ContaminantDB: Valproic acid

Identification Taxonomy Biological Properties Physical Properties Toxicity Profile Spectra Concentrations Links References Targets (43)XML

Record Information

Version

1.0

Creation Date

2009-07-05 02:58:24 UTC

Update Date

2026-05-14 16:25:21 UTC

Accession Number

CHEM002085

Identification

Common Name

Valproic acid

Class

Small Molecule

Description

Valproic acid (VPA) is considered to be a drug of first choice and one of the most frequently-prescribed antiepileptic drugs worldwide for the therapy of generalized and focal epilepsies, including special epileptic. It is a broad-spectrum antiepileptic drug and is usually well tolerated. Rarely, serious complications may occur in some patients, including hemorrhagic pancreatitis, coagulopathies, bone marrow suppression, VPA-induced hepatotoxicity and encephalopathy, but there is still a lack of knowledge about the incidence and occurrence of these special side effects. VPA has been approved for stabilization of manic episodes in patients with bipolar disorder. It is also used to treat migraine headaches and schizophrenia. As the use of VPA increases, the number of both accidental and intentional exposures increases. This is paralleled by more reports of VPA-induced toxicity. VPA is relatively contraindicated in pregnancy due to its teratogenicity. It is a known folate antagonist, which can cause neural tube defects. Thus, folic acid supplements may alleviate teratogenic problems. Women who become pregnant whilst taking valproate should be counselled as to its risks. VPA is an inhibitor of the enzyme histone deacetylase 1 (HDAC1). HDAC1 is needed for HIV to remain in infected cells. Patients treated with valproic acid in addition to highly active antiretroviral therapy (HAART) showed a median 75% reduction in latent HIV infection. VPA is believed to affect the function of the neurotransmitter GABA (as a GABA transaminase inhibitor) in the human brain. Valproic Acid dissociates to the valproate ion in the gastrointestinal tract. (6, 7).

Contaminant Sources

FooDB Chemicals
STOFF IDENT Compounds
Suspected Compounds
T3DB toxins
ToxCast & Tox21 Chemicals

Contaminant Type

Anticonvulsant
Antimanic Agent
Drug
Enzyme Inhibitor
Food Toxin
GABA Agent
Metabolite
Organic Compound
Synthetic Compound

