Summary
The trans isomer of 2-en-valproate (trans-2-en-VPA), an unsaturated metabolite of the clinically established antiepileptic valproate (VPA), was examined in the kindling model of epilepsy. As in the case of VPA, trans-2-en-VPA exerted potent anticonvulsant effects against partial seizures and secondarily generalized clonic seizures in amygdala-kindled rats after i.p. administration of acute doses. The anticonvulsant potency of trans-2-en-VPA appeared to be higher than that of VPA, especially in the case of secondarily generalized seizures. However, as previously reported for effects of valproate in the kindling model, trans-2-en-VPA exerted anticonvulsant effects against kindled seizures only at doses which were associated with motor impairment. Pharmacokinetic experiments with trans-2-en-VPA indicated non-linear kinetics with dose-dependent elimination rate and enterohepatic recirculation. According to the initial rapid decline in plasma concentrations of trans-2-en-VPA, the duration of anticonvulsant action in kindled rats was short-lasting so that an experimental protocol with 3 daily administrations was chosen for chronic experiments with this drug. During chronic treatment of kindled rats with 3 times daily injection of 100 mg/kg trans-2-en-VPA for 2 weeks, there was a marked reduction of anticonvulsant activity during the second week of treatment. This loss of anticonvulsant activity was not due to metabolic tolerance, i.e. reduction of drug levels by increased drug metabolism. Furthermore, additional experiments with altered experimental protocol indicated that the loss of anticonvulsant activity was not due to contingent tolerance, i.e. involvement of learning processes due to too frequent drug testing. However, the size of chronic treatment dose was important for the rate and degree of tolerance development, since an increase of dosage to 150 mg/kg 3 times daily resulted in significant anticonvulsant effects throughout the period of treatment with almost no indication of tolerance. The date indicate that trans-2-en-VPA is as effective as valproate in the kindling model. In view of previously reported experimental evidence that trans-2-en-VPA might have a lower hepatotoxic and teratogenic potential as valproate, the present study substantiates that trans-2-en-VPA might be an interesting alternative to valproate in antiepileptic therapy.
Similar content being viewed by others
References
Dickinson RG, Harland RC, Ilias AM, Rodgers RM, Kaufman SN, Lynn RK, Gerber N (1979) Disposition of valproic acid in the rat: Dose-dependent metabolism, distribution, and enterohepatic recirculation and choleretic effect. J Pharmacol Exp Ther 211: 583–595
Freeman FG, Jarvis MF (1981) The effect of interstimulation interval on the assessment and stability of kindled seizure thresholds. Brain Res Bull 7: 629–633
Hönack D, Löscher W (1989) Amygdala-kindling as a model for chronic efficacy studies on antiepileptic drugs: Experiments with carbamazepine. Neuropharmacology 28: 599–610
Kalant H, Khanna JM (1990) Methods for the study of tolerance. In: Adler MW, Cowan A (eds) Modern methods in pharmacology, vol 6: testing and evaluation of drugs of abuse. Wiley-Liss, New York, pp 43–66
Kesterson JW, Grannemann GR, Machinist JM (1984) The hepatotoxicity of valproic acid and its metabolites in rats. I. Toxicologic, biochemical and histopathologic studies. Hepatology 4: 1143–1152
Litchfield JT, Wilcoxon F (1949) A simplified method of evaluating dose-effect experiments. J Pharmacol Exp Ther 96: 99–113
Löscher W (1981) Concentration of metabolites of valproic acid in plasma of epileptic patients. Epilepsia 22: 169–178
Löscher W (1992) Pharmacologic, toxicologic and neurochemical effects of trans-2-en-valproate in animals. Pharm Weekblad (in press)
Löscher W, Hönack D (1989) Comparison of the anticonvulsant efficacy of primidone and phenobarbital during chronic treatment of amygdal-kindled rats. Eur J Pharmacol 162: 309–322
Löscher W, Hönack D (1990) The effect of interstimulation interval on the assessment of anticonvulsant drug potency in fully kindled rats. Epilepsy Res 7: 182–196
