Skip to main content
SpringerLink
Log in

Valproate

  • Chapter
Antiepileptic Drugs

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 138))

Abstract

Valproate is a major and well established antiepileptic agent which is in contemporary widespread use in the treatment of the disorder, especially the generalized variety, for which it has become the drug of first choice. It also appears to be finding new uses in the management of a more extensive range of neurological and psychiatric disorders.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Abbott FS, Kassam J, Acheampong A et al. (1986a) Capillary gas chromatography-mass spectrometry of valproic acid metabolites in serum and urine using tert-butyldimethylsilyl derivatives. J Chromatogr 375:285–298

    Article  PubMed  CAS  Google Scholar 

  • Abbott F, Panesar S, Orr J, Burton R, Farrell K (1986b) Effect of carbamazepine on valproic acid metabolism. Epilepsia 27:591

    Google Scholar 

  • Abbott FS, Kassam J, Orr JM, Farrell K (1986c) The effect of aspirin on valproic acid metabolism. Clin Pharmacol Ther 40:94–100

    Article  PubMed  CAS  Google Scholar 

  • Adkison KD, Shen DD (1996) Uptake of valproic acid into rat brain is mediated by a medium-chain fatty acid transporter. J Pharmacol Exp Ther 276:1189–1200

    PubMed  CAS  Google Scholar 

  • Adkison KDK, Ojemann GA, Rapport R, Dills RL, Shen DD (1995) Distribution of unsaturated metabolites of valproate in human and rat brain—pharmacologic relevance? Epilepsia 36:772–782

    Article  PubMed  CAS  Google Scholar 

  • Anderson GD, Acheampong AA, Wilensky AJ, Levy RH (1992) Effect of valproate dose on formation of hepatotoxic metabolites. Epilepsia 33:736–742

    Article  PubMed  CAS  Google Scholar 

  • Anderson GD, Gidal BE, Hendryx RJ, Awan AB, Temkin NR, Wilensky AJ, Winn HR (1994) Decreased plasma protein binding of valproate in patients with acute head trauma. Br J Clin Pharmacol 37:559–562

    PubMed  CAS  Google Scholar 

  • Anderson GD, Yau MK, Gidal BE et al. (1996) Bidirectional interaction of valproate and lamotrigine in healthy subjects. Clin Pharmacol Ther 60:145–156

    Article  PubMed  CAS  Google Scholar 

  • Anderson GD, Awan AB, Adams CA, Temkin NR, Winn HR (1998) Increases in metabolism of valproate and excretion of 6beta-hydroxycortisol in patients with traumatic brain injury. Br J Clin Pharmacol 45:101–105

    Article  PubMed  CAS  Google Scholar 

  • Baillie TA, Sheffels PR (1995) Valproic acid: chemistry and biotransformation. In: Levy RH, Mattson RH, Meldrum BS (eds) Antiepileptic drugs, 4th edn, Raven Press, New York

    Google Scholar 

  • Bernus I, Dickinson RG, Hooper WD, Eadie MJ (1994) Inhibition of phenobarbitone N-glucosidation by valproate. Br J Clin Pharmacol 38:411–416

    PubMed  CAS  Google Scholar 

  • Bowdle TA, Patel IH, Levy RH, Wilensky AJ (1980) Valproic acid dosage and plasma protein binding and clearance. Clin Pharmacol Ther 28:486–492

    Article  PubMed  CAS  Google Scholar 

  • Carrigan PJ, Brinker DR, Cavanaugh JH, Lamm JE, Cloyd JC (1990) Absorption characteristics of a new valproate formulation of divalproex sodium-coated particles in capsules (DepakoteTM Sprinkle). J Clin Pharmacol 30:743–747

    PubMed  CAS  Google Scholar 

  • Cavanaugh JH, Granneman R, Lamm J, Linnen P, Chun AHC (1997) Effect of food on the bioavailability of a controlled-release formulation of depakote under multiple-dose conditions. Epilepsia 38:S54

    Article  Google Scholar 

  • Cloyd JC, Kriel RL (1981) Bioavailability of rectally administered valproic acid syrup. Neurology 31:1348–1352

