ...

in children and adolescents, resulting in decreased height. Valproic acid can also cause mydriasis, a dilation of the pupils. There is evidence that shows valproic acid may increase the chance of

polycystic ovary syndrome Polycystic ovary syndrome, or PCOS, is the most common endocrine disorder in women of reproductive age. The syndrome is named after the characteristic cysts which may form on the ovaries, though it is important to note that this is a sign and no ...

(PCOS) in women with epilepsy or bipolar disorder. Studies have shown this risk of PCOS is higher in women with epilepsy compared to those with bipolar disorder. Weight gain is also possible.

Pregnancy

Valproate causes birth defects; exposure during

is associated with about three times as many major abnormalities as usual, mainly

spina bifida Spina bifida (Latin for 'split spine'; SB) is a birth defect in which there is incomplete closing of the spine and the membranes around the spinal cord during early development in pregnancy. There are three main types: spina bifida occulta, men ...

with the risks being related to the strength of medication used and use of more than one drug. More rarely, with several other defects, including a "valproate syndrome". Characteristics of this valproate syndrome include facial features that tend to evolve with age, including a triangle-shaped forehead, tall forehead with bifrontal narrowing,

epicanthic fold An epicanthic fold or epicanthus is a skin fold of the upper eyelid that covers the inner corner (medial canthus) of the eye. However, variation occurs in the nature of this feature and the possession of "partial epicanthic folds" or "slight ...

s, medial deficiency of eyebrows, flat nasal bridge, broad

nasal root The human nose is the most protruding part of the face. It bears the nostrils and is the first organ of the respiratory system. It is also the principal organ in the olfactory system. The shape of the nose is determined by the nasal bones a ...

, anteverted nares, shallow

philtrum The philtrum ( la, philtrum from Ancient Greek ''phíltron,'' lit. "love charm"), or medial cleft, is a vertical indentation in the middle area of the upper lip, common to therian mammals, extending in humans from the nasal septum to the tubercl ...

, long upper lip and thin vermillion borders, thick lower lip and small downturned mouth. While

developmental delay Global developmental delay is an umbrella term used when children are significantly delayed in their cognitive and physical development. It can be diagnosed when a child is delayed in one or more milestones, categorised into motor skills, speech ...

is usually associated with altered physical characteristics (

dysmorphic feature A dysmorphic feature is an abnormal difference in body structure. It can be an isolated finding in an otherwise normal individual, or it can be related to a congenital disorder, genetic syndrome or birth defect. Dysmorphology is the study of dysm ...

s), this is not always the case. Children of mothers taking valproate during pregnancy are at risk for lower IQs. Maternal valproate use during pregnancy increased the probability of autism in the offspring compared to mothers not taking valproate from 1.5% to 4.4%. A 2005 study found rates of autism among children exposed to sodium valproate before birth in the cohort studied were 8.9%. The normal incidence for autism in the general population is estimated at 1 in 44 (2.3%). A 2009 study found that the 3-year-old children of pregnant women taking valproate had an IQ nine points lower than that of a well-matched control group. However, further research in older children and adults is needed. Sodium valproate has been associated with paroxysmal tonic upgaze of childhood, also known as Ouvrier–Billson syndrome, from childhood or fetal exposure. This condition resolved after discontinuing valproate therapy. Women who intend to become pregnant should switch to a different medication if possible or decrease their dose of valproate. Women who become pregnant while taking valproate should be warned that it causes birth defects and cognitive impairment in the newborn, especially at high doses (although valproate is sometimes the only drug that can control seizures, and seizures in pregnancy could have worse outcomes for the fetus than exposure to valproate). Studies have shown that taking

folic acid Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing and ...

supplements can reduce the risk of congenital

neural tube In the developing chordate (including vertebrates), the neural tube is the embryonic precursor to the central nervous system, which is made up of the brain and spinal cord. The neural groove gradually deepens as the neural fold become elevated, ...

defects. The use of valproate for migraine or bipolar disorder during pregnancy is contraindicated in the

European Union The European Union (EU) is a supranational political and economic union of member states that are located primarily in Europe. The union has a total area of and an estimated total population of about 447million. The EU has often been de ...

and the

United States The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 states, a federal district, five major unincorporated territori ...

