Divalproex

• 44089

WeightAverage: 144.2114
Chemical FormulaC₈H₁₆O₂

UNII614OI1Z5WI, CAS number99-66-1, 76584-70-8

2-propylpentanoic acid, DIVALPROEX SODIUM, 76584-70-8, Valproate semisodium, Epival, Depakote, Sodium divalproate, Semisodium Valproate, Abbott 50711, ValdisovalValproic Acid 
CAS Registry Number: 99-66-1 
CAS Name: 2-Propylpentanoic acid 
Additional Names: 2-propylvaleric acid; di-n-propylacetic acid 
Trademarks: Convulex (Pharmacia); Depakene (Abbott) 
Molecular Formula: C8H16O2 
Molecular Weight: 144.21 
Percent Composition: C 66.63%, H 11.18%, O 22.19% 
Literature References: Antiepileptic; increases levels of g-aminobutyric acid (GABA) in the brain. Prepn: B. S. Burton, Am. Chem. J.3, 385 (1882); E. Oberreit, Ber.29, 1998 (1896); M. Tiffeneau, Y. Deux, Compte Rend.212, 105 (1941). Anticonvulsant activity: H. Meunier et al.,Therapie18, 435 (1963). Toxicity data: Jenner et al.,Food Cosmet. Toxicol.2, 327 (1964). Comprehensive description: Z. L. Chang, Anal. Profiles Drug Subs.8, 529-556 (1979). Review of teratogenicity studies: H. Nau et al.,Pharmacol. Toxicol.69, 310-321 (1991); R. Alsdorf, D. F. Wyszynski, Expert Opin. Drug Safety4, 345-353 (2005). Review of pharmacology and clinical experience in epilepsy: E. M. Rimmer, A. Richens, Pharmacotherapy5, 171-184 (1985); in psychiatric disease: D. R. P. Guay, ibid.15, 631-647 (1995); in migraine prophylaxis: C. E. Shelton, J. F. Connelly, Ann. Pharmacother.30, 865-866 (1996). Review of pharmacodynamics and mechanisms of action: W. Löscher, Prog. Neurobiol.58, 31-59 (1999). 
Properties: Colorless liquid with characteristic odor. bp 219.5°. nD24.5 1.425. d40 0.9215. pKa 4.6. Very sol in organic solvents. Soly in water: 1.3 mg/ml. LD50 orally in rats: 670 mg/kg (Jenner). 
Boiling point: bp 219.5° 
pKa: pKa 4.6 
Index of refraction:nD24.5 1.425 
Density: d40 0.9215 
Toxicity data: LD50 orally in rats: 670 mg/kg (Jenner) 
Derivative Type: Sodium salt (1:1) 
CAS Registry Number: 1069-66-5 
Additional Names: Sodium valproate 
Trademarks: Depacon (Abbott); Depakin (Sanofi-Synthelabo); Dépakine (Sanofi-Aventis); Epilim (Sanofi-Aventis); Ergenyl (Sanofi-Synthelabo); Leptilan (Dolorgiet); Orfiril (Desitin) 
Molecular Formula: C8H15NaO2 
Molecular Weight: 166.19 
Percent Composition: C 57.82%, H 9.10%, Na 13.83%, O 19.25% 
Properties: White, odorless, crystalline, deliquescent powder. pKa 4.8. Hygroscopic. One gram is sol in 0.4 ml water; 1.5 ml ethanol; 5 ml methanol. Practically insol in common organic solvents. LD50 orally in mice: 1700 mg/kg (Meunier). 
pKa: pKa 4.8 
Toxicity data: LD50 orally in mice: 1700 mg/kg (Meunier) 
Derivative Type: Sodium salt (2:1) 
CAS Registry Number: 76584-70-8 
Additional Names: Sodium hydrogen bis(2-propylpentanoate); divalproex sodium; valproate semisodium 
Manufacturers’ Codes: Abbott 50711 
Trademarks: Depakote (Abbott); Valcote (Abbott) 
Molecular Formula: C16H31NaO4 
Molecular Weight: 310.40 
Percent Composition: C 61.91%, H 10.07%, Na 7.41%, O 20.62% 
Derivative Type: Magnesium salt 
Trademarks: Depamag (Sigma-Tau) 
Molecular Formula: C16H30MgO4 
Molecular Weight: 310.71 
Percent Composition: C 61.85%, H 9.73%, Mg 7.82%, O 20.60% 
Therap-Cat: Anticonvulsant; antimanic; antimigraine.Keywords: Anticonvulsant; Antimigraine; Antimanic.