    PubMed  CAS  Google Scholar 

  • Cramer JA, Mattson RH, Bennett DM, Swick CT (1986) Variable free and total valproic acid concentrations in sole- and multidrug therapy. Ther Drug Monit 8:411–415

    Article  PubMed  CAS  Google Scholar 

  • Dencker L, Nau H, D’Argy R (1990) Marked accumulation of valproic acid in embryonic neuroepithelium of the mouse during early organogenesis. Teratology 41:699–706

    Article  PubMed  CAS  Google Scholar 

  • Fanello RG, Varasi M, Smith MC (1995) Valproic acid: mechanisms of action. In: Levy RH, Mattson RH, Meldrum BS (eds) Antiepileptic drugs, 4th edn. Raven Press, New York

    Google Scholar 

  • Fischer JH, Barr AN, Paloucek FP, Dorociak JV, Spunt AL (1988) Effect of food on the serum concentration profile of enteric-coated valproic acid. Neurology 38:1319–1322

    PubMed  CAS  Google Scholar 

  • Franceschetti S, Hamon B, Heineman U (1986) The action of valproate on spontaneous epileptiform activity in the absence of synaptic transmission on evoked changes in [Ca++] and [K+] in the hippocampal slice. Brain Res 386:1–11

    Article  PubMed  CAS  Google Scholar 

  • Frey H-H, Löscher W (1978) Distribution of valproate across the interface between blood and cerebrospinal fluid. Neuropharmacology 17:637–642

    Article  PubMed  CAS  Google Scholar 

  • Gale K (1988) Progression and generalization of seizure discharge: anatomical and neurochemical substrates. Epilepsia 29:S15–S34

    Article  PubMed  Google Scholar 

  • Gean P-W, Hung C-C, Hung C-R, Tsai J-J (1994) Valproic acid suppresses the synaptic response mediated by the NMDA receptors in rat amygdalar slices. Brain Res Bull 33:333–336

    Article  PubMed  CAS  Google Scholar 

  • Gomez Bellver MJ, Garcia Sanchez MJ, Alonso Gonzalez AC, Santo Buelga D, Dominquez-Gil A (1993) Plasma protein binding kinetics of valproic acid over a broad dosage range: therapeutic implications. J Clin Pharmacol Ther 18:191–197

    Article  Google Scholar 

  • Granneman GR, Marriott TB, Wang SI, Sennello LT, Hagen NS, Sonders RC (1984) Aspects of the dose-dependent metabolism of valproic acid. In: Levy RH, Pitlick WH, Eichelbaum M, Meijer J (eds) Metabolism of antiepileptic drugs. Raven Press, New York, pp 97–104

    Google Scholar 

  • Green MD, Bishop WP, Tephley TR (1995) Expressed human UGT-1.4 protein catalyzes the formation of quaternary ammonium-linked glucuronides. Drug Metab Dispos 23:299–302

    PubMed  CAS  Google Scholar 

  • Hooper WD, Franklin ME, Glue P, Banfield CR, Radwanski E, McLaughlin DB, McIntyre ME, Dickinson RG, Eadie MJ (1996) Effect of falbamate on valproic acid disposition in healthy volunteers: Inhibition of β-oxidation. Epilepsia 37:91–97

    Article  PubMed  CAS  Google Scholar 

  • Hurst S, Labroo R, Carlson S, Mather G, Levy R (1997) In vitro inhibition profile of valproic acid for cytochrome P450. International Society for the Study of Xeno-biotics. Hilton Head, South Carolina (abstract):64

    Google Scholar 

  • Kerr BM, Rettie AW, Eddy AC, Loiseau P, Guyot M, Wilensky AJ, Levy RH (1989) Inhibition of human liver microsomal epoxide hydrolase by valproate and val-promide: in vitro/in vivo correlation. Clin Pharmacol Ther 46:82–93

    Article  PubMed  CAS  Google Scholar 

  • Klotz U, Rapp T, Müller WA (1978) Disposition of valproic acid in patients with liver disease. Eur J Clin Pharmacol 13:55–60

    Article  PubMed  CAS  Google Scholar 

  • Ko GY-PL, Brown-Croyts LM, Teyler TJ (1997) The effects of anticonvulsant drugs on NMDA-EPSP, AMPA-DPSP, and GABA-IPSP in the rat hippocampus. Brain Res Bull 42:297–302