, and the medicines are not recommended for epilepsy during pregnancy unless there is no other effective treatment available.

Elderly

Valproate may cause increased somnolence in the elderly. In a trial of valproate in elderly patients with

dementia Dementia is a disorder which manifests as a set of related symptoms, which usually surfaces when the brain is damaged by injury or disease. The symptoms involve progressive impairments in memory, thinking, and behavior, which negatively affe ...

, a significantly higher portion of valproate patients had somnolence compared to placebo. In approximately one-half of such patients, there was associated reduced nutritional intake and weight loss.

Overdose and toxicity

Excessive amounts of valproic acid can result in somnolence, tremor, stupor, respiratory depression, coma,

metabolic acidosis Metabolic acidosis is a serious electrolyte disorder characterized by an imbalance in the body's acid-base balance. Metabolic acidosis has three main root causes: increased acid production, loss of bicarbonate, and a reduced ability of the kidneys ...

, and death. In general, serum or plasma valproic acid concentrations are in a range of 20–100 mg/L during controlled therapy, but may reach 150–1500 mg/L following acute poisoning. Monitoring of the serum level is often accomplished using commercial immunoassay techniques, although some laboratories employ gas or liquid chromatography. In contrast to other antiepileptic drugs, at present there is little favorable evidence for salivary therapeutic drug monitoring. Salivary levels of valproic acid correlate poorly with serum levels, partly due to valproate's weak acid property (p''K''a of 4.9). In severe intoxication,

hemoperfusion Hemoperfusion or hæmoperfusion (see spelling differences) is a method of filtering the blood extracorporeally (that is, outside the body) to remove a toxin. As with other extracorporeal methods, such as hemodialysis (HD), hemofiltration (HF), ...

hemofiltration Hemofiltration, also haemofiltration, is a renal replacement therapy which is used in the intensive care setting. It is usually used to treat acute kidney injury (AKI), but may be of benefit in multiple organ dysfunction syndrome or sepsis. During ...

can be an effective means of hastening elimination of the drug from the body. Supportive therapy should be given to all patients experiencing an overdose and urine output should be monitored. Supplemental L-carnitine is indicated in patients having an acute overdose and also prophylactically in high risk patients. Acetyl-L-carnitine lowers

hyperammonemia Hyperammonemia is a metabolic disturbance characterised by an excess of ammonia in the blood. It is a dangerous condition that may lead to brain injury and death. It may be primary or secondary. Ammonia is a substance that contains nitrogen. It i ...

less markedly than L-carnitine.

Interactions

Valproate inhibits

CYP2C9 Cytochrome P450 family 2 subfamily C member 9 (abbreviated CYP2C9) is an enzyme protein. The enzyme is involved in metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, the prote ...

glucuronyl transferase Uridine 5'-diphospho-glucuronosyltransferase ( UDP-glucuronosyltransferase, UGT) is a microsomal glycosyltransferase () that catalyzes the transfer of the glucuronic acid component of UDP-glucuronic acid to a small hydrophobic molecule. This is ...

, and

epoxide hydrolase Epoxide hydrolases (EH's), also known as epoxide hydratases, are enzymes that metabolize compounds that contain an epoxide residue; they convert this residue to two hydroxyl residues through an epoxide hydrolysis reaction to form diol products. ...

and is highly protein bound and hence may interact with drugs that are substrates for any of these enzymes or are highly protein bound themselves. It may also potentiate the CNS depressant effects of alcohol. It should not be given in conjunction with other antiepileptics due to the potential for reduced clearance of other antiepileptics (including

carbamazepine Carbamazepine (CBZ), sold under the trade name Tegretol among others, is an anticonvulsant medication used primarily in the treatment of epilepsy and neuropathic pain. It is used as an adjunctive treatment in schizophrenia along with other m ...