Synthesis Reference

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

US5017613

Patent

https://patents.google.com/patent/WO2007004238A2/enDivalproex sodium is one of the most widely used epileptic agents presently available in the market. Both the constituents, valproic acid and sodium valproate themselves have also been used for the treatment of epileptic seizures and convulsions. But their utility has remained restricted since valproic acid is a liquid and is difficult to formulate for an oral dosage form whereas sodium valproate is a hygroscopic solid with poor stability characteristics. Divalproex sodium is an oligomer having 1:1 molar ratio of valproic acid and sodium valproate containing 4 to 6 units. The relevant prior art includes US 4,988,731 (’73I) relates to a non-hygroscopic stable sodium hydrogen divalproate oligomer. Its probable structure is shown in Fig 1

Fig 1 – Divalproex sodiumWhere M is a about 2.As can be seen from the displayed structure, one mole each of the valproic acid forms coordinate bonds with the sodium of the sodium valproate molecule, and the valproate ion is ionically bonded to the sodium atom. The structure is thus consistent with the unique characteristic of the compound. However the preferred mode of representing Divalproex sodium is by reference to single compound of the formula{(CH₃CH₂CH₂)₂CHCO₂} {(CH₃CH₂CH₂)₂CHCO₂}Na, HThe said patent also describes two alternative processes for the preparation of the oligomer. According to one aspect, the oligomer is produced by dissolving sodium valproate and valproic acid in equimolar amount in acetone and crystallizing from chilled acetone at around O⁰C. Alternatively Divalproex sodium can be isolated from a two component liquid medium, which includes acetone where in half equivalent of NaOH to the valproic acid present, preferable as a solution in an acetone miscible solvent eg. water. The new compound can be recovered from the liquid phase by evaporating the solvent(s) and, if desired, the new compound can be recrystallized, for instance from acetonitrile or others or the material may be spay-dried, lyophilized or purified by chromatography.US ‘731 claims yield of 90% of theory.Drawbacks of the above mentioned reported methods for the preparation of Divalproex sodium described in US 4988731 are difficult to reproduce on a large scale and provides inconsistent yields and the material obtained is not always free flowing in nature. The process involves the crystallization of a 1:1 mixture of valproic acid and sodium valproate from a chilled solution of acetone, followed by washing with chilled acetone. Divalproex sodium is as such fairly soluble in acetone at temperatures above 1O⁰C and extreme care has to be. taken while performing washing with chilled acetone as any rise in temperature would lead to the loss of yield. This problem actually comes to the fore while scaling up the process during commercialization since during centrifugation of the large volume the temperature of the mixture rises and acetone has to be cooled below O⁰C, which require large amount of liquid nitrogen or dry ice. Moreover it was also observed that due to the cooled nature of the solvent, the isolated Divalproex sodium absorbs considerable amount of moisture and therefore requires longer time to dry eventually leading to longer time cycle for the otherwise simple single step process. Also the high moisture content in the recovered acetone makes it unsuitable for reuse. Alternatively, to avoid absorption of water, the centrifugation had to be carried out under a blanket of dry nitrogen gas. These additional infrastructural loads add to input costs eventually making the otherwise single step low cost process becoming uncompetitive and economically unviable.Similarly the other process involves the addition of half molar equivalent of sodium hydroxide dissolved in water to valproic acid and the solvent has to be evaporated to obtain crude product, which has to be recrystallized to get Divalprox of the desired specification. The process is operationally tedious and requires the reduction in the level of water in the reaction mass via evaporation of the solvent followed by re- crystallization from acetonitrile making the process lengthy and economically unviable. There is therefore a need for operationally making this single step process more efficient and high yieldingExample I:To lOOg of Valproic acid with stirring at 20-30⁰C, powdered NaOH ( 13g; half molar) is added & the resulting reaction mixture is stirred at 40-50⁰C for 1 hr. Then acetonitrile(600ml) is added to obtain clear solution at 40-50⁰C and the solution is charcoalized at 40-50⁰C followed by filtration at 40-50⁰C through hyflo-bed. The resultant reaction mixture was stirred at 10-20⁰C for 2-3 hr. The solid , thus obtained, was filtered and product was dried at 40-45⁰C for 10-12 