Chemical Structure

MOL SDF PDB SMILES InChI

Synonyms

Value	Source
2-N-Propyl-N-valeric acid	ChEBI
2-PROPYL-pentanoIC ACID	ChEBI
2-Propylpentanoic acid	ChEBI
2-Propylvaleric acid	ChEBI
4-Heptanecarboxylic acid	ChEBI
Acide valproique	ChEBI
Acido valproico	ChEBI
Acidum valproicum	ChEBI
Depakene	ChEBI
Di-N-propylacetic acid	ChEBI
Di-N-propylessigsaeure	ChEBI
Dipropylacetic acid	ChEBI
DPA	ChEBI
N-DPA	ChEBI
Valproinsaeure	ChEBI
VPA	ChEBI
2-N-Propyl-N-valerate	Generator
2-PROPYL-pentanoate	Generator
2-Propylpentanoate	Generator
2-Propylvalerate	Generator
4-Heptanecarboxylate	Generator
Di-N-propylacetate	Generator
Dipropylacetate	Generator
Valproate	Generator
(N-C3H7)2chcooh	HMDB
(S)-2-Propyl-4-pentanoate	HMDB
(S)-2-Propyl-4-pentanoic acid	HMDB
Alti-valproic	HMDB
Apo-divalproex	HMDB
Apo-valproic	HMDB
Apo-valproic syrup	HMDB
Avugane	HMDB
Baceca	HMDB
Convulex	HMDB
Delepsine	HMDB
Depakin	HMDB
Depakin chrono	HMDB
Depakine	HMDB
Depakine chrono	HMDB
Deproic	HMDB
Di-N-propylessigsaure	HMDB
Divalproex	HMDB
DOM-divalproex	HMDB
Dom-valproate	HMDB
DOM-valproic	HMDB
Dom-valproic acid	HMDB
DOM-valproic acid e.c.	HMDB
Dom-valproic acid syrup	HMDB
Epiject i.v.	HMDB
Epilex	HMDB
Epilim	HMDB
Epival	HMDB
Epival er	HMDB
Ergenyl	HMDB
Gen-divalproex	HMDB
Kyselina 2-propylvalerova	HMDB
Med valproic	HMDB
Mylproin	HMDB
Myproate	HMDB
Myproic acid	HMDB
N-Dipropylacetic acid	HMDB
Novo-divalproex	HMDB
Novo-valproic	HMDB
Novo-valproic - ecc	HMDB
Novo-valproic soft gel cap	HMDB
Nu-valproic	HMDB
PEAC	HMDB
Penta-valproic	HMDB
PHL-Valproate	HMDB
PHL-Valproic acid	HMDB
PHL-Valproic acid e.c.	HMDB
PMS-Divalproex	HMDB
PMS-Valproate	HMDB
PMS-Valproic acid	HMDB
PMS-Valproic acid e.c.	HMDB
Propylvaleric acid	HMDB
Ratio-valproic - ecc	HMDB
S(-)-4-En-valproate	HMDB
S(-)-4-En-valproic acid	HMDB
S-2-N-Propyl-4-pentenoate	HMDB
S-2-N-Propyl-4-pentenoic acid	HMDB
Sandoz valproic	HMDB
Savicol	HMDB
Sprinkle	HMDB
Valcote	HMDB
Valparin	HMDB
Valproic acid usp	HMDB
Dipropyl acetate	HMDB
Valproate, sodium	HMDB
Calcium, valproate	HMDB
Convulsofin	HMDB
Semisodium valproate	HMDB
Sodium valproate	HMDB
Valproate calcium	HMDB
Valproate, calcium	HMDB
Valproic acid, sodium salt (2:1)	HMDB
Acetate, dipropyl	HMDB
Depakote	HMDB
Divalproex sodium	HMDB
Magnesium valproate	HMDB
Sodium, divalproex	HMDB
Sodium, valproate	HMDB
Vupral	HMDB
2 Propylpentanoic acid	HMDB
Acid, propylisopropylacetic	HMDB
Acid, valproic	HMDB
Calcium valproate	HMDB
Propylisopropylacetic acid	HMDB
Valproate sodium	HMDB
Valproate, magnesium	HMDB
Valproate, semisodium	HMDB

Chemical Formula

C₈H₁₆O₂

Average Molecular Mass

144.211 g/mol

Monoisotopic Mass

144.115 g/mol

CAS Registry Number

99-66-1

IUPAC Name

2-propylpentanoic acid

Traditional Name

valproic acid

SMILES

CCCC(CCC)C(O)=O

InChI Identifier

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

InChI Key

NIJJYAXOARWZEE-UHFFFAOYSA-N

Chemical Taxonomy

Description

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

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

Biological Properties

Status

Detected and Not Quantified

Origin

Exogenous

Cellular Locations

Extracellular
Membrane

Biofluid Locations

Not Available

Tissue Locations

Brain
Liver

Pathways

Not Available

Applications

Biological Roles

Chemical Roles

EC 3.5.1.98 (histone deacetylase) inhibitor

Physical Properties

State

Solid

Appearance

White crystals.