, lamotrigine,

phenytoin Phenytoin (PHT), sold under the brand name Dilantin among others, is an anti-seizure medication. It is useful for the prevention of tonic-clonic seizures (also known as grand mal seizures) and focal seizures, but not absence seizures. The in ...

and

phenobarbitone Phenobarbital, also known as phenobarbitone or phenobarb, sold under the brand name Luminal among others, is a medication of the barbiturate type. It is recommended by the World Health Organization (WHO) for the treatment of certain types of ep ...

) and itself. It may also interact with: *

Aspirin Aspirin, also known as acetylsalicylic acid (ASA), is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and/or inflammation, and as an antithrombotic. Specific inflammatory conditions which aspirin is used to treat inc ...

: may increase valproate concentrations. May also interfere with valproate's metabolism. * Benzodiazepines: may cause CNS depression and there are possible pharmacokinetic interactions. *

Carbapenem Carbapenems are a class of very effective antibiotic agents most commonly used for the treatment of severe bacterial infections. This class of antibiotics is usually reserved for known or suspected multidrug-resistant (MDR) bacterial infections. ...

antibiotics: reduce valproate levels, potentially leading to seizures. * Cimetidine: inhibits valproate's metabolism in the liver, leading to increased valproate concentrations. * Erythromycin: inhibits valproate's metabolism in the liver, leading to increased valproate concentrations. *

Ethosuximide Ethosuximide, sold under the brand name Zarontin among others, is a medication used to treat absence seizures. It may be used by itself or with other antiseizure medications such as valproic acid. Ethosuximide is taken by mouth. Ethosuximide i ...

: valproate may increase ethosuximide concentrations and lead to toxicity. *

Felbamate Felbamate (marketed under the brand name Felbatol by MedPointe) is an anticonvulsant used in the treatment of epilepsy. It is used to treat partial seizures (with and without generalization) in adults and partial and generalized seizures associa ...

: may increase plasma concentrations of valproate. * Mefloquine: may increase valproate metabolism combined with the direct epileptogenic effects of mefloquine. * Oral contraceptives: may reduce plasma concentrations of valproate. * Primidone: may accelerate metabolism of valproate, leading to a decline of serum levels and potential breakthrough seizure. * Rifampicin: increases the clearance of valproate, leading to decreased valproate concentrations *

Warfarin Warfarin, sold under the brand name Coumadin among others, is a medication that is used as an anticoagulant (blood thinner). It is commonly used to prevent blood clots such as deep vein thrombosis and pulmonary embolism, and to prevent st ...

: valproate may increase free warfarin concentration and prolong bleeding time. *

Zidovudine Zidovudine (ZDV), also known as azidothymidine (AZT), is an antiretroviral medication used to prevent and treat HIV/AIDS. It is generally recommended for use in combination with other antiretrovirals. It may be used to prevent mother-to-child ...

: valproate may increase zidovudine serum concentration and lead to toxicity.

Pharmacology

Pharmacodynamics

Although the mechanism of action of valproate is not fully understood, traditionally, its anticonvulsant effect has been attributed to the blockade of

s and increased brain levels of gamma-aminobutyric acid (GABA). The GABAergic effect is also believed to contribute towards the anti-manic properties of valproate. In animals, sodium valproate raises cerebral and cerebellar levels of the inhibitory synaptic neurotransmitter, GABA, possibly by inhibiting GABA degradative enzymes, such as

GABA transaminase In enzymology, 4-aminobutyrate transaminase (), also called GABA transaminase or 4-aminobutyrate aminotransferase, or GABA-T, is an enzyme that catalyzes the chemical reaction: :4-aminobutanoate + 2-oxoglutarate \rightleftharpoons succinate sem ...

, succinate-semialdehyde dehydrogenase and by inhibiting the re-uptake of GABA by neuronal cells. Prevention of neurotransmitter-induced hyperexcitability of nerve cells, via Kv7.2 channel and AKAP5, may also contribute to its mechanism. Also, it has been shown to protect against a seizure-induced reduction in phosphatidylinositol (3,4,5)-trisphosphate (PIP3) as a potential therapeutic mechanism. It also has histone-deacetylase-inhibiting effects. The inhibition of histone deacetylase, by promoting more transcriptionally active chromatin structures, likely presents the epigenetic mechanism for regulation of many of the neuroprotective effects attributed to valproic acid. Intermediate molecules mediating these effects include

VEGF Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors ...

