Valproic Acid

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Valproic Acid
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Executive Summary Information

Compound Valproic Acid
Toxicities Steatosis, cytotoxicity
Mechanisms As a fatty acid analogue, the compound is a competitive inhibitor of fatty acid metabolism, which accounts for steatosis. The parent compound is also hepatotoxic by a mechanism that has not been resolved; however, this hydrophobic compound is used at very high concentrations and its promiscuous activity at these concentrations is likely due to disruption of membrane integrity. P450 ω-oxidation produces a reactive alkylating and free radical-propagating agent that adds to the toxicity profile.
Comments This compound was selected as a reference standard for steatosis via inhibition of β-oxidation.
Feedback Contact Gold Compound Working Group (GCWG)
Valproic Acid
Valproic acid.png


Identifiers
Leadscope Id LS-2068
CAS 99-66-1
DrugBank DB00313
ChemSpider 3009
UNII 614OI1Z5VM
Pathway DBs
KEGG D00399
Assay DBs
PubChem CID 3121
ChEMBL 109
Omics DBs
Open TG-Gate 00005
Properties
pKa 4.72
ToxCast Accepted yes
Toxic Effect Steatosis
ToxBank Accepted yes
Approved on 2011-06-28
Target GABA transaminase
Toxicities Cytotoxicity


In Vivo Data ? Compound Assessment
Adverse Events ? “The foremost and most severe concern for anyone taking valproic acid is its potential for sudden and severe, possibly fatal, fulminating impairments in liver, hematopoietic and/or pancreatic function, especially in those just starting the medication. This particular warning is the first one listed on any drug adverse effect listing when one receives the drug at the pharmacy.”

References:

-http://en.wikipedia.org/wiki/Valproic_acid

Hepatitis with elevated blood enzymes in 11% of patients. 42 cases of fatal hepatitis reported up to 1984. Hyperammonaemia is observed in patients with deficiencies in urea cycle enzymes. Microvesicular fat is observed in approximately half of patients with hepatitis.

References:

-P R Powell-Jackson, J M Tredger, And Roger Williams, “Hepatotoxicity to sodium valproate: a review”, Gut (1984) 25, 673-681.

In persons on valproate therapy, a dose related elevation in liver enzymes may occur. Those elevations may be more than three times the normal level and the findings of low fibrinogen or an elevated prothrombin time were regarded as important manifestations of biochemical evidence for serious hepatic function disorder.

References:

-Dreifuss FE, Santilli N, Langer DH, Sweeney KP, Moline KA, Menander KB., “Valproic acid hepatic fatalities: a retrospective review”, Neurology, 1987 Mar;37(3):379-85.

Other toxicities in addition to hepatic are thoroughly reviewed in Sebastian et al., 2010.

References:

-Sebastien Chateauvieux, Franck Morceau, Mario Dicato, and Marc Diederich, “Molecular and Therapeutic Potential and Toxicity of Valproic Acid”, Journal of Biomedicine and Biotechnology, Volume 2010, Article ID 479364.

A recent review of data indicates that pancreatitis may be underreported. It is a reasonable assumption that pancreatitis arises via the same mechanisms as hepatitis, but we have not researched this question or the mechanism of hematopoietic impairment.

References:

-Thorsten Gerstner, et al., “Valproic acid-induced pancreatitis: 16 new cases and a review of the literature”, J Gastroenterol 2007; 42:39–48.
Toxicity Mechanisms ? Hepatotoxicity

Valproic acid is a branched-chain fatty acid that is recognized as a substrate by the fatty acid oxidation pathway. This pathway accounts for 40% of valproic acid metabolites in humans. Silva et al. provide a review.

References:

-M. F. B. Silva, C. C. P. Aires, P. B. M. Luis, J. P. N. Ruiter, L. IJlst, M. Duran, R. J. A. Wanders, I. Tavares de Almeida, “Valproic acid metabolism and its effects on mitochondrial fatty acid oxidation: A review”, J Inherit Metab Dis (2008) 31:205–216.

As a substrate for the fatty acid oxidation pathway, valproic acid is a competitive inhibitor vs. oxidation of the normal fatty acid substrates. In particular, the valproic acid-CoA ester is stable to turnover and accumulates. In effect, then, valproic acid depletes availability of free CoASH, hence labelling this toxin as a CoASH sequestering agent. This has been demonstrated explicitly in rats.

References:

-Kesterson JW, Granneman GR, Machinist JM (1984) “The hepatotoxicity of valproic acid and its metabolites in rats. I. Toxicologic, biochemical and histopathologic studies.”, Hepatology 4: 1143–1152.

Valproic acid has also been reported to deplete free carnitine. Because of the role of carnitine in the urea cycle, this activity is presumed to account for the observation of hyperammonaemia in the clinic. Preliminary results indicate that valproyl-CoA competitively inhibits transfer of fatty acids from the carnitine ester to the CoA ester in the mitochondrial import system. As a result carnitine ester intermediates build up and deplete free carnitene.

References:

-M. F. B. Silva, C. C. P. Aires, P. B. M. Luis, J. P. N. Ruiter, L. IJlst, M. Duran, R. J. A. Wanders, I. Tavares de Almeida, “Valproic acid metabolism and its effects on mitochondrial fatty acid oxidation: A review”, J Inherit Metab Dis (2008) 31:205–216.

Competitive inhibition of fatty acid metabolism is qualitatively sufficient to explain steatosis, but does not in an obvious way account for cell death that is observed in vivo and in vitro. Valproic acid is oxidized by P450’s to the 4-ene metabolite, which is converted to the CoA ester of 2,4-diene valproic acid by the fatty acid oxidation system. This metabolite is a reactive Michael acceptor, and in addition will have free-radical propagating activity similar to the activity of acrylic acid. Adducts of this intermediate with glutathione are identified as metabolites in humans, which infers the formation of Michael adducts with cellular proteins. However, P450 inhibitors do not block the cellular toxicity of valproic acid. (Note that the effects of P450 inhibitors specifically on lipid accumulation have not been determined) The molecular mechanism of valproate-induced cell death, therefore, is unclear.

References:

-Sashi V. Gopaul, Kevin Farrell, And Frank S. Abbott, “Identification And Characterization Of N-Acetylcysteine Conjugates Of Valproic Acid In Humans And Animals”,Drug Metab Disp 28:823–832, 2000.
-Tony K.L. Kiang, Xiao Wei Teng, Jayakumar Surendradoss, Stoyan Karagiozov, Frank S. Abbott, Thomas K.H. Chang, “Glutathione depletion by valproic acid in sandwich-cultured rat hepatocytes: Role of biotransformation and temporal relationship with onset of toxicity”,Toxicology and Applied Pharmacology 252 (2011) 318–324.
Therapeutic Target ? Valproic acid was originally used as an inert formulating agent and discovered by accident to have antiepileptic activity. Subsequent attempts to understand its pharmacological mechanism revealed numerous biological activities in excitable cells: increased GABA activity via multiple mechanisms, attenuation of the NMDA receptor, inhibition of Na+ channels, inhibition of voltage dependent L-type Ca2+ channels and inhibition of voltage-gated K+ channels.

References:

-Sebastien Chateauvieux, Franck Morceau, Mario Dicato, and Marc Diederich, “Molecular and Therapeutic Potential and Toxicity of Valproic Acid”, Journal of Biomedicine and Biotechnology, Volume 2010, Article ID 479364.

Valproic acid is a competitive inhibitor of histone deacetylases at concentrations comparable to its cellular steatotic and cytotoxic activities. This activity has been related to anti-tumor and neuroprotective activities for this drug. This result increases the enormous spectrum of activities for this nonselective reagent and difficulty in understanding the mechanism of its pharmacological and toxicological effects.

References:

-Christopher J. Phiel, Fang Zhang, Eric Y. Huang, Matthew G. Guenther, Mitchell A. Lazar, and Peter S. Klein, “Histone Deacetylase Is a Direct Target of Valproic Acid, a Potent Anticonvulsant, Mood Stabilizer, and Teratogen”, JBC 276:36734–36741 (2001)
-Göttlicher, M.; Minucci, S.; Zhu, P.; Krämer, O. H.; Schimpf, A.; Giavara, S.; Sleeman, J. P.; Lo Coco, F.; Nervi, C.; Pelicci, P. G.; Heinzel, T., “Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells” EMBO J. 2001, 20, 6969-7698.
-Barbara Monti, Elisabetta Polazzi and Antonio Contestabile, “Biochemical, Molecular and Epigenetic Mechanisms of Valproic Acid Neuroprotection”,Current Molecular Pharmacology, 2009, 2, 95-1

Human Adverse Events

The following data table has been mined from the Adverse Events Reporting System (AERS) of the US FDA. Significant human liver events. The first column ("# Reports") is the number of reports found for the corresponding adverse event reported in the third column ("Adverse Event"). The second column ("Report:Baseline Ratio") is ratio calculated from the number of reports ("# Reports") divided by a calculated expected statistical baseline number of reports.

# Reports Report:Baseline Ratio Adverse Event
1 38.1785 gallbladder anomaly congenital
2 4.64781 hepatic adenoma
1 7.42359 hepatitis neonatal
9 3.75233 hepatocellular injury
259 41.4725 hyperammonaemia
3 10.1487 mixed liver injury
7 9.40073 reye's syndrome

FDA and Label Information

The following link will display all of the currently approved FDA drug products on the market. The web page will contain a table listing all current products by their respective Tradenames and primary active ingredients. The list is navigable by simply clicking on the product of interest, which will in turn list all of the NDA's and ANDA's associated with that product. From here users can click on a specific NDA or ANDA and see documents that have been submitted for the product that the FDA has made available via their website. The types of documents include approval history, letters, reviews and labels.
FDA Approved Products

This next url will perform a search in the FDA's system for all labels for products that contain "Valproic acid" as an active ingredient.
FDA Label Search

PubMed references

The following resource link will perform a PubMed query for the terms "Valproic acid" and "liver toxicity".
Valproic acid Search

The table listed below contains a summarized listing of toxic effect information leveraged from the 6th European Framework Programme project LIINTOP. For a complete listing of the Gold Compound evaluation criteria please see the Gold Compound Evaluation and Comments immediately following the summary table below.

SMILES CCCC(CCC)C(=O)O
InChI

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

Summary Hepatotoxic Effects from the LIINTOP FP6 Program
Hepatocellular necrosis.gif Apoptosis.gif Transporter inhibition.gif Cholestatic.gif Steatotic.gif Phospholipidosis.gif Hepatocyte function.gif Mithochondria impairment.gif Oxidative stress.gif DNA synthesis genotoxicity.gif Covalent binding.gif Idiosyncrasia metabolic.gif Idiosyncrasia immune.gif Bioactivation required.gif LIINTOP severity.gif References
+ + + + + + 3

[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24]

References

  1. Donato, M.T., Martinez-Romero, A., Jimenez, N., Negro, A., Herrera, G., Castell, J.V., O’Connor, J.E., Gomez-Lechon, M.J., 2009. Cytometric analysis for drug-induced steatosis in HepG2 cells. Chem. Biol. Interact. 181, 417–423.
  2. Ioannides, C., Lewis, D.F., 2004. Cytochromes P450 in the bioactivation of chemicals. Curr. Top. Med. Chem. 4, 1767–1788.
  3. Kang, P., Dalvie, D., Smith, E., Zhou, S., Deese, A., Nieman, J.A., 2008. Bioactivation of flutamide metabolites by human liver microsomes. Drug Metab. Dispos. 36, 1425–1437.
  4. Li, A.P., 2002. A review of the common properties of drugs with idiosyncratic hepatotoxicity and the ‘‘multiple determinant hypothesis” for the manifestation of idiosyncratic drug toxicity. Chem. Biol. Interact. 142, 7–23.
  5. Park, K., Williams, D.P., Naisbitt, D.J., Kitteringham, N.R., Pirmohamed, M., 2005b. Investigation of toxic metabolites during drug development. Toxicol. Appl. Pharmacol. 207, 425–434.
  6. Reddy, M.V., Storer, R.D., Laws, G.M., Armstrong, M.J., Barnum, J.E., Gara, J.P., McKnight, C.G., Skopek, T.R., Sina, J.F., DeLuca, J.G., Galloway, S.M., 2002. Genotoxicity of naturally occurring indolecompounds: correlation between covalentDNAbinding and other genotoxicity tests. Environ. Mol. Mutagen. 40, 1–17.
  7. Hynes, J., Marroquin, L.D., Ogurtsov, V.I., Christiansen, K.N., Stevens, G.J., Papkovsky, D.B., Will, Y., 2006. Investigation of drug-induced mitochondrial toxicity using fluorescence-based oxygen-sensitive probes. Toxicol. Sci. 92, 186–200.
  8. Johannsen, D.L., Ravussin, E., 2009. The role of mitochondria in health and disease. Curr. Opin. Pharmacol. 9, 780–786.
  9. Jones, D.P., Lemasters, J.J., Han, D., Boelsterli, U.A., Kaplowitz, N., 2010. Mechanisms of pathogenesis in drug hepatotoxicity putting the stress on mitochondria. Mol. Interv. 10, 98–111.
  10. Labbe, G., Pessayre, D., Fromenty, B., 2008. Drug-induced liver injury through mitochondrial dysfunction: mechanisms and detection during preclinical safety studies. Fundam. Clin. Pharmacol. 22, 335–353.
  11. Masubuchi, Y., 2006. Metabolic and non-metabolic factors determining troglitazone hepatotoxicity: a review. Drug Metab. Pharmacokinet. 21, 347–356.
  12. Bradbury, M.W., Berk, P.D., 2004. Lipid metabolism in hepatic steatosis. Clin. Liver Dis. 8, 639–671 (xi).
  13. Chariot, P., Drogou, I., de Lacroix-Szmania, I., Eliezer-Vanerot, M.C., Chazaud, B., Lombes, A., Schaeffer, A., Zafrani, E.S., 1999. Zidovudine-induced mitochondrial disorder with massive liver steatosis, myopathy, lactic acidosis, and mitochondrial DNA depletion. J. Hepatol. 30, 156–160.
  14. Donato, M.T., Martinez-Romero, A., Jimenez, N., Negro, A., Herrera, G., Castell, J.V., O’Connor, J.E., Gomez-Lechon, M.J., 2009. Cytometric analysis for drug-induced steatosis in HepG2 cells. Chem. Biol. Interact. 181, 417–423.
  15. Fromenty, B., Pessayre, D., 1995. Inhibition of mitochondrial beta-oxidation as a mechanism of hepatotoxicity. Pharmacol. Ther. 67, 101–154.
  16. Fromenty, B., Pessayre, D., 1997. Impaired mitochondrial function in microvesicular steatosis. Effects of drugs, ethanol, hormones and cytokines. J. Hepatol. 26 (Suppl. 2), 43–53.
  17. Letteron, P., Sutton, A., Mansouri, A., Fromenty, B., Pessayre, D., 2003. Inhibition of microsomal triglyceride transfer protein: another mechanism for drug-induced steatosis in mice. Hepatology 38, 133–140.
  18. Shokolenko, I., Venediktova, N., Bochkareva, A., Wilson, G.L., Alexeyev, M.F., 2009. Oxidative stress induces degradation of mitochondrial DNA. Nucleic Acids Res. 37, 2539–2548.
  19. Criddle, D.N., Gillies, S., Baumgartner-Wilson, H.K., Jaffar, M., Chinje, E.C., Passmore, S., Chvanov, M., Barrow, S., Gerasimenko, O.V., Tepikin, A.V., Sutton, R., Petersen, O.H., 2006. Menadione-induced reactive oxygen species generation via redox cycling promotes apoptosis of murine pancreatic acinar cells. J. Biol. Chem. 281, 40485–40492.
  20. Hanley, P.J., Ray, J., Brandt, U., Daut, J., 2002. Halothane, isoflurane and sevoflurane inhibit NADH:ubiquinone oxidoreductase (complex I) of cardiac mitochondria. J. Physiol. 544, 687–693.
  21. Moridani, M.Y., Cheon, S.S., Khan, S., O’Brien, P.J., 2003. Metabolic activation of 3- hydroxyanisole by isolated rat hepatocytes. Chem. Biol. Interact. 142, 317–333.
  22. Pereira, C.V., Moreira, A.C., Pereira, S.P., Machado, N.G., Carvalho, F.S., Sardao, V.A., Oliveira, P.J., 2009. Investigating drug-induced mitochondrial toxicity: a biosensor to increase drug safety? Curr. Drug Saf. 4, 34–54.
  23. Sanz, A., Caro, P., Gomez, J., Barja, G., 2006. Testing the vicious cycle theory of mitochondrial ROS production: effects of H2O2 and cumene hydroperoxide treatment on heart mitochondria. J. Bioenerg. Biomembr. 38, 121–127.
  24. Yuan, L., Kaplowitz, N., 2009. Glutathione in liver diseases and hepatotoxicity. Mol. Aspects Med. 30, 29–41.