Experimental Properties

Property	Value
Melting Point	120 - 130°C
Boiling Point	222°C
Solubility	1.3 mg/mL

Predicted Properties

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

Spectra

Spectrum Type	Description	Splash Key	View
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	splash10-004m-9300000000-e66da5fefd079f7426a4	Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (1 TMS) - 70eV, Positive	splash10-00b9-9100000000-7bb11c5d52ffa09851f8	Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	Not Available	Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	Not Available	Spectrum
LC-MS/MS	LC-MS/MS Spectrum - Quattro_QQQ 10V, N/A (Annotated)	splash10-0udi-2900000000-156413e81733a6236c1f	Spectrum
LC-MS/MS	LC-MS/MS Spectrum - Quattro_QQQ 25V, N/A (Annotated)	splash10-0f6y-2900000000-a769cafb885b78532cac	Spectrum
LC-MS/MS	LC-MS/MS Spectrum - Quattro_QQQ 40V, N/A (Annotated)	splash10-0gbj-7900000000-46a522b9a26459334f5a	Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 10V, Negative	splash10-0006-0900000000-39a45d4e3201082d9d89	Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 20V, Negative	splash10-0002-9000000000-4ddd957d8c8dc2b1de03	Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 10V, Negative	splash10-0006-0900000000-6ba582ae102c4721034d	Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 20V, Negative	splash10-0006-0900000000-58d9ba88010f1b370c58	Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 30V, Negative	splash10-0006-3900000000-2d1032d7e8ac58235b4f	Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 40V, Negative	splash10-0a4j-9000000000-0d39870bc4521a42c50a	Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 50V, Negative	splash10-00di-9000000000-3c4e21b69b8877d6df3e	Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ , negative	splash10-0006-0900000000-39a45d4e3201082d9d89	Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ , negative	splash10-0002-9000000000-4ddd957d8c8dc2b1de03	Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ , negative	splash10-0006-0900000000-6ba582ae102c4721034d	Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ , negative	splash10-0006-0900000000-58d9ba88010f1b370c58	Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ , negative	splash10-0006-3900000000-2d1032d7e8ac58235b4f	Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ , negative	splash10-0a4j-9000000000-0d39870bc4521a42c50a	Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ , negative	splash10-00di-9000000000-3c4e21b69b8877d6df3e	Spectrum
LC-MS/MS	LC-MS/MS Spectrum - Linear Ion Trap , negative	splash10-0006-0900000000-5b83f0d6c36f8249285a	Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 20V, Negative	splash10-0006-0900000000-51a760d50a87d131ad67	Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-0002-3900000000-be0e79e3b65dad2e2d08	Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-0005-9500000000-37d8981251a94cfd51e3	Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-0006-9000000000-b63be8686bbf9a96b2ba	Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-0006-3900000000-25f23d80c7431c074a74	Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-0005-9500000000-144b6cc9fea5bae4f269	Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-052e-9100000000-eb5e97329782125f6615	Spectrum
MS	Mass Spectrum (Electron Ionization)	splash10-0fk9-9300000000-1a0314ea63d5a3c9bba1	Spectrum
1D NMR	1H NMR Spectrum	Not Available	Spectrum
1D NMR	1H NMR Spectrum	Not Available	Spectrum
1D NMR	13C NMR Spectrum	Not Available	Spectrum
1D NMR	1H NMR Spectrum	Not Available	Spectrum
1D NMR	13C NMR Spectrum	Not Available	Spectrum
1D NMR	1H NMR Spectrum	Not Available	Spectrum
1D NMR	13C NMR Spectrum	Not Available	Spectrum
1D NMR	1H NMR Spectrum	Not Available	Spectrum
1D NMR	13C NMR Spectrum	Not Available	Spectrum
1D NMR	1H NMR Spectrum	Not Available	Spectrum
1D NMR	13C NMR Spectrum	Not Available	Spectrum
1D NMR	1H NMR Spectrum	Not Available	Spectrum
1D NMR	13C NMR Spectrum	Not Available	Spectrum
1D NMR	1H NMR Spectrum	Not Available	Spectrum
1D NMR	13C NMR Spectrum	Not Available	Spectrum
1D NMR	1H NMR Spectrum	Not Available	Spectrum
1D NMR	13C NMR Spectrum	Not Available	Spectrum
1D NMR	1H NMR Spectrum	Not Available	Spectrum
1D NMR	13C NMR Spectrum	Not Available	Spectrum
1D NMR	1H NMR Spectrum	Not Available	Spectrum
1D NMR	13C NMR Spectrum	Not Available	Spectrum
1D NMR	1H NMR Spectrum	Not Available	Spectrum
1D NMR	13C NMR Spectrum	Not Available	Spectrum
2D NMR	[1H,13C] 2D NMR Spectrum	Not Available	Spectrum