BDNF Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein found in the and the periphery. that, in humans, is encoded by the ''BDNF'' gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the canon ...

, and

GDNF Glial cell line-derived neurotrophic factor (GDNF) is a protein that, in humans, is encoded by the ''GDNF'' gene. GDNF is a small protein that potently promotes the survival of many types of neurons. It signals through GFRα receptors, particula ...

Endocrine actions

Valproic acid has been found to be an antagonist of the

androgen An androgen (from Greek ''andr-'', the stem of the word meaning "man") is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This in ...

and progesterone receptors, and hence as a

nonsteroidal A nonsteroidal compound is a drug that is not a steroid nor a steroid derivative. Nonsteroidal anti-inflammatory drugs (NSAIDs) are distinguished from corticosteroids as a class of anti-inflammatory agents. List of nonsteroidal steroid receptor mo ...

antiandrogen Antiandrogens, also known as androgen antagonists or testosterone blockers, are a class of drugs that prevent androgens like testosterone and dihydrotestosterone (DHT) from mediating their biological effects in the body. They act by blocking the ...

and

antiprogestogen Antiprogestogens, or antiprogestins, also known as progesterone antagonists or progesterone blockers, are a class of drugs which prevent progestogens like progesterone from mediating their biological effects in the body. They act by blocking the ...

, at concentrations much lower than therapeutic serum levels. In addition, the drug has been identified as a potent

aromatase inhibitor Aromatase inhibitors (AIs) are a class of drugs used in the treatment of breast cancer in postmenopausal women and in men, and gynecomastia in men. They may also be used off-label to reduce estrogen conversion when supplementing testosterone ex ...

, and suppresses

estrogen Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal ac ...

concentrations. These actions are likely to be involved in the reproductive endocrine disturbances seen with valproic acid treatment. Valproic acid has been found to directly stimulate androgen biosynthesis in the gonads via inhibition of histone deacetylases and has been associated with

hyperandrogenism Hyperandrogenism is a medical condition characterized by high levels of androgens. It is more common in women than men. Symptoms of hyperandrogenism may include acne, seborrhea (inflamed skin), hair loss on the scalp, increased body or facia ...

in women and increased 4-androstenedione levels in men. High rates of

and menstrual disorders have also been observed in women treated with valproic acid.

Pharmacokinetics

Taken by mouth, valproate is rapidly and virtually completely absorbed from the gut. When in the bloodstream, 80–90% of the substance are bound to

plasma protein Blood-proteins, also termed plasma proteins, are proteins present in blood plasma. They serve many different functions, including transport of lipids, hormones, vitamins and minerals in activity and functioning of the immune system. Other blood pr ...

s, mainly

albumin Albumin is a family of globular proteins, the most common of which are the serum albumins. All the proteins of the albumin family are water-soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Albumins ...

. Protein binding is saturable: it decreases with increasing valproate concentration, low albumin concentrations, the patient's age, additional use of other drugs such as

aspirin Aspirin, also known as acetylsalicylic acid (ASA), is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and/or inflammation, and as an antithrombotic. Specific inflammatory conditions which aspirin is used to treat inc ...

, as well as liver and kidney impairment.Valproate . Accessed 6 August 2021. Concentrations in the

cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates. CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the ...

and in breast milk are 1 to 10% of blood plasma concentrations. The vast majority of valproate

metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run c ...

occurs in the

liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...

. Valproate is known to be metabolized by the

cytochrome P450 Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various co ...

enzymes CYP2A6, CYP2B6,

, and

CYP3A5 Cytochrome P450 3A5 is a protein that in humans is encoded by the ''CYP3A5'' gene. Tissue distribution ''CYP3A5'' encodes a member of the cytochrome P450 superfamily of enzymes. Like most of the cytochrome P450, the CYP3A5 is expressed in the ...

