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药品详细

Valproic Acid(丙戊酸)

化学结构式图
中文名
丙戊酸
英文名
Valproic Acid
分子式
C8H16O2
化学名
2-propylpentanoic acid
分子量
Average: 144.2114
Monoisotopic: 144.115029756
CAS号
99-66-1
ATC分类
N03A 未知
药物类型
small molecule
阶段
approved
商品名
同义名
基本介绍

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.

生产厂家
  • Abbott laboratories pharmaceutical products div
  • Alpharma uspd inc
  • Apotex inc richmond hill
  • Banner pharmacaps inc
  • Catalent pharma solutions llc
  • High technology pharmacal co inc
  • Par pharmaceutical inc
  • Pharmaceutical assoc inc div beach products
  • Rp scherer north america div rp scherer corp
  • Sun pharmaceutical industries inc
  • Teva pharmaceuticals usa
  • Usl pharma inc
  • Vintage pharmaceuticals llc
  • Wockhardt eu operations (swiss) ag
封装厂家
参考
Synthesis Reference Not Available
General Reference
  1. 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
  2. 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
  3. 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
  4. 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
剂型
规格
化合物类型
Type small molecule
Classes
  • Fatty Acids
Substructures
  • Hydroxy Compounds
  • Acetates
  • Carboxylic Acids and Derivatives
  • Fatty Acids
适应症
药理
Indication For treatment and management of seizure disorders, mania, and prophylactic treatment of migraine headache.
Pharmacodynamics 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.
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. It is also a histone deacetylase inhibitor.
Absorption Rapid absorption from gastrointestinal tract.
Volume of distribution
  • 11 L/1.73 m2 [total valproate]
  • 92 L/1.73 m2 [free valproate]
Protein binding Concentration-dependent, from 90% at 40 µg/mL to 81.5% at 130 µg/mL.
Metabolism
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.

Important The metabolism module of DrugBank is currently in beta. Questions or suggestions? Please contact us.

Substrate Enzymes Product
Valproic Acid
4-ene-Valproic acid Details
Valproic Acid
5-Hydroxyvalproic acid Details
Valproic Acid
3-Hydroxyvalproic acid Details
Valproic Acid
4-Hydroxyvalproic acid Details
Valproic Acid
Valpronic acid beta-O-glucuronide Details
Valproic Acid
2-ene-Valproic acid Details
Valproic Acid
(3Z)-2-Propylpent-3-enoic acid Details
Valproic Acid
(3E)-2-Propylpent-3-enoic acid Details
Valproic Acid
    		Valproic acid glucuronide Details
    Valproic Acid
      		2-ene-valproic acid CoA Details
      Valproic Acid
        		2,3-diene-valproic acid-CoA Details
        Valproic Acid
          		3-ene-valproic acid CoA Details
          Valproic Acid
            		3-hydroxyvalproicd acid CoA Details
            Valproic Acid
              		3-oxo-valproic acid CoA Details
              Valproic Acid
                		4-ene-valproic acid CoA Details
                Valproic Acid
                  		Valproic acid CoA Details
                  Route of elimination Valproate is metabolized almost entirely by the liver. Less than 3% of an administered dose is excreted unchanged in urine. Mitochondrial ß-oxidation is the other major metabolic pathway, typically accounting for over 40% of the dose.
                  Half life 9-16 hours
                  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]
                  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
                  Pathways Not Available
                  理化性质
                  Properties
                  State solid
                  Experimental Properties
                  Property Value Source
                  melting point 120-130 °C Not Available
                  water solubility 2000 mg/L (at 20 °C) RIEMENSCHNEIDER (1986)
                  logP 2.75 SANGSTER (1993)
                  logS -1.86 ADME Research, USCD
                  pKa 4.6 BUDAVARI,S ET AL. (1996)
                  Predicted Properties
                  Property Value Source
                  water solubility 2.36e+00 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 ChemAxon
                  rotatable bond count 5 ChemAxon
                  refractivity 40.25 ChemAxon
                  polarizability 17 ChemAxon
                  药物相互作用
                  Drug Interaction
                  Acetylsalicylic acid Acetylsalicylic acid increases the effect of valproic acid.
                  Asenapine Valproate completely inhibits the glucuronidation of asenapine but does not effect its exposure. Dose adjustment is not necessary with concomitant therapy.
                  Carbamazepine Decreases the effect of valproic acid
                  Clarithromycin The macrolide antibiotic, Erythromycin, may increase the serum concentratin of Valproic acid. Consider alternate therapy or monitor for changes in Valproic acid therapeutic and adverse effects if Clarithromycin is initiated, discontinued or dose changed.
                  Eltrombopag Affects hepatic CYP2C9/10 metabolism, will increase effect/level of eltrombopag.
                  Erythromycin The macrolide antibiotic, Erythromycin, may increase the serum concentratin of Valproic acid. Consider alternate therapy or monitor for changes in Valproic acid therapeutic and adverse effects if Erythromycin is initiated, discontinued or dose changed.
                  Felbamate Felbamate, a CYP2C19 inhibitor, may decrease the metabolism of Valproic acid, a CYP2C19 substrate. Consider alternate therapy or monitor for changes in Valproic acid therapeutic and adverse effects if Felbamate is initiated, discontinued or dose changed.
                  Glycerol Phenylbutyrate Valproic acid may induce hyperammonemia. Monitor ammonia levels closely when use of valproic acid is necessary in UCD patients.
                  Lacosamide Valproic acid toxicity may occur at any time during the treatment course and should be considered in patients with acute changes in mentation, especially if there has been a recent change in antiepileptic therapy.
                  Lamotrigine Valproic acid may increase the adverse effects of Lamotrigine by increasing Lamotrigine serum concentration. The Lamotrigine dose should be reduced by 50% during concomitant therapy. Monitor for changes in Lamotrigine therapeutic and adverse effects if Valproic acid is initiated, discontinued or dose changed.
                  Lorazepam Valproic acid may increase the serum concentration of Lorazepam by reducing Lorazepam metabolism. The Lorazepam dose should be reduced by 50% during concomitant therapy. Monitor for increased Lorazepam effects and toxicity.
                  Nimodipine Valproic acid increases the effect of nimodipine
                  Rifampin Rifampin may reduce the serum concentration of Valproic acid by increasing Valproic acid metabolism. Valproic acid dose adjustments may be required during concomitant therapy. Monitor Valproic acid serum concentrations, efficacy and toxicity if Rifampin is initiated, discontinued or dose changed.
                  Rufinamide Valproic acid may increase the therapeutic/toxic effects of Rufinamide. Consider alternate therapy or monitor for changes in Rufinamide serum concentrations, therapeutic and adverse effects if Valproic acid is initiated, discontinued or dose changed. Decreases clearance of rufinamide and is a selective inhibitor of human carboxylesterase thus increasing serum concentrations.
                  Silodosin Strong UGT2B7 inhibitors may increase levels of silodosin. Monitor concomitant therapy closely.
                  Telithromycin The macrolide antibiotic, Erythromycin, may increase the serum concentratin of Valproic acid. Consider alternate therapy or monitor for changes in Valproic acid therapeutic and adverse effects if Telithromycin is initiated, discontinued or dose changed.
                  Tipranavir Tipranavir decreases the concentration of Valproic acid. Monitor Valproid acid efficacy.
                  Vigabatrin Vigabatrin reduces serum concentrations of valproic acid by 8%.
                  食物相互作用
                  • Avoid alcohol.
                  • Do not take with milk.
                  • Take with food.

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