hr. (102.25g, 95%)Example II;To lOOg of Valproic acid with stirring at 20-30⁰C, powdered NaOH (13g; half molar) is added & the resulting reaction mixture is stirred at 30-40⁰C for 1 hr. Then acetone (600ml) is added to obtain clear solution at 30-40⁰C and the material is charcoalized at 30-40⁰C followed by filtration through hyflo-bed. The resultant reaction solution was stirred at -5°C to -1O⁰C for 2-3 hr. The solid , thus obtained, was filtered and product was dried at 40-45⁰C for 10-12 hr. ( 55g, 51.11%) Example III:To a solution of Valproic acid (10Og) in dichloromethane (200ml) at 20-30⁰C, powdered caustic (13g ; half molar) is added & the reaction mixture is stirred at 30- 40⁰C for 1 hr to get clear solution. Then acetonitrile (600ml) is added to it inorder to crystallize the product. The solid, thus obtained, is further stirred at 0-5⁰C for 2-3 hr followed by filtration. The product was dried at 40-45⁰C for 10-12 hr. (10Og; 93%)Example IV:To a solution of Valproic acid (10Og) in diisopropyl ether(200ml) at 20-30⁰C, powdered caustic (13g ; half molar) is added & the reaction mixture is stirred at 40-50⁰C for 1 hr to get clear solution. Then acetonitrile (800ml) is added to it inorder to crystallize the product. The solid, thus obtained, is further stirred at 0-5⁰C for 2-3 hr followed by filtration. The product was dried at 40-45⁰C for 10-12 hr. (104g; 96.65%)Example V:To a solution of Valproic acid (10Og) in methyl tertiary butyl ether(200ml) at 20- 30⁰C, powdered caustic (13g ; half molar) is added & the reaction mixture is stirred at 40-50⁰C for 1 hr to get clear solution. Then acetonitrile (800ml) is added to it inorder to crystallize the product. The solid, thus obtained, is further stirred at 0-5⁰C for 2-3 hr followed by filtration. The product was dried at 40-45⁰C for 10-12 hr. (102g;94.79%)Example VI:To a solution of Valproic acid (10Og) in toluene (200ml) at 20-30⁰C, powdered caustic (13g ; half molar) is added & the reaction mixture is stirred at 40-50⁰C for 1 hr to get clear solution. Then acetonitrile (800ml) is added to it inorder to crystallize the product. The solid, thus obtained, is further stirred at 0-5⁰C for 2-3 hr followed by filtration. The product was dried at 40-45⁰C for 10-12 hr. (101g; 93.87%)Example VII: A mixture of sodium valproate (6Og) and valproic acid (52.04g) was taken in acetonitrile (800ml) and heated at reflux to obtain a clear solution, which was filtered through hyflo-bed to remove suspended particles. Then the solution was stirred at 10- 20⁰C for 2-3 hr. The solid, thus obtained, was filtered and washed with acetonitrile (100ml). The product was dried at 40-45⁰C for 10-12 hr. (105g ; 93.75%)Example VIII;To a solution of valproic acid (10Og) in methanol (200ml) at 20-30⁰C₅ caustic (13g; half molar) is added & the reaction mixture is stirred at 20-30⁰C for 1 hr. Then the methanol was recovered at reduced pressure and acetonitrile (600ml) is added to it with stirring. The reaction mixture was further stirred at 0-5⁰C for 2-3 hr. The solid, thus obtained, is filtered, washed with acetonitrile (100ml) and product was dried at 40-45°C for 10-12 hr.(102g; ~ 95%) Example IX:To a solution of valproic acid (10Og) in methanol (200ml) at 20-30⁰C, caustic (13g; half molar) is added & the reaction mixture is stirred at 20-30⁰C for 1 hr. Then the methanol was recovered at reduced pressure and acetone (600ml) is added to it with stirring. The reaction mixture was further stirred at -5°C to -1O⁰C for 2-3 hr. The solid, thus obtained, is filtered, washed with chilled acetone (100ml) and product was dried at 40-45⁰C for 10-12 hr.(54g; ~ 50.11%)Example X:To a solution of valproic acid (10Og) in ethanol (200ml) at 20-30⁰C, caustic (13g; half molar) is added & the reaction mixture is stirred at 20-30⁰C for 1 hr. Then the ethanol was recovered at reduced pressure and acetonitrile (600ml) is added to it with stirring.The reaction mixture was further stirred at 0-5⁰C for 2-3 hr. The solid, thus obtained, is filtered, washed with acetonitrile (100ml) and product was dried at 40-45⁰C for 10-12 hr.(101g; ~ 93.87%)Example XI: To a solution of valproic acid (10Og) in ethanol (200ml) at 20-30°C, caustic (13g; half molar) is added & the reaction mixture is stirred at 20-30⁰C for 1 hr. Then the ethanol was recovered at reduced pressure and acetone (600ml) is added to it with stirring. The reaction mixture was further stirred at -5°C to -10⁰C for 2-3 hr. The solid, thus obtained, is filtered, washed with chilled acetone (100ml) and product was dried at 40-45⁰C for 10-12 hr.(55g; ~ 51%)ADVANTAGES:> The process is high yielding. > The process produces Divalproex sodium with improved flowability.> The process produces Divalproex sodium that is non-hygroscopic and more stable.> The process is industrially feasible, precise, reproducible and does not require sophisticated infrastructure.

