Drug/Small Molecule:

valproic acid

Overview

Generic Names:	DPA; Di-n-propylacetic acid; Di-n-propylessigsaure; Dipropylacetic acid; Kyselina 2-propylvalerova; Myproic Acid; Propylvaleric acid; Sodium hydrogen divalproate; Valproate semisodique [French]; Valproate semisodium; Valproato semisodico [Spanish]; Valproatum seminatricum [Latin]; n-DPA; n-Dipropylacetic acid; valproic acid
IUPAC Name:	2-propylpentanoic acid
Trade Names:	Alti-Valproic; Avugane; Baceca; Convulex; Delepsine; Depakene; Depakine; Deproic; Dom-Valproic; Epilex; Epilim; Epival; Ergenyl; Med Valproic; Mylproin; Novo-Valproic; Nu-Valproic; PMS-Valproic Acid; Penta-Valproic; Sprinkle; Valcote; Valparin; Valproic acid USP; Valproic acid USP24
PharmGKB Accession Id:	PA451846

Description

A fatty acid with anticonvulsant properties used in the treatment of epilepsy. The mechanisms of its therapeutic actions are not well understood. It may act by increasing gamma-aminobutyric acid levels in the brain or by altering the properties of voltage dependent sodium channels. [PubChem]

Indication

For use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types which include absence seizures.

ATC Therapeutic Category

• N03AG:Fatty acid derivatives

Pharmacology and Interactions

Mechanism Of Action

Valproic Acid binds to and inhibits GABA transaminase. The drug's anticonvulsant activity may be related to increased brain concentrations of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter in the CNS, by inhibiting enzymes that catabolize GABA or block the reuptake of GABA into glia and nerve endings. Valproic Acid may also work by suppressing repetitive neuronal firing through inhibition of voltage-sensitive sodium channels.

Pharmacology

Valproic Acid is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder. It is also used to treat migraine headaches and schizophrenia. 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. Valproic Acid 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. Valproic acid has also been shown to be an inhibitor of an enzyme called histone deacetylase 1 (HDAC1). HDAC1 is needed for HIV to remain in infected cells. A study published in August 2005 revealed that patients treated with valproic acid in addition to highly active antiretroviral therapy (HAART) showed a 75% reduction in latent HIV infection.

Food Interactions

Avoid alcohol. Do not take with milk. Take with food.

Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation

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 ß-oxidation is the other major metabolic pathway, typically accounting for over 40% of the dose. 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.

Protein Binding

The plasma protein binding of valproate is concentration dependent and the free fraction increases from approximately 10% at 40 µg/mL to 18.5% at 130 µg/mL.

Absorption

Rapid absorption from gastrointestinal tract.

Half Life

9-16 hours

Toxicity

Oral, mouse: LD₅₀ = 1098 mg/kg; Oral, rat: LD₅₀ = 670 mg/kg. Symptoms of overdose may include coma, extreme drowsiness, and heart problems.

Chemical Properties

Chemical Formula:

C₈H₁₆O₂

SMILES Code:

CCCC(CCC)C(=O)O

(Format: OpenEye Isomeric)

Molecular Weight ( average / monoisotopic )

144.2114 / 144.115

Curated Annotations ()

1. rs2032582 at chr7:86998554 in ABCB1
   This variant maybe associated with drug resistance in chinese epilepsy patients. Sample size: 464 chinese epilepsy patients (270 drug responsive, 194 drug resistant).

   Variant Name:

   ABCB1: 2677T/A>G

   Related Drugs:

   carbamazepine, clobazam, clonazepam, gabapentin, lamotrigine, levetiracetam, phenobarbital, phenytoin, topiramate, valproic acid, vigabatrin

   Related Diseases:

   Epilepsy

   Evidence:

   PMID:19450124
   

2. rs3789243 at chr7:87058822 in ABCB1
   This variant maybe associated with drug resistance in chinese epilepsy patients. Sample size: 464 chinese epilepsy patients (270 drug responsive, 194 drug resistant).

   Related Drugs:

   carbamazepine, clobazam, clonazepam, gabapentin, lamotrigine, levetiracetam, phenobarbital, phenytoin, topiramate, valproic acid, vigabatrin

   Related Diseases:

   Epilepsy

   Evidence:

   PMID:19450124
   

Curated Information

The following genes are in curated knowledge about this drug.

	Gene	Relationship	Evidence
	ABCB1	PK FA GN	Publications, Variants
	ABCC11	PK	Publications
	ABCG2	PK	Publications
	CYP2A6	PK	Publications
	CYP2B6	PK	Publications
	CYP2C9	PK	Publications
	EPHX1		Publications
	FMR1	FA	Publications
	NR1I2	FA	Publications
	SMN2	PD	Publications
	UGT1A3	PK	Publications
	UGT2B7	PD PK    GN	Publications

Non-Curated Information

A list of non-curated publications that mention this drug along with other genes is available.

Drug Targets

• HDAC9
• ABAT

Curated Information

The following drugs are in curated knowledge about this drug.

	Drug	Relationship	Evidence
	carbamazepine		Publications
	losartan	PK	Publications

Non-Curated Information

A list of non-curated publications that mention this drug along with other drugs is available.

Curated Information

The following diseases are in curated knowledge about this drug.

	Disease	Relationship	Evidence
	Bipolar Disorder	PK    GN	Publications
	Epilepsy	PD PK FA GN	Publications, Variants
	Fragile X Syndrome	FA	Publications
	Leukemia, Myeloid, Acute	PK	Publications
	Spinal Muscular Atrophies of Childhood	PD	Publications
	Toxic liver disease	PD	Publications

Non-Curated Information

A list of non-curated publications that mention this drug along with other diseases is available.

Additional Datasets

These datasets are minimally curated and are sorted alphabetically by title.

1. Physicochemical determinants of human renal clearance
2. The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease

LinkOuts

Common Searches

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Non-Curated Publications

A list of non-curated publications that mention this drug is available.