Toxicity Profile

Route of Exposure

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

Mechanism of Toxicity

Valproic Acid binds to and inhibits GABA transaminase. This leads to increased brain concentrations of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter in the CNS. Acute poisoning by VPA can lead to severe CNS depression including coma, confusion, somnolence, dizziness or hallucinations. Hypotension, respiratory depression and hypo/hyperthermia are also common. VPA is also hepatotoxic, which is likely due to its mitochondrial toxicity. VPA appears to exert its mitochondrial toxicity by impairing mitochondrial functions leading to oxidative stress and cytochrome c expulsion, which leads to apoptosis (17). VPA is contraindicated in pregnancy due to its teratogenicity. VPA is a known folate antagonist, which can cause neural tube defects in developing fetuses. Thus, folic acid supplements in pregnant women may alleviate teratogenic problems associated with VPA use. VPA and its metabolites inhibit the biosynthesis of carnitine by decreasing the concentration of alpha-ketoglutarate (through direct inhibition of alpha-ketoglutarate dehydrogenase) and may contribute to carnitine deficiency. It is postulated that carnitine supplementation may increase the beta-oxidation of VPA, thereby limiting cytosolic omega-oxidation and the production of toxic metabolites that are involved in liver toxicity and ammonia accumulation. VPA-induced hepatotoxicity and hyperammonemic encephalopathy may be promoted either by a pre-existing carnitine deficiency or by deficiency induced by VPA per se. VPA has been shown to downregulate levels of superoxide dismutase (SOD), glutathione (GSH), histone deacetylase (HDAC) and folate. It has also been shown to upregulate H2O2 and homocysteine. Elevated levels of H2O2 negatively affect the NADPH reducing system for dihydrofolate reductase (DHFR) and methylene tetrahydrofolate reductase (MTHFR) (18).

Metabolism

Valproic acid is rapidly absorbed from gastrointestinal tract. Valproic acid is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50% of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial oxidation is the other major metabolic pathway, typically accounting for over 40% of the dose. These products include 2-n-propylpent-2-enoic acid (delta 2,3 VPE) and several coenzyme A (CoA) derivatives including VPA-CoA, and delta 2,3 VPE-CoA. Usually, less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose is excreted unchanged in urine (1). Half Life: 9-16 hours (following oral administration of 250 mg to 1000 mg).

Toxicity Values

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

Lethal Dose

Not Available

Carcinogenicity (IARC Classification)

No indication of carcinogenicity to humans (not listed by IARC).

Uses/Sources

For treatment and management of seizure disorders, mania, and prophylactic treatment of migraine headache. In epileptics, valproic acid is used to control absence seizures, tonic-clonic seizures (grand mal), complex partial seizures, and the seizures associated with Lennox-Gastaut syndrome (1).

Minimum Risk Level

Not Available

Health Effects

Valproic acid causes hyperammonemia, which can lead to brain damage. Rarely, it can cause blood dyscrasia, impaired liver function, jaundice, thrombocytopenia, and prolonged coagulation times. In about 5% of pregnant users, valproic acid will cross the placenta and cause congenital anomalies. Valproic acid may also cause acute hematological toxicities, especially in children, including rare reports of myelodysplasia and acute leukemia-like syndrome (20). May cause a potentially dangerous rash that may develop into Stevens Johnson syndrome, an extremely rare but potentially fatal skin disease. Acute overdoses of VPA can lead to hypo/hyperthermia, tachycardia, hypotension, respiratory depression, coma, confusion, somnolence, dizziness, headaches and cerebral edema. Extended use of VPA can cause hepatotoxicity. Allopecia, anorexia, renal failure, tremors and miosis are also associated with chronic toxicity. VPA is a known teratogen (due to folate antagonism). The teratogenicity of VPA is mostly found at genetic and somatic levels, causing teratogenesis involving neural tube defects (NTDs), anencephaly, lumbosacral meningomyelocele, and leg dysfunction due to spina bifida aperta.