    Article  PubMed  CAS  Google Scholar 

  • Kondo T, Otani K, Hirano T, Kaneko S, Fukushima Y (1990) The effects of phenytoin and carbamazepine on serum concentration of mono-unsaturated metabolites of valproic acid. Br J Clin Pharmacol 29:116–119

    PubMed  CAS  Google Scholar 

  • Kondo T, Kaneko S, Otani K et al. (1992) Associations between risk factors for valproate hepatotoxicity and altered valproate metabolism. Epilepsia 33:172–177

    Article  PubMed  CAS  Google Scholar 

  • Lertora J, Rege A, Greenspan D, Akula S (1994) Pharmacokinetic interaction between zidovudine and valproic acid in patients infected with immunodeficiency virus. Clin Pharmacol Ther 56:272–278

    Article  PubMed  CAS  Google Scholar 

  • Leveil V, Naquet R (1977) A study of the action of valproic acid on the kindling effect. Epilepsia 18:229–234

    Article  Google Scholar 

  • Levy RH (1980) CSF and plasma pharmacokinetics: relationship to mechanisms of action as exemplified by valproic acid in monkey. In: Lockard J, Ward A (eds) Epilepsy: a window to brain mechanisms. Raven Press, New York 11:191–200

    Google Scholar 

  • Levy RH, Shen DD (1995) Valproic acid: absorption, distribution, and excretion. In: Levy RH, Mattson RH, Meldrum BS (eds) Antiepileptic drugs, 4th edn. Raven Press, New York

    Google Scholar 

  • Levy RH, Cenraud B, Loiseau P et al. (1980) Meal-dependent absorption of enteric-coated sodium valproate. Epilepsia 21:273–280

    Article  PubMed  CAS  Google Scholar 

  • Levy RH, Moreland TA, Morselli PL, Guyot M, Brachet-Liermain A, Loiseau P (1984) Carbamazepine/valproic acid interaction in man and rhesus monkey. Epilepsia 25:338–345

    Article  PubMed  CAS  Google Scholar 

  • Levy RH, Rettenmeier AW, Anderson GD et al. (1990) Effects of polytherapy with phenytoin, carbamazepine, and stiripentol on formation of 4-ene-valproate, a hepatotoxic metabolite of valproic acid. Clin Pharmacol Ther 48:225–235

    Article  PubMed  CAS  Google Scholar 

  • Loiseau P, Brachet-Liesmain A, Guyot M, Morselli P (1982) Diurnal variations in steady state plasma concentrations of valproic acid in epileptic patients. Clin Pharm 7:544–552

    Article  CAS  Google Scholar 

  • Löscher W (1993) Effects of the antieplieptic drug valproate on metabolism and function of inhibitory and excitatory amino acids in the brain. Neurochem Res 18:485–502

    Article  PubMed  Google Scholar 

  • Löscher W, Nau H (1984) Comparative transfer of valproic acid and of an active metabolite into brain and liver: possible pharmacological and toxicological consequences. Arch Int Pharmacodyn Ther 270:192–202

    PubMed  Google Scholar 

  • Löscher W, Vetter M (1984) Drug-induced changes in GABA content of nerve endings in 11 rat brain regions: correlation to pharmacological effects. Neurosci Lett 47:325–331

    Article  PubMed  Google Scholar 

  • Löscher W, Fisher JE, Nau H, Hönack D (1988) Marked increase in anticonvulsant activity but decrease in wet-dog shake behaviour during short-term treatment of amygdala-kindled rats with valproic acid. Eur J Pharmacol 150:221–232

    Article  PubMed  Google Scholar 

  • Löscher W, Hönack D, Nolting B, Fassbender CP (1991) Trans-2-en-valproate: reevaluation of its anticonvulsant efficacy in standardized seizure models in mice, rats and dogs. Epilepsy Res 9:195–210

    Article  PubMed  Google Scholar 

  • McLean MJ, MacDonald RL (1986) Sodium valproate, but not ethosuximide, produces use and voltage-dependent limitation of high frequency repetitive firing of action potentials of mouse central neurons in cell culture. J Pharmacol Exp Ther 237:1001–1011