Divalproex Sodium is a stable coordination compound comprised of sodium valproate and valproic acid with anticonvulsant and antiepileptic activities. Divalproex dissociates to the valproate ion in the gastrointestinal tract. This agent binds to and inhibits gamma-aminobutyric acid (GABA) transaminase and its anticonvulsant activity may be exerted by increasing brain concentration of GABA and by inhibiting enzymes that catabolize GABA or block the reuptake of GABA into glia and nerve endings. Divalproex may also work by suppressing repetitive neuronal firing through inhibition of voltage-sensitive sodium channels.

Valproate semisodium is a mixture of valproic acid and its sodium salt in a 1:1 molar ratio. It is used for the management and treatment of seizure disorders, mania, and prophylactic treatment of migraine headache. It has a role as an antimanic drug, an anticonvulsant and a GABA agent. It contains a valproic acid and a sodium valproate.

Divalproex sodium, valproate sodium, and valproic acid, are all similar medications that are used by the body as valproic acid. Therefore, the term valproic acid will be used to represent all of these medications in this discussion.

Valproate (VPA) and its valproic acid, sodium valproate, and valproate semisodium forms are medications primarily used to treat epilepsy and bipolar disorder and prevent migraine headaches.^[2] They are useful for the prevention of seizures in those with absence seizures, partial seizures, and generalized seizures.^[2] They can be given intravenously or by mouth, and the tablet forms exist in both long- and short-acting formulations.^[2]

Common side effects of valproate include nausea, vomiting, sleepiness, and dry mouth.^[2] Serious side effects can include liver failure, and regular monitoring of liver function tests is therefore recommended.^[2] Other serious risks include pancreatitis and an increased suicide risk.^[2] Valproate is known to cause serious abnormalities in babies if taken during pregnancy,^[2][3] and as such it is not typically recommended for women of childbearing age who have migraines.^[2]

Valproate’s precise mechanism of action is unclear.^[2][4] Proposed mechanisms include affecting GABA levels, blocking voltage-gated sodium channels, and inhibiting histone deacetylases.^[5][6] Valproic acid is a branched short-chain fatty acid (SCFA) made from valeric acid.^[5]

Valproate was first made in 1881 and came into medical use in 1962.^[7] It is on the World Health Organization’s List of Essential Medicines^[8] and is available as a generic medication.^[2] It is marketed under the brand names Depakote, among others.^[2] In 2018, it was the 131st most commonly prescribed medication in the United States, with more than 5 million prescriptions.^[9][10]

Terminology

Valproic acid (VPA) is an organic weak acid. The conjugate base is valproate. The sodium salt of the acid is sodium valproate and a coordination complex of the two is known as valproate semisodium.^[11]