Symptoms

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

Treatment

In case of acute oral exposure, administer charcoal as a slurry. Consider gastric lavage after ingestion of a potentially life-threatening amount of the compound if it can be performed soon after ingestion (generally within 1 hour). Protect the patient’s airway by placement in Trendelenburg position (head down) and on their left side (left lateral decubitus position) or by endotracheal intubation. Control any seizures first. Some experimental and clinical data suggest that early intravenous supplementation with l-carnitine could improve survival in severe VPA-induced hepatotoxicity. Carnitine administration has been shown to speed the decrease of ammonemia in patients with VPA-induced encephalopathy. As it does not appear to be harmful, l-carnitine is commonly recommended in severe VPA poisoning, especially in children (19). In case of inhalation, move patient to fresh air, monitor for respiratory distress. If the exposure occurred via eye contact, irrigate exposed eyes with copious amounts of room temperature water for at least 15 minutes. Remove contaminated clothing and wash exposed area thoroughly with soap and water if the exposure occurred via dermal contact. (22).

Concentrations

Not Available

External Links

DrugBank ID

DB00313

HMDB ID

HMDB0001877

FooDB ID

FDB022722

Phenol Explorer ID

Not Available

KNApSAcK ID

Not Available

BiGG ID

Not Available

BioCyc ID

Not Available

METLIN ID

2986

PDB ID

Not Available

Wikipedia Link

Chemspider ID

ChEBI ID

PubChem Compound ID

Kegg Compound ID

YMDB ID

Not Available

ECMDB ID

Not Available

References

Synthesis Reference

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

MSDS

Link

General References

1. Bell EC, Willson MC, Wilman AH, Dave S, Silverstone PH: Differential effects of chronic lithium and valproate on brain activation in healthy volunteers. Hum Psychopharmacol. 2005 Aug;20(6):415-24.

2. Nemeroff CB: The role of GABA in the pathophysiology and treatment of anxiety disorders. Psychopharmacol Bull. 2003;37(4):133-46.

3. Sztajnkrycer MD: Valproic acid toxicity: overview and management. J Toxicol Clin Toxicol. 2002;40(6):789-801.

4. Seyfert S, Bernarding J, Braun J: Volume-selective 1H MR spectroscopy for in vivo detection of valproate in patients with epilepsy. Neuroradiology. 2003 May;45(5):295-9. Epub 2003 Mar 27.

5. Eyal S, Lamb JG, Smith-Yockman M, Yagen B, Fibach E, Altschuler Y, White HS, Bialer M: The antiepileptic and anticancer agent, valproic acid, induces P-glycoprotein in human tumour cell lines and in rat liver. Br J Pharmacol. 2006 Oct;149(3):250-60. Epub 2006 Aug 7.

6. Loscher W: Basic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy. CNS Drugs. 2002;16(10):669-94.

7. Huang YL, Hong HS, Wang ZW, Kuo TT: Fatal sodium valproate-induced hypersensitivity syndrome with lichenoid dermatitis and fulminant hepatitis. J Am Acad Dermatol. 2003 Aug;49(2):316-9.

8. Anderson GD, Temkin NR, Chandler WL, Winn HR: Effect of valproate on hemostatic function in patients with traumatic brain injury. Epilepsy Res. 2003 Dec;57(2-3):111-9.

9. Ho PC, Abbott FS, Zanger UM, Chang TK: Influence of CYP2C9 genotypes on the formation of a hepatotoxic metabolite of valproic acid in human liver microsomes. Pharmacogenomics J. 2003;3(6):335-42.