Löscher W, Hönack D (1991) Anticonvulsant and behavioral effects of two novel competitive N-methyl-d-aspartic acid receptor antagonists, CGP 37849 and CGP 39551, in the kindling model of epilepsy. Comparison with MK-801 and carbamazepine. J Pharmacol Exp Ther 256: 432–440
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
Löscher W, Rundfeldt C (1990) Development of tolerance to clobazam in fully kindled rats: effects of intermittent flumazenil administration. Eur J Pharmacol 180: 255–271
Löscher W, Schmidt D (1988) Which animal models should be used in the search for new antiepileptic drugs? A proposal based on experimental and clinical considerations. Epilepsy Res 2: 145–181
Löscher W, Schwark WS (1985) Development of tolerance to the anticonvulsant effect of diazepam in amygdala-kindled rats. Exp Neurol 90: 373–384
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
Löscher W, Fisher JE, Nau H, Hönack D (1989a) Valproic acid in amygdala-kindled rats: Alterations in anticonvulsant efficacy, adverse effects and drug and metabolite levels in various brain regions during chronic treatment. J Pharmacol Exp Ther 250: 1067–1078
Löscher W, Hönack D, Hashem A (1987) Anticonvulsant efficacy of clonazepam and the \-carboline ZK 93 423 during chronic treatment in amygdala-kindled rats. Eur J Pharmacol 143: 403–414
Löscher W, Hönack D, Nolting B, Fassbender CP (1991) Trans-2-envalproate: reevaluation of its anticonvulsant efficacy in standardized seizure models in mice, rats and dogs. Epilepsy Res 9: 195–210
Löscher W, Jäckel R, Czuczwar SJ (1986) Is amygdala kindling in rats a model for drug-resistant partial epilepsy? Exp Neurol 93: 211–226
Löscher W, Jäckel R, Müller F (1989b) Anticonvulsant and proconvulsant effects of inhibitors of GABA degradation in the amygdalakindling model. Eur J Pharmacol 163: 1–14
Löscher W, Nau H, Marescaux C, Vergnes M (1984) Comparative evaluation of anticonvulsant and toxic potencies of valproic acid and 2-en-valproic acid in different animal models of epilepsy. Eur J Pharmacol 99: 211–218
Nau H, Löscher W (1984) Valproic acid and metabolites: Pharmacological and toxicological studies. Epilepsia 25 [Suppl 1]: S14-S22
Nau H, Löscher W (1985) Valproic acid and active unsaturated metabolite (2-en): transfer to mouse liver following human therapeutic doses. Biopharm Drug Dispos 6: 1–8
Pinel JPJ, Kim CK, Mana MJ (1990) Contingent tolerance to the anticonvulsant effects of drugs on kindled convulsions. In: Wada I (ed) Kindling 4. Plenum-Press, New York, pp 283–297
Racine RJ (1972) Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroenceph Clin Neurophysiol 32: 281–294
Rogawski MA, Porter RJ (1990) Antiepileptic drugs: Pharmacological mechanisms and clinical efficacy with consideration of promising developmental stage compounds. Pharmacol Rev 42: 223–286
Schmidt D (1985) Adverse effects. In: Frey HH, Jane D (eds) Antiepileptic drugs. Handbook of experimental pharmacology, vol 74. Springer, Berlin Heidelberg New York, pp 791–830
Schmidt D, Morselli PL (1986) Intractable epilepsy: Experimental and clinical aspects. Raven Press, New York
Semmes RLO, Shen DD (1991) Comparative pharmacodynamics and brain distribution of E-Δ2-valproate and valproate in rats. Epilepsia 32: 232–241
Singh K, Orr JM, Abbott FS (1990) Pharmacokinetics and enterohepatic circulation of (E)-2-ene valproic acid in the rat. J Pharmacobio-Dyn 13: 622–627
Wahle H, Frey H-H (1990) Development of tolerance to the anticonvulsant effect of valproate but not to ethosuximide in a rat model of absence epilepsy. Eur J Pharmacol 181: 1–8
Wahnschaffe U, Löscher W (1990) Effect of selective bilateral destruction of the substantia nigra on antiepileptic drug actions in kindled rats. Eur J Pharmacol 186: 157–167
Author information
Authors and Affiliations
Additional information
Send offprint requests to W. Löscher at the above address
Rights and permissions
About this article
Cite this article
Hönack, D., Rundfeldt, C. & Löscher, W. Pharmacokinetics, anticonvulsant efficacy, and adverse effects of trans-2-en-valproate after acute and chronic administration in amygdala-kindled rats. Naunyn-Schmiedeberg's Arch Pharmacol 345, 187–196 (1992). https://doi.org/10.1007/BF00165735
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00165735