Medical uses

It is used primarily to treat epilepsy and bipolar disorder. It is also used to prevent migraine headaches.^[12]

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 and myoclonic seizures and as a second-line treatment for partial seizures and infantile spasms.^[12][13] It has also been successfully given intravenously to treat status epilepticus.^[14][15]

Mental illness

Bipolar disorder

Valproate products are also used to treat manic or mixed episodes of bipolar disorder.^[16][17]

Schizophrenia

A 2016 systematic review compared the efficacy of valproate as an add-on for people with schizophrenia:^[18]

Dopamine dysregulation syndrome

Based upon five case reports, valproic acid may have efficacy in controlling the symptoms of the dopamine dysregulation syndrome that arise from the treatment of Parkinson’s disease with levodopa.^[19][20][21]

Migraines

Valproate is also used to prevent migraine headaches. Because this medication can be potentially harmful to the fetus, valproate should be considered for those able to become pregnant only after the risks have been discussed.^[22]

Other

The medication has been tested in the treatment of AIDS and cancer, owing to its histone-deacetylase-inhibiting effects.^[23]

Contraindications

Contraindications include:

• Pre-existing acute or chronic liver dysfunction or family history of severe liver inflammation (hepatitis), particularly medicine related.^[24]
• Known hypersensitivity to valproate or any of the ingredients used in the preparation^[24]
• Urea cycle disorders^[24]
• Hepatic porphyria^[24]
• Hepatotoxicity^[24]
• Mitochondrial disease^[24]
• Pancreatitis^[24]
• Porphyria^[25]

Adverse effects

See also: List of adverse effects of valproic acid and List of adverse effects of valproate semisodium

Most common adverse effects include:^[22]

• Nausea (22%)
• Drowsiness (19%)
• Dizziness (12%)
• Vomiting (12%)
• Weakness (10%)

Serious adverse effects include:^[22]

• Bleeding
• Low blood platelets
• Encephalopathy
• Suicidal behavior and thoughts
• Low body temperature

Valproic acid has a black box warning for hepatotoxicity, pancreatitis, and fetal abnormalities.^[22]

There is evidence that valproic acid may cause premature growth plate ossification in children and adolescents, resulting in decreased height.^{[26][27][28][29]} Valproic acid can also cause mydriasis, a dilation of the pupils.^[30] There is evidence that shows valproic acid may increase the chance of polycystic ovary syndrome (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.^[31] Weight gain is also possible.^[32]

Pregnancy

Valproate causes birth defects;^[33] exposure during pregnancy is associated with about three times as many major abnormalities as usual, mainly spina bifida with the risks being related to the strength of medication used and use of more than one drug.^[34][35] More rarely, with several other defects, including a “valproate syndrome”.^[36] 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 folds, medial deficiency of eyebrows, flat nasal bridge, broad nasal root, anteverted nares, shallow philtrum, long upper lip and thin vermillion borders, thick lower lip and small downturned mouth.^[37] While developmental delay is usually associated with altered physical characteristics (dysmorphic features), this is not always the case.^[38]

Children of mothers taking valproate during pregnancy are at risk for lower IQs.^[39][40][41] 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%.^[42] A 2005 study found rates of autism among children exposed to sodium valproate before birth in the cohort studied were 8.9%.^[43] The normal incidence for autism in the general population is estimated at less than one percent.^[44] 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.^[45][46][47]

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.^[48][49]

Women who intend to become pregnant should switch to a different medication if possible or decrease their dose of valproate.^[50] 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 supplements can reduce the risk of congenital neural tube defects.^[22] The use of valproate for migraine or bipolar disorder during pregnancy is contraindicated in the European Union, and the medicines are not recommended for epilepsy during pregnancy unless there is no other effective treatment available.^[51]

Elderly

Valproate in elderly people with dementia caused increased sleepiness. More people stopped the medication for this reason. Additional side effects of weight loss and decreased food intake were also associated with one-half of people who become sleepy.^[22]

Overdose and toxicity

Excessive amounts of valproic acid can result in sleepiness, tremor, stupor, respiratory depression, coma, metabolic acidosis, and death.^[54] 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.^[55] 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 (pKa of 4.9).^[56]

In severe intoxication, hemoperfusion or hemofiltration can be an effective means of hastening elimination of the drug from the body.^[57][58] Supportive therapy should be given to all patients experiencing an overdose and urine output should be monitored.^[22] Supplemental L-carnitine is indicated in patients having an acute overdose^[59][60] and also prophylactically^[59] in high risk patients. Acetyl-L-carnitine lowers hyperammonemia less markedly^[61] than L-carnitine.