    PubMed  CAS  Google Scholar 

  • Naora K, Shen DD (1995) Mechanism of valproic acid uptake by isolated rat brain microvessels. Epilepsy Res 22:97–106

    Article  PubMed  CAS  Google Scholar 

  • Nau H, Krauer B (1986) Serum protein binding of valproic acid in fetus-mother pairs throughout pregnancy: correlation with oxytocin administration and albumin and free fatty acid concentrations. J Clin Pharmacol 26:215–221

    PubMed  CAS  Google Scholar 

  • Nowack WJ, Johnson RN, Englander RN, Hanna GR (1979) Effects of valproate and ethosuximide on thalamocortical excitability. Neurology 29:96–99

    PubMed  CAS  Google Scholar 

  • Philbert A, Dam M (1982) The epileptic mother and her child. Epilepsia 23:85–99

    Article  PubMed  CAS  Google Scholar 

  • Pisani F, Caputo M, Fazio A et al (1990) Interaction of carbamazepine-10,11-epoxide, an active metabolite of carbamazepine, with valproate: a pharmacokinetic study. Epilepsia 31:339–342

    Article  PubMed  CAS  Google Scholar 

  • Piasse J-C, Revol M, Chabert G, Ducerf F (1979) Neonatal pharmacokinetics of valproic acid. In: Schaaf D, van der Kleijn E (eds) Progress in clinical pharmacy. Else-vier/North-Holland Biomedical Press, Amsterdam, pp 247–252

    Google Scholar 

  • Pollack GM, Shen DD (1985) A timed intravenous pentylenetetrazol infusion seizure model for quantitating the anticonvulsant effect of valproic acid in the rat. J Pharmacol Methods 13:135–146

    Article  PubMed  CAS  Google Scholar 

  • Rettenmeier AW, Prickett KS, Gordon WP, Bjorge SM, Chang SL, Levy RH, Baillie TA (1985) Studies on the biotransformation in the perfused rat liver of 2-n-propyl-4-pentenoic acid, a metabolite of the antiepileptic drug valproic acid. Evidence for the formation of chemically reactive intermediates. Drug Metab Dispos 13:81–96

    PubMed  CAS  Google Scholar 

  • Robbins DK, Wedlund PJ, Kuhn R, Baumann RJ, Levy RH, Chang S-L (1990) Inhibition of epoxide hydrolase by valproic acid in epileptic patients receiving carbamazepine. Br J Clin Pharmacol 29:759–762

    PubMed  CAS  Google Scholar 

  • Roberts D, Easter D, O’Bryan-Tear G (1996) EpilimR chrono: a multidose, crossover comparison of two formulations of valproate in healthy volunteers. Biopharm Drug Dispos 17:175–182

    Article  PubMed  CAS  Google Scholar 

  • Rohlfs A, Rundfeldt C, Koch R, Löscher W (1996) A comparison of the effects of valproate and its major active metabolite E-2-en-valproate on single unit activity of sustantia nigra pars reticulata neurons in rats. J Pharmacol Exp Ther 277:1305–1314

    PubMed  CAS  Google Scholar 

  • Samara E, Granneman R, Achari R, Locke C, Cavanaugh J, Boellner S (1997a) Bioavailability of a controlled-release formulation of depakote. Epilepsia 38:S102

    Google Scholar 

  • Samara EE, Granneman RG, Witt GF, Cavanaugh JH (1997b) Effect of valproate on the pharmacokinetics and pharmacodynamics of lorazepam. J Clin Pharmacol 37:442–450

    PubMed  CAS  Google Scholar 

  • Scism JL, Powers KM, Artru AA, Shen DD (1996) The effect of probenecid on extracellular and intracellular compartmentation of valproic acid in the rabbit brain as determined by microdialysis. Pharm Res 13:S456

    Google Scholar 

  • Semmes RLO, Shen DD (1991) Comparative pharmacodynamics and brain distribution of E-Δ2-valproate and valproate in rats. Epilepsia 32:232–241

    Article  PubMed  CAS  Google Scholar 

  • Shen DD, Pollack GM, Cohen ME, Duffner P, Lacey D, Ryan-Dudek P (1984) Effect of age on the serum metabolite pattern of valproic acid. Epilespsia 25:674

