| Item |
Information |
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Drug Groups
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approved; investigational |
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Description
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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. Typically supplied in the sodium salt form (76584-70-8). Valproic Acid is also a histone deacetylase inhibitor and is under investigation for treatment of HIV and various cancers. |
| Indication |
For treatment and management of seizure disorders, mania, and prophylactic treatment of migraine headache. |
| 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. |
| Toxicity |
Oral, mouse: LD50 = 1098 mg/kg; Oral, rat: LD50 = 670 mg/kg. Symptoms of overdose may include coma, extreme drowsiness, and heart problems. |
| Affected Organisms |
| • |
Humans and other mammals |
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| 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. |
| Absorption |
Rapid absorption from gastrointestinal tract. |
| Half Life |
9-16 hours |
| Protein Binding |
Concentration-dependent, from 90% at 40 μg/mL to 81.5% at 130 μg/mL. |
| Elimination |
Valproate is metabolized almost entirely by the liver. Less than 3% of an administered dose is excreted unchanged in urine. Mitochondrial ?-oxidation is the other major metabolic pathway, typically accounting for over 40% of the dose. |
| Distribution |
* 11 L/1.73 m2 [total valproate]
* 92 L/1.73 m2 [free valproate] |
| Clearance |
* total valproate cl=0.56 L/hr/1.73 m2
* free valproate cl=4.6 L/hr/1.73 m2
* 4.8 +/- 0.17 L/hr/1.73 m2 [males, unbound clearance]
* 4.7+/- 0.07 L/hr/1.73 m2 [females, unbound clearance] |
| References |
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Rosenberg G: The mechanisms of action of valproate in neuropsychiatric disorders: can we see the forest for the trees? Cell Mol Life Sci. 2007 Aug;64(16):2090-103.
[Pubmed]
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Lehrman G, Hogue IB, Palmer S, Jennings C, Spina CA, Wiegand A, Landay AL, Coombs RW, Richman DD, Mellors JW, Coffin JM, Bosch RJ, Margolis DM: Depletion of latent HIV-1 infection in vivo: a proof-of-concept study. Lancet. 2005 Aug 13-19;366(9485):549-55.
[Pubmed]
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Schwartz C, Palissot V, Aouali N, Wack S, Brons NH, Leners B, Bosseler M, Berchem G: Valproic acid induces non-apoptotic cell death mechanisms in multiple myeloma cell lines. Int J Oncol. 2007 Mar;30(3):573-82.
[Pubmed]
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Valentini A, Gravina P, Federici G, Bernardini S: Valproic acid induces apoptosis, p16INK4A upregulation and sensitization to chemotherapy in human melanoma cells. Cancer Biol Ther. 2007 Feb;6(2):185-91. Epub 2007 Feb 5.
[Pubmed]
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