Interactions

Valproate inhibits CYP2C9, glucuronyl transferase, and epoxide hydrolase 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.^[24] It may also potentiate the CNS depressant effects of alcohol.^[24] It should not be given in conjunction with other antiepileptics due to the potential for reduced clearance of other antiepileptics (including carbamazepine, lamotrigine, phenytoin and phenobarbitone) and itself.^[24] It may also interact with:^[22][24][62]

• Aspirin: may increase valproate concentrations. May also interfere with valproate’s metabolism.
• Benzodiazepines: may cause CNS depression and there are possible pharmacokinetic interactions.
• Carbapenem 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: valproate may increase ethosuximide concentrations and lead to toxicity.
• Felbamate: 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: valproate may increase free warfarin concentration and prolong bleeding time.
• Zidovudine: valproate may increase zidovudine serum concentration and lead to toxicity.

Pharmacology

Pharmacodynamics

Although the mechanism of action of valproate is not fully understood,^[24] traditionally, its anticonvulsant effect has been attributed to the blockade of voltage-gated sodium channels and increased brain levels of gamma-aminobutyric acid (GABA).^[24] The GABAergic effect is also believed to contribute towards the anti-manic properties of valproate.^[24] 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, succinate-semialdehyde dehydrogenase and by inhibiting the re-uptake of GABA by neuronal cells.^[24]

Prevention of neurotransmitter-induced hyperexcitability of nerve cells, via Kv7.2 channel and AKAP5, may also contribute to its mechanism.^[63] Also, it has been shown to protect against a seizure-induced reduction in phosphatidylinositol (3,4,5)-trisphosphate (PIP3) as a potential therapeutic mechanism.^[64]

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, BDNF, and GDNF.^[65][66]

Endocrine actions

Valproic acid has been found to be an antagonist of the androgen and progesterone receptors, and hence as a nonsteroidal antiandrogen and antiprogestogen, at concentrations much lower than therapeutic serum levels.^[67] In addition, the drug has been identified as a potent aromatase inhibitor, and suppresses estrogen concentrations.^[68] These actions are likely to be involved in the reproductive endocrine disturbances seen with valproic acid treatment.^[67][68]

Valproic acid has been found to directly stimulate androgen biosynthesis in the gonads via inhibition of histone deacetylases and has been associated with hyperandrogenism in women and increased 4-androstenedione levels in men.^[69][70] High rates of polycystic ovary syndrome and menstrual disorders have also been observed in women treated with valproic acid.^[70]

Pharmacokinetics

Some metabolites of valproic acid. Glucuronidation and β-oxidation are the main metabolic pathways; ω-oxidation metabolites are considered hepatotoxic.^[71][72] Details see text.

Taken by mouth, valproate is rapidly and virtually completely absorbed from the gut.^[71] When in the bloodstream, 80–90% of the substance are bound to plasma proteins, mainly albumin. 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, as well as liver and kidney impairment.^[73][74] Concentrations in the cerebrospinal fluid and in breast milk are 1 to 10% of blood plasma concentrations.^[71]

The vast majority of valproate metabolism occurs in the liver.^[75] Valproate is known to be metabolized by the cytochrome P450 enzymes CYP2A6, CYP2B6, CYP2C9, and CYP3A5.^[75] It is also known to be metabolized by the UDP-glucuronosyltransferase enzymes UGT1A3, UGT1A4, UGT1A6, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B15.^[75] Some of the known metabolites of valproate by these enzymes and uncharacterized enzymes include (see image):^[75]

• via glucuronidation (30–50%): valproic acid β-O-glucuronide
• via beta oxidation (>40%): 2E-ene-valproic acid, 2Z-ene-valproic acid, 3-hydroxyvalproic acid, 3-oxovalproic acid
• via omega oxidation: 5-hydroxyvalproic acid, 2-propyl-glutaric acid
• some others: 3E-ene-valproic acid, 3Z-ene-valproic acid, 4-ene-valproic acid, 4-hydroxyvalproic acid