    Google Scholar 

  • Shen DD, Ojemann GA, Rapport RL, Dills RL, Friel PN, Levy RH (1992) Low and variable presence of valproic acid in human brain. Neurology 42:582–585

    PubMed  CAS  Google Scholar 

  • Snead OC III, Miles MV (1985) Treatment of status epilepticus in children with rectal sodium valproate. J Pediatr 106:323–325

    Article  PubMed  Google Scholar 

  • Sugimoto T, Muro H, Woo M, Nishida N, Murakami K (1996) Metabolite profiles in patients on high-dose valproate monotherapy. Epilepsy Res 25:107–112

    Article  PubMed  CAS  Google Scholar 

  • Swinyard EA (1964) The pharmacology of dipropylacetic acid sodium with special emphasis on its effects on the central nervous system. Thesis, University of Utah, College of Pharmacy, Salt Lake City, pp 1–25

    Google Scholar 

  • Ticku MK, Davis WC (1981) Effect of valproic acid on H-diazepam and H-dihydropi-crotoxin in binding sites at the benzodiazepine-GABA receptor-ionophore complex. Brain Res 223:218–222

    Article  PubMed  CAS  Google Scholar 

  • Vajda FJE, Mihaly GW, Miles JL, Donnan GA, Bladin PF (1978) Rectal administration of sodium valproate in status epilepticus. Neurology 28:897–899

    PubMed  CAS  Google Scholar 

  • Wagner ML, Graves NM, Leppik IE, Remmel RP, Shumaker RC, Ward DL, Perhach JL (1994) The effect of felbamate on valproic acid disposition. Clin Pharmacol Ther 56:494–502

    Article  PubMed  CAS  Google Scholar 

  • Wikinski SI, Acosta GB, Rubio MC (1996) Valproic acid differs in its in vitro effect on glutamic acid decarboxylase activity in neonatal and adult rat brain. Gen Pharmacol 27:635–638

    PubMed  CAS  Google Scholar 

  • Willmore JL, Shu V, Wallin B, and the M88–194 Study Group (1996) Efficacy and safety of add-on divalproex sodium in the treatment of complex partial seizures. Neurology 46:49–53

    PubMed  CAS  Google Scholar 

  • Yoshiyama Y, Nakano S, Ogawa N (1989) Chronopharmacokinetics study of valproic acid in man: comparison of oral and rectal administration. J Clin Pharmacol 29:1048–1052

    PubMed  CAS  Google Scholar 

  • Yuen AWC, Land G, Weatherley BC, Peck AW (1992) Sodium valproate acutely inhibits lamotrigene metabolism. Br J Clin Pharmacol 33:511–513

    PubMed  CAS  Google Scholar 

  • Zeise ML, Kasparow S, Zieglgänsberger W (1991) Valproate suppresses N-methyl-D-aspartate-evoked, transient depolarizations in the rat neocortex in vitro. Brain Res 544:345–348

    Article  PubMed  CAS  Google Scholar 

  • Zhang Y-F, Gibbs JW, Coulter DA (1996) Anticonvulsant drug effects on spontaneous thalamocortical rhythms in vitro: valproic acid, clonazepam, and α-methyl-α-phenylsuccinimide. Epilepsy Res 23:37–53

    Article  PubMed  CAS  Google Scholar 

Download references

Authors
  1. D. D. Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R. H. Levy
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Departments of Medicine, Royal Brisbane Hospital, University of Queensland, Clinical Sciences Building, Herston, Qld., 4029, Australia

    Mervyn J. Eadie AO, MD, PhD

  2. Australian Centre for Clinical Neuropharmacology, St. Vincent’s Hospital, Fitzroy, Victoria, 3065, Australia

    Frank J. E. Vajda M.D.

Rights and permissions

Reprints and permissions

Copyright information

© 1999 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Shen, D.D., Levy, R.H. (1999). Valproate. In: Eadie, M.J., Vajda, F.J.E. (eds) Antiepileptic Drugs. Handbook of Experimental Pharmacology, vol 138. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-60072-2_13

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-60072-2_13

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-64244-9

  • Online ISBN: 978-3-642-60072-2

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation