Pharmaceutisch Weekblad

, Volume 14, Issue 3, pp 139–143 | Cite as

Pharmacological, toxicological and neurochemical effects of Δ2(E)-valproate in animals

  • Wolfgang Löscher
Recent Developments on Valproate and its Metabolites


TheE isomer of 2-ene-valproic acid (Δ2(E)-VPA) is the major active metabolite of the antiepileptic drug valproate (VPA) in various species, including humans. Experimental studies on Δ2(E)-VPA and VPA indicate that Δ2(E)-VPA may be a useful antiepileptic drug itself. Δ2(E)-VPA has the same wide spectrum of anticonvulsant activity as VPA with a somewhat higher anticonvulsant potency in rodent and dog models of different seizure types. As VPA, Δ2(E)-VPA increases presynaptic γ-aminobutyric acid (GABA) levels in the brain, presumably by an effect on GABA synthesis and/or GABA degradation. Δ2(E)-VPA is a much more potent inhibitor of the human brain GABA-degrading enzyme than VPA. In high doses. Δ2(E)-VPA is more sedative in rodents than is VPA; LD50 values are about the same. In mouse and rat models for teratogenicity, Δ2(E)-VPA does not induce teratogenic effects, whereas VPA is teratogenic in these models. Pilot rat studies on liver toxicity of VPA and VPA metabolites suggest that Δ2(E)-VPA is not hepatotoxic. In view of the rare but serious hepatotoxicity and teratogenicity of VPA in humans, Δ2(E)-VPA obviously merits interest as a valuable alternative drug in antiepileptic therapy.


Animals, laboratory Drug evaluation Neuropharmacology 2-n-Propyl-2-pentenoic acid Scizures Side effects Teratogens Toxicology Valproic acid 


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  1. 1.
    Löscher W. Valproic acid. In: Frey H-H, Janz D, eds. Antiepileptic drugs. (Handbook of experimental pharmacology; vol. 74.) Heidelberg: Springer-Verlag, 1985: 507–36.Google Scholar
  2. 2.
    Taillandier G, Benot-Guyot J-L, Boucherie A, Broll M, Eymard P. Recherches dans la série dipropylacétique XII. Acides et alcools aliphatiques ramifiés anticonvulsivants. Eur J. Med Chem Chim Ther 1975;10:453–62.Google Scholar
  3. 3.
    Weissman D, Simler S, Ciesielski L, Mandel P. Variations de la teneur en GABA de certaines zones du cerveau de la souris sous l'effet de l'acide propyl-2- pentène-2-oique. CR Soc Biol (Paris) 1978;172:707–12.Google Scholar
  4. 4.
    Löscher W. Anticonvulsant activity of metabolites of valproic acid. Arch Int Pharmacodyn Ther 1981;249:158–63.PubMedGoogle Scholar
  5. 5.
    Nau H, Löscher W, Schäfer H. Anticonvulsant activity and embryotoxicity of valproic acid. Neurology 1984;34:400–1.Google Scholar
  6. 6.
    Kesterson JW, Grannemann GR, Machinist JM. The hepatotoxicity of valproic acid and its metabolites in rats. I. Toxicologic, biochemical and histopathologic studies. Hepatology 1984;4:1143–52.PubMedGoogle Scholar
  7. 7.
    Löscher W, Nau H. Pharmacological evaluation of various metabolites and analogues of valproic acid. Anticonvulsant and toxic potencies in mice. Neuropharmacology 1985;24:427–35.CrossRefPubMedGoogle Scholar
  8. 8.
    Löscher W, Hönack D, Nolting B, Fassbender CP.Trans-2-en-valproate: reevaluation of its anticonvulsant efficacy in standardized seizure models in mice, rats and dogs. Epilepsy Res 1991;9:135–210.Google Scholar
  9. 9.
    Löscher W, Nau H, Marescaux C, Vergnes M. Comparative evaluation of anticonvulsant and toxic potencies of valproic acid and 2-en-valproic acid in different animal models of epilepsy. Eur J Pharmacol 1984; 99:211–8.CrossRefPubMedGoogle Scholar
  10. 10.
    Löscher W, Jäckel R, Czuczwar SJ. Is amygdala kindling in rats a model for drug-resistant partial epilepsy? Exp Neurol 1986;93:211–26.CrossRefPubMedGoogle Scholar
  11. 10a.
    Hönack D, Ruudfeldt C, Löscher W. Pharmacokinetics, anticonvulsant efficacy, and adverse effects oftrans-2-en-valproate after acute and chronic administration in amygdalakindled rats. Naunyn-Schmiedebergs Arch Pharmacol 1992;345:187–96.CrossRefPubMedGoogle Scholar
  12. 11.
    Löscher W, Nau H. Distribution of valproic acid and its metabolites in various brain areas of dogs and rats after acute and prolonged treatment. J Pharmacol Exp Ther 1983;226:845–54.PubMedGoogle Scholar
  13. 12.
    Nau H, Löscher W. Valproic acid: brain and plasma levels of the drug and its metabolites, anticonvulsant effects and γ-aminobutyric acid (GABA) metabolism in the mouse. J Pharmacol Exp Ther 1982;220:654–9.PubMedGoogle Scholar
  14. 13.
    Löscher W. Alterations in CSF GABA levels and seizure susceptibility developing during repeated administration of pentetrazole in dogs. Effects of γ-acetylenic GABA, valproic acid and phenobarbital. Neurochem Int 1983;5:405–12.CrossRefGoogle Scholar
  15. 14.
    Löscher W, Fisher JE, Nau H, Hönack D. Marked increase in anticonvulsant activity but decrease in wetdog shake behaviour during short-term treatment of amygdala-kindled rats with valproic acid. Eur J Pharmacol 1988;150:221–32.CrossRefPubMedGoogle Scholar
  16. 15.
    Nau H, Löscher W. Valproic acid and metabolites: pharmacological and toxicological studies. Epilepsia 1984;25 Suppl 1:S14–22.Google Scholar
  17. 16.
    Lewandowski C, Klug S, Nau H, Neubert D. Pharmacokinetic aspects of drug effectsin vivo: effects of serum protein binding on concentration and teratogenicity of valproic acid and 2-en-valproic acid in whole embryos in culture. Arch Toxicol 1986;58: 239–42.CrossRefPubMedGoogle Scholar
  18. 17.
    Nau H. Transfer of valproic acid and its main active unsaturated metabolite to the gestational tissue: correlation with neural tube defect formation in the mouse. Teratology 1986;33:21–7.CrossRefPubMedGoogle Scholar
  19. 18.
    Nau H, Löscher W. Pharmacologic evaluation of various metabolites and analogs of valproic acid: teratogenic potencies in mice. Fund Appl Toxicol 1986;6:669–76.CrossRefGoogle Scholar
  20. 19.
    Nau H, Hendrickx AG. Valproic acid teratogenesis. ISI Atlas Sci Pharmacol 1987:52–6.Google Scholar
  21. 20.
    Lewis JH, Zimmermann HJ, Garrett CT, Rosenberg E. Valproate-induced hepatic steatogenesis in rats. Hepatology 1982;2:870–3.PubMedGoogle Scholar
  22. 21.
    Nau H, Merker H-J, Brendel K, Häuser I, Gansau C, Wittfoht W. Disposition, embryotoxicity and hepatotoxicity of valproic acid in the mouse as related to man. In: Levy RH, ed. Metabolism of antiepileptic drugs. New York: Raven Press, 1984:85–96.Google Scholar
  23. 22.
    Schäfer H, Lührs R. Responsibility of the metabolite pattern for potential side effects in the rat being treated with valproic acid, 2-propylpenten-2-oic acid and 2-propylpenten-4-oic acid. In: Levy RH, Pitlick WH, Eichelbaum M, Meijer J, eds. Metabolism of antiepileptic drugs. New York: Raven Press, 1984:73–84.Google Scholar
  24. 23.
    Löscher W, Nau H. Comparative transfer of valproic acid and of an active metabolite into brain and liver: possible pharmacological and toxicological consequences. Arch Int Pharmacodyn Ther 1984;270:192–202.PubMedGoogle Scholar
  25. 24.
    Nau H, Löscher W. Valproic acid and active unsatu- rated metabolite (2-en): transfer to mouse liver following human therapeutic doses. Biopharm Drug Dispos 1985;6:1–8.PubMedGoogle Scholar
  26. 25.
    Löscher W, Böhme G, Schäfer H, Kochen W. Effect of metabolites of valproic acid on the metabolism of GABA in brain nerve endings. Neuropharmacology 1981;20:1187–92.CrossRefPubMedGoogle Scholar
  27. 26.
    Maitre M, Ciesielski L, Cash C, Mandel P. Comparison of the structural characteristics of the 4-aminobutyrate:2-oxoglutarate transaminases from rat and human brain, and of their affinities for certain inhibitors. Biochim Biophys Acta 1978;522:385–99.PubMedGoogle Scholar
  28. 27.
    McLean MJ, Macdonald RL. 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 1986;237:1001–11.PubMedGoogle Scholar
  29. 28.
    Handley SL, Singh L. Neurotransmitters and shaking behaviour — more than a ‘gut-bath’ for the brain? TiPS 1986:324–8.Google Scholar
  30. 29.
    Horton RW, Anlezark GM, Sawaya MCB, Meldrum BS. Monoamine and GABA metabolism and the anticonvulsant action of di-n-propylacetate and ethanolamine-O-sulphate. Eur J Pharmacol 1977;41:387–97.CrossRefPubMedGoogle Scholar
  31. 30.
    Hwang EC, Van Woert MH. Effect of valproic acid on serotonin metabolism. Neuropharmacology 1979;18:391–7.CrossRefPubMedGoogle Scholar

Copyright information

© Royal Dutch Association for Advancement of Pharmacy 1992

Authors and Affiliations

  • Wolfgang Löscher
    • 1
  1. 1.Department of Pharmacology, Toxicology and PharmacySchool of Veterinary MedicineHannoverFRG

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