. It is also known to be metabolized by the UDP-glucuronosyltransferase enzymes

UGT1A3 UDP-glucuronosyltransferase 1-3 is an enzyme that in humans is encoded by the ''UGT1A3'' gene. This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, ...

, UGT1A4, UGT1A6, UGT1A8,

UGT1A9 UDP-glucuronosyltransferase 1-9 is an enzyme that in humans is encoded by the ''UGT1A9'' gene. Function This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such a ...

, UGT1A10,

UGT2B7 UGT2B7 (UDP-Glucuronosyltransferase-2B7) is a phase II metabolism isoenzyme found to be active in the liver, kidneys, epithelial cells of the lower gastrointestinal tract and also has been reported in the brain. In humans, UDP-Glucuronosyltrans ...

, and UGT2B15. Some of the known metabolites of valproate by these enzymes and uncharacterized enzymes include (see image): * via

glucuronidation Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. These linkages involve gl ...

(30–50%): valproic acid β-O-

glucuronide A glucuronide, also known as glucuronoside, is any substance produced by linking glucuronic acid to another substance via a glycosidic bond. The glucuronides belong to the glycosides. Glucuronidation, the conversion of chemical compounds to glucu ...

* via

beta oxidation In biochemistry and metabolism, beta-oxidation is the catabolic process by which fatty acid molecules are broken down in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA, which enters the citric acid cyc ...

(>40%): 2''E''-ene-valproic acid, 2''Z''-ene-valproic acid, 3-hydroxyvalproic acid, 3-oxovalproic acid * via omega oxidation: 5-hydroxyvalproic acid, 2-propyl-glutaric acid * some others: 3''E''-ene-valproic acid, 3''Z''-ene-valproic acid, 4-ene-valproic acid, 4-hydroxyvalproic acid All in all, over 20 metabolites are known. In adult patients taking valproate alone, 30–50% of an administered dose is excreted in

urine Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excreted from the body through the urethra. Cellular ...

as the glucuronide conjugate. The other major pathway in the metabolism of valproate is mitochondrial beta oxidation, which typically accounts for over 40% of an administered dose. Typically, less than 20% of an administered dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose of valproate is excreted unchanged (i.e., as valproate) in urine. Only a small amount is excreted via the faeces.

Elimination half-life Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the bl ...

is 16±3 hours and can decrease to 4–9 hours when combined with

enzyme inducer An enzyme inducer is a type of drug that increases the metabolic activity of an enzyme either by binding to the enzyme and activating it, or by increasing the expression of the gene coding for the enzyme. It is the opposite of an enzyme repressor ...

Chemistry

Valproic acid is a branched

and the 2-''n''-

propyl In organic chemistry, propyl is a three-carbon alkyl substituent with chemical formula for the linear form. This substituent form is obtained by removing one hydrogen atom attached to the terminal carbon of propane. A propyl substituent is often ...

derivative of

History

Valproic acid was first synthesized in 1882 by Beverly S. Burton as an analogue of

, found naturally in valerian. Valproic acid is a carboxylic acid, a clear liquid at room temperature. For many decades, its only use was in laboratories as a "metabolically inert" solvent for organic compounds. In 1962, the French researcher Pierre Eymard serendipitously discovered the anticonvulsant properties of valproic acid while using it as a vehicle for a number of other compounds that were being screened for antiseizure activity. He found it prevented

pentylenetetrazol Pentylenetetrazol, also known as pentylenetetrazole, leptazol, metrazol, pentetrazol (INN), pentamethylenetetrazol, Corazol, Cardiazol, Deumacard, or PTZ, is a drug formerly used as a circulatory and respiratory stimulant. High doses cause convul ...

-induced convulsions in laboratory rats. It was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide. Valproic acid has also been used for migraine

prophylaxis Preventive healthcare, or prophylaxis, consists of measures taken for the purposes of disease prevention.Hugh R. Leavell and E. Gurney Clark as "the science and art of preventing disease, prolonging life, and promoting physical and mental hea ...

and bipolar disorder.