PK-ADME ? Compound Assessment
PK parameters ?
  • Cmax at 500 mg oral dose= 103 ± 13 mg/L (710 uM)
  • Half-life =9-16 hours for the valproate ion.
  • Vd = 15% of body wt.
  • Cl(total) = 0.11 ml/kg/min
  • 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
  • Vd of total or free valproic acid is 11 and 92 L per 1.73 m2, respectively
  • Recommended dose is dependent on presented condition but is usually between 500mg-1000mg per day based on human adult.

References:

-Drugs.com
-Wolfgang Loescher (1978) “Serum Protein Binding and Pharmacokinetics of Valproate in Man, Dog, Rat, and Mouse”, J Pharm Exp Ther 204:255-261.
-M. F. B. Silva, C. C. P. Aires, P. B. M. Luis, J. P. N. Ruiter, L. IJlst, M. Duran, R. J. A. Wanders, I. Tavares de Almeida (2008) “Valproic acid metabolism and its effects on mitochondrial fatty acid oxidation: A review”, J Inherit Metab Dis 31:205–216
Therapeutic window ? Elevated liver enzymes are observed at 10% frequency in children at the maximum recommended dose indicating a therapeutic window near 1x.
Metabolically activated ? 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
EnzymeMetabolite Reaction Km Vmax
Prostaglandin G/H synthase 12-ene-Valproic acid
Prostaglandin G/H synthase 1(3Z)-2-Propy lpent-3-enoic acid
Prostaglandin G/H synthase 1(3E)-2-Propyl pent-3-enoic acid
Cytochrome P450 3A55-Hydroxy-valproic acid
Cytochrome P450 3A53-Hydroxyvalproic acid
Cytochrome P450 3A54-Hydroxyvalproic acid
Cytochrome P450 2C94-ene-Valproic acid (active metabolite)
Cytochrome P450 2A64-ene-Valproic acid (active metabolite)
Cytochrome P450 2B64-ene-Valproic acid (active metabolite)
UDP-glucuronosyltransferase 1-9Valpronic acid beta-glucuronide

Omics and IC50 Data ? Compound Assessment
Gene expression profiles known. ?
Series GSE2303
Title: Rat liver response to Clofibrate, DEHP or VPA
Organism(s): Rattus norvegicus
Summary: The project had 2 goals:
1) To evaluate the transcriptional response of 3 prototypical toxicants (Clofibrate, VPA, and DEHP) on rat lever.
2) To evaluate the impact pooling samples has on data analysis.

References:

-Jolly RA, Goldstein KM, Wei T, Gao H et al. Pooling samples within microarray studies: a comparative analysis of rat liver transcription response to prototypical toxicants. Physiol Genomics 2005 Aug 11;22(3):346-55
Series GSE2187
Title: Classification of a large micro-array dataset. Algorithm comparison and analysis of drug signatures.
Organism(s): Rattus norvegicus

References:

-Natsoulis G, El Ghaoui L, Lanckriet GR, Tolley AM et al. Classification of a large microarray data set: algorithm comparison and analysis of drug signatures. Genome Res 2005 May;15(5):724-36. pmid:15867433
-Toxicol Appl Pharmacol. 2008 Feb 1;226(3):271-84. Epub 2007 Sep 22 pmid:17963808 .

Subchronic effects of valproic acid on gene expression profiles for lipid metabolism in mouse liver.