All in all, over 20 metabolites are known.^[71]

In adult patients taking valproate alone, 30–50% of an administered dose is excreted in urine as the glucuronide conjugate.^[75] The other major pathway in the metabolism of valproate is mitochondrial beta oxidation, which typically accounts for over 40% of an administered dose.^[75] Typically, less than 20% of an administered dose is eliminated by other oxidative mechanisms.^[75] Less than 3% of an administered dose of valproate is excreted unchanged (i.e., as valproate) in urine.^[75] Only a small amount is excreted via the faeces.^[71] Elimination half-life is 16±3 hours and can decrease to 4–9 hours when combined with enzyme inducers.^[71][74]

Chemistry

Valproic acid is a branched short-chain fatty acid and the 2-n–propyl derivative of valeric acid.^[5]

History

Valproic acid was first synthesized in 1882 by Beverly S. Burton as an analogue of valeric acid, found naturally in valerian.^[76] 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-induced convulsions in laboratory rats.^[77] It was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide.^[78] Valproic acid has also been used for migraine prophylaxis and bipolar disorder.^[79]

Society and culture

Valproate is available as a generic medication.^[2]

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.^[110][111]

Some studies have suggested that valproate may reopen the critical period for learning absolute pitch and possibly other skills such as language.^[112][113]

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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.^[114]

Brand names of valproic acid

Branded products include:

• Absenor (Orion Corporation Finland)
• Convulex (G.L. Pharma GmbH Austria)
• Depakene (Abbott Laboratories in US and Canada)^[115]
• Depakine (Sanofi Aventis France)
• Depakine (Sanofi Synthelabo Romania)
• Depalept (Sanofi Aventis Israel)
• Deprakine (Sanofi Aventis Finland)
• Encorate (Sun Pharmaceuticals India)
• Epival (Abbott Laboratories US and Canada)
• Epilim (Sanofi Synthelabo Australia and South Africa)
• Stavzor (Noven Pharmaceuticals Inc.)
• Valcote (Abbott Laboratories Argentina)
• Valpakine (Sanofi Aventis 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^[116]
• Epilim Sugar Free Liquid Sanofi^[116]
• Epilim Syrup Sanofi^[116]
• Epilim Tablets Sanofi^[116]
• 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.^[117]

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^[118]
• 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 include Apo-Valproic and ratio-Valproic.

Japan

• Tablets – Depakene by Kyowa Hakko Kirin
• 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 (Chinese: 帝拔癲; pinyin: di-ba-dian) 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.

India, Russia and CIS countries

• Valparin Chrono by Torrent Pharmaceuticals 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 Sanofi-Aventis and generics
• United States – Depakote and Depakote ER (extended release) by Abbott Laboratories and generics^[22]
• 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

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External links

• “Valproic acid”. Drug Information Portal. U.S. National Library of Medicine.
• “Valproate sodium”. Drug Information Portal. U.S. National Library of Medicine.
• “Divalproex sodium”. Drug Information Portal. U.S. National Library of Medicine.

Patent 

Publication numberPriority datePublication dateAssigneeTitleCA1144558A *1979-10-221983-04-12Francis E. FischerProcess for making sodium hydrogen divalproateUS4988731A *1979-08-201991-01-29Abbott LaboratoriesSodium hydrogen divalproate oligomerUS5212326A *1979-08-201993-05-18Abbott LaboratoriesSodium hydrogen divalproate oligomerWO2001032595A1 *1999-11-022001-05-10Cilag AgMethod for producing compounds of the valproinic acidUS20030018215A1 *2001-06-292003-01-23Procos S.P.A.Process for the preparation of sodium divalproatePublication numberPriority datePublication dateAssigneeTitleUS20110040122A1 *2009-08-112011-02-17Sci Pharmtech, Inc.Method for preparing metal salt of valproic acidCN102942467A *2012-10-172013-02-27山东方明药业集团股份有限公司Preparation method of divalproex sodiumCN103183600A *2011-12-302013-07-03北大方正集团有限公司Method for preparing divalproex sodium

////// divalproex, Anticonvulsant,  Antimigraine, Antimanic, valproic acid, sodium valproate

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