Society and culture

Valproate is available as a generic medication.

Approval status

Off-label uses

In 2012, pharmaceutical company Abbott paid $1.6 billion in fines to US federal and state governments for illegal promotion of off-label uses for Depakote, including the sedation of elderly nursing home residents. Some studies have suggested that valproate may reopen the

critical period In developmental psychology and developmental biology, a critical period is a maturational stage in the lifespan of an organism during which the nervous system is especially sensitive to certain environmental stimuli. If, for some reason, the org ...

for learning absolute pitch and possibly other skills such as language.

Formulations

Valproate exists in two main molecular variants: ''sodium valproate'' and ''valproic acid without sodium'' (often implied by simply ''valproate''). A mixture between these two is termed ''semisodium valproate''. It is unclear whether there is any difference in efficacy between these variants, except from the fact that about 10% more mass of ''sodium valproate'' is needed than ''valproic acid without sodium'' to compensate for the sodium itself.

Brand names of valproic acid

Branded products include: * Absenor (

Orion Corporation Orion Corporation ( fi, Orion Oyj), founded in 1917 and headquartered at Espoo, Finland, is a globally operating Finnish company which develops, manufactures and markets human and veterinary pharmaceuticals and active pharmaceutical ingredients ...

Finland) * Convulex ( G.L. Pharma GmbH Austria) * Depakene ( Abbott Laboratories in US and Canada) * Depakine (

Sanofi Aventis Sanofi S.A. is a French multinational pharmaceutical and healthcare company headquartered in Paris, France. Originally, the corporation was established in 1973 and merged with Synthélabo in 1999 to form Sanofi-Synthélabo. In 2004, Sanofi-Syn ...

France) * Depakine ( Sanofi Synthelabo Romania) * Depalept (

Israel) * Deprakine (

Finland) * Encorate (

Sun Pharmaceuticals The Sun is the star at the center of the Solar System. It is a nearly perfect ball of hot plasma, heated to incandescence by nuclear fusion reactions in its core. The Sun radiates this energy mainly as light, ultraviolet, and infrared radi ...

India) * Epival ( Abbott Laboratories US and Canada) * Epilim ( Sanofi Synthelabo Australia and South Africa) * Stavzor ( Noven Pharmaceuticals Inc.) * Valcote ( Abbott Laboratories Argentina) * Valpakine (

Brazil) * Orfiril (Desitin Arzneimittel GmbH Norway)

Brand names of sodium valproate

=Portugal

= * Tablets – Diplexil-R by Bial.

=United States

= * Intravenous injection – Depacon by Abbott Laboratories. * Syrup – Depakene by Abbott Laboratories. (Note Depakene ''capsules'' are valproic acid). * Depakote tablets are a mixture of sodium valproate and valproic acid. * Tablets – Eliaxim by Bial.

=Australia

= *Epilim Crushable Tablets Sanofi *Epilim Sugar Free Liquid Sanofi *Epilim Syrup Sanofi *Epilim Tablets Sanofi *Sodium Valproate Sandoz Tablets Sanofi *Valpro Tablets Alphapharm *Valproate Winthrop Tablets Sanofi *Valprease tablets Sigma

=New Zealand

= *Epilim by Sanofi-Aventis All the above formulations are Pharmac-subsidised.

=UK

= * Depakote Tablets (as in USA) * Tablets – Orlept by Wockhardt and Epilim by Sanofi * Oral solution – Orlept Sugar Free by Wockhardt and Epilim by Sanofi * Syrup – Epilim by Sanofi-Aventis * Intravenous injection – Epilim Intravenous by Sanofi * Extended release tablets – Epilim Chrono by Sanofi is a combination of sodium valproate and valproic acid in a 2.3:1 ratio. * Enteric-coated tablets – Epilim EC200 by Sanofi is a 200-mg sodium valproate enteric-coated tablet.