Open TG-GATEs Human Liver
Status: Public on Feb 25, 2011
Title: Genomics Assisted Toxicity Evaluation system study - Human Hepatocytes
Organism(s): Homo Sapiens
Type: Expression profiling by array
Summary: TGP (Toxicogenomics project) is engaged by the Pharmaceutical Institute for Fundamental Research, National Institute of Health, and pharmaceutical companies (3) the public-private collaborative project. From FY 2002 through FY 2006 a large and high-quality Toxicogenomics database was built studying gene expression and toxicity information for 150 compounds in populations of rats and human hepatocytes exposed to drug.
References:
-Takeki Uehara, Atsushi Ono, Toshiyuki Maruyama, Ikuo Kato, Hiroshi Yamada, Yasuo Ohno, Tetsuro Urushidani. The Japanese toxicogenomics project: application of toxicogenomics. Molecular nutrition & food research. 2010 Feb;54(2): 218-27 pmid:20041446
Proteomics profiles known. ?
Metabonomics profiles known. ?

References:

-Single valproic acid treatment inhibits glycogen and RNA ribose

turnover while disrupting glucose-derived cholesterol synthesis in liver as revealed by the [U-13C6]-D-glucose tracer in mice

Metabolomics (2009) 5:336–345
-Schnackenberg, L. K., Jones, R. C., Thyparambil, S., et al. (2006). An integrated study of acute effects of valproic acid in the liver using metabonomics, proteomics, and transcriptomics platforms. Omics, 10, 1–14.
Fluxomics profiles known. ?
Epigenomics profiles known. ?
Observed IC50 for in vitro cellular efficacy. ? GABA transaminase IC50 = 0.6 mM

Sodium current EC50 = 2 mM

References:

-Wolfgang Löscher, “Basic Pharmacology of Valproate: A Review After 35 Years of Clinical Use for the Treatment of Epilepsy”, CNS Drugs 2002; 16 (10): 669-694.

NMDA receptor IC50 = 1 mM

References:

-Po-Wu Gean, Chiung-Chun Huang, Chen-Road Hung, and Jing-Jane Tsai, “Valproic Acid Suppresses the Synaptic Response Mediated by the NMDA Receptors in Rat Amygdalar Slices”, Brain Research Bulletin. Vol. 33, pp. 333-336. 1994
HDAC1 IC50=0.4 mM
HDAC2 IC50=0.5 mM
HDAC5 IC50=3 mM
HDAC6 IC50=2 mM

References:

-Christopher J. Phiel, Fang Zhang, Eric Y. Huang, Matthew G. Guenther, Mitchell A. Lazar, and Peter S. Klein, “Histone Deacetylase Is a Direct Target of Valproic Acid, a Potent Anticonvulsant, Mood Stabilizer, and Teratogen”, JBC 276:36734–36741 (2001)
-Göttlicher, M.; Minucci, S.; Zhu, P.; Krämer, O. H.; Schimpf, A.; Giavara, S.; Sleeman, J. P.; Lo Coco, F.; Nervi, C.; Pelicci, P. G.; Heinzel, T., “Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells” EMBO J. 2001, 20, 6969-7698.
Observed IC50 for in vitro cellular toxicity studies. ? HepG2 cells at 24 h
  • Lipid accumulation MEC = 1 mM
  • NADH depletion (MTT tetrazolium dye) IC50 = 18 mM
  • ROS MEC = 1 mM

References:

-M. Teresa Donato, et al., “Cytometric analysis for drug-induced steatosis in HepG2 cells”, Chemico-Biological Interactions 181 (2009) 417–423.

Rat hepatocytes at 24 h

  • GSH depletion IC50 = 13 mM

References:

-Tony K.L. Kiang, Xiao Wei Teng, Jayakumar Surendradoss, Stoyan Karagiozov, Frank S. Abbott, Thomas K.H. Chang, “Glutathione depletion by valproic acid in sandwich-cultured rat hepatocytes: Role of biotransformation and temporal relationship with onset of toxicity”,Toxicology and Applied Pharmacology 252 (2011) 318–324.

Rat hepatocytes at 24 h

  • NADH depletion (WST-1 tetrazolium dye) IC50 = 1 mM
  • ROS MEC = 6 mM
  • LDH release IC50 = 12 mM

References:

-Tony K. L. Kiang, Xiao Wei Teng, Stoyan Karagiozov, Jayakumar Surendradoss, Thomas K. H. Chang, and Frank S. Abbott, “Role of Oxidative Metabolism in the Effect of Valproic Acid on Markers of Cell Viability, Necrosis, and Oxidative Stress in Sandwich-Cultured Rat Hepatocytes”,Toxicological Sciences 118(2), 501–509 (2010).