UK only

* Capsules – Episenta prolonged release by Beacon * Sachets – Episenta prolonged release by Beacon * Intravenous solution for injection – Episenta solution for injection by Beacon

=Germany, Switzerland, Norway, Finland, Sweden

= * Tablets – Orfiril by Desitin Pharmaceuticals * Intravenous injection – Orfiril IV by Desitin Pharmaceuticals

=South Africa

= * Syrup – Convulex by Byk Madaus * Tablets – Epilim by Sanofi-synthelabo

=Malaysia

= * Tablets – Epilim by Sanofi-Aventis

=Romania

= * Companies are SANOFI-AVENTIS FRANCE, GEROT PHARMAZEUTIKA GMBH and DESITIN ARZNEIMITTEL GMBH * Types are Syrup, Extended release mini tablets, Gastric resistant coated tablets, Gastric resistant soft capsules, Extended release capsules, Extended release tablets and Extended release coated tablets

=Canada

= * Intravenous injection – Epival or Epiject by Abbott Laboratories. * Syrup – Depakene by Abbott Laboratories its generic formulations includ
Apo-Valproic
an
ratio-Valproic

=Japan

= * Tablets – Depakene by

Kyowa Hakko Kirin is a Japanese pharmaceutical and biotechnology company under the Kirin Holdings, and is among the 40 largest in the world by revenue. The company is headquartered in Chiyoda-ku, Tokyo and is a member of the Nikkei 225 stock index. History On ...

* Extended release tablets – Depakene-R by Kyowa Hakko Kogyo and Selenica-R by Kowa * Syrup – Depakene by Kyowa Hakko Kogyo

=Europe

= In much of Europe, Dépakine and Depakine Chrono (tablets) are equivalent to Epilim and Epilim Chrono above.

=Taiwan

= *Tablets (white round tablet) – Depakine () by Sanofi Winthrop Industrie (France)

=Iran

= *Tablets – Epival 200 (enteric coated tablet) and Epival 500 (extended release tablet) by Iran Najo *Slow release tablets – Depakine Chrono by Sanofi Winthrop Industrie (France)

=Israel

= Depalept and Depalept Chrono (extended release tablets) are equivalent to Epilim and Epilim Chrono above. Manufactured and distributed by

Sanofi-Aventis Sanofi S.A. is a French multinational pharmaceutical and healthcare company headquartered in Paris, France. Originally, the corporation was established in 1973 and merged with Synthélabo in 1999 to form Sanofi-Synthélabo. In 2004, Sanofi-Syn ...

= India, Russia and CIS countries

= *Valparin Chrono by Sanofi India * Valprol CR by Intas Pharmaceutical (India) * Encorate Chrono by Sun Pharmaceutical (India) * Serven Chrono by Leeven APL Biotech (India)

Brand names of valproate semisodium

* Brazil – Depakote by Abbott Laboratories and Torval CR by Torrent do Brasil * Canada – Epival by Abbott Laboratories * Mexico – Epival and Epival ER (extended release) by Abbott Laboratories * United Kingdom – Depakote (for psychiatric conditions) and Epilim (for epilepsy) by

and generics * United States – Depakote and Depakote ER (extended release) by Abbott Laboratories and generics * India – Valance and Valance OD by Abbott Healthcare Pvt Ltd, Divalid ER by Linux laboratories Pvt Ltd, Valex ER by Sigmund Promedica, Dicorate by Sun Pharma * Germany – Ergenyl Chrono by Sanofi-Aventis and generics * Chile – Valcote and Valcote ER by Abbott Laboratories * France and other European countries — Depakote * Peru – Divalprax by AC Farma Laboratories * China – Diprate OD

References

External links

* * * {{DEFAULTSORT:Valproic Acid Anticonvulsants Antiprogestogens Aromatase inhibitors AbbVie brands Carboxylic acids CYP3A4 inhibitors Endocrine disruptors GABA analogues GABA transaminase inhibitors Hepatotoxins Histone deacetylase inhibitors Mood stabilizers Nonsteroidal antiandrogens Teratogens World Health Organization essential medicines Wikipedia medicine articles ready to translate