Physical Properties ? Compound Assessment
Accepted and listed within the ToxCast/Tox21 program. ? Yes - Included in ToxCast Phase I and II Chemicals List.
Substance stability. ? Yes
Soluble in buffer solution at 30 times the in vitro IC50 for toxicity. ?

Valproic acid Water solubility: 2 mg/ml(20 °C) [RIEMENSCHNEIDER,W (1986) from SRC PhysProp Database]

Valproic acid Water solubility: 1.3 mg/ml FDA, DEPACON NDA 20-593/S-011

Valproic acid estimated intrinsic solubility : 2.02 mg/ml Valproic acid estimated solubility in pure water at pH 3.33: 2.09 mg/ml Valproic acid estimated solubility in water at pH 7.4: 727.34 mg/ml (Calculations performed using ACD/PhysChem v 9.14) Solubility as a function of pH and other parameters available on the wiki

Sodium Valproate Water solubility: 50 mg/ml Sigma Aldrich P4543 Product Details

Solubility in DMSO 100 times buffer solubility. ? 5 mg/ml Cayman Chemical 13033 Product Information
Vessel binding properties. ? Partial sorption (about 10%) of valproic acid into polypropylene material when testing commercial valproate sodium syrup in plastic containers for 20 days at 25°C

References:

-Sartnurak S and Christensen JM. Stability of valproate sodium syrup in various unit dose containers. Am J Hosp Pharm 1982; 39: 627-629
Vapor pressure. (Non-volatile) ? Valproic acid: Estimated vapor pressure 0.0847 mmHg (Calculation performed using EPI Suite v4.10)

Sodium Valproate: Estimated vapor pressure 8.62E-9 mmHg (25°C)

References

-NEELY,WB & BLAU,GE (1985) from SRC PhysProp Database

Calculated/Predicted Properties

Water Solubility Results
pH Sol,mg/ml 0 9- Graph
2 2.02 99.8 0.2 Valproic acid solubility.png
5.5 11.77 17.2 82.8
6.5 98.73 2 98
7.4 727.34 0.3 99.7
10 1000 - 100
Summary Solubility Data
Intrinsic Solubility,mg/ml 2.0218
Intrinsic Solubility,log(S,mol/l) -1.8533
Solubility in Pure Water at pH = 3.33,mg/ml 2.0884
Calculations performed using ACD/PhysChem v 9.14
LogD Results
pH LogD Graph
2 2.72 Valproic acid logd.png
5.5 1.95
6.5 1.03
7.4 0.16
10 -1.02
Calculations performed using ACD/PhysChem v 9.14
Single-valued Properties
Property Value Units Error
LogP 2.72 0.19
MW 144.21 -
PSA 37.3 -
FRB 5 -
HDonors 1 -
HAcceptors 2 -
Rule Of 5 0 -
Molar Refractivity 40.64 cm3 0.3
Molar Volume 155.59 cm3 3
Parachor 369.61 cm3 4
Index of Refraction 1.44 0.02
Surface Tension 31.84 dyne/cm 3
Density 0.93 g/cm3 0.06
Polarizability 16.11 10E-24 cm3 0.5
Calculations performed using ACD/PhysChem v 9.14
Property Name Value Units Source
pKa 4.72 SPARC v4.5
Estimated VP 0.0847 mm Hg EPI Suite v4.10
Estimated VP 11.29 Pa EPI Suite v4.10
Estimated Water Solubility 894.6 mg/L EPI Suite v4.10
WATERNT Frag Water Solubility Estimate 1861.5 mg/L EPI Suite v4.10
pKa Results
Acidic/Basic Acidic/Basic Aparrent pKa Value Error
9 MA 4.82 0.2
A = Acidic
B = Basic
MA = Most Acidic
MB = Most Basic
Calculations performed using ACD/PhysChem v 9.14

Authors of this ToxBank wiki page

Roman Affentranger, David Bower, Egon Willighagen, Matthew Clark
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