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Increased Sensitivity to the Anticonvulsant Effect of Valproate in Aging BN/BiRij Rats

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Abstract

The aim of the present investigations was to study the influence of increasing age on the pharmacodynamics of valproate in BN/BiRij rats, applying a threshold for electrically induced localized seizure activity as a measure of the anticonvulsant effect. Seven groups of healthy male BN/BiRij rats were used, aged 3, 6, 12, 19, 25, 31, and 37 months. Individual plasma concentration versus anticonvulsant effect relationships were determined during a continuous intravenous infusion of sodium valproate at a rate of 5.5 mg/min/kg. The infusion was terminated when the anticonvulsant effect intensity had reached the maximum attainable level or at a total infusion time of three hours. A nonlinear relationship between valproate concentration and anticonvulsant effect intensity was observed with no maximal effect in the concentration range up to 1200 mg · L−1. With increasing age a parallel shift in the concentration versus anticonvulsant effect relationships toward lower concentrations occurred. Thus increasing age appears to be associated with an increased sensitivity to the anticonvulsant effect of valproate.

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REFERENCES

  1. E. Perucca, R. Grimaldi, G. Gatti, S. Pirracchio, F. Crema, and G. M. Frigo. Pharmacokinetics of valproic acid in the elderly. Br. J. Clin. Pharmacol. 17:665–669 (1984).

    Google Scholar 

  2. Editorial: Sodium valproate and the liver. Lancet 2:1119–1120 (1980).

  3. E. S. Zafrani and P. Berthelot. Sodium valproate in the induction of unusual hepatotoxicity. Hepatology 2:648–649 (1982).

    Google Scholar 

  4. C. A. Williams, S. Tiefenbach, and J. W. McReynolds. Valproic acid-induced hyperammonemia in mentally retarded adults. Neurology 34:550–553 (1984).

    Google Scholar 

  5. S. M. Bryson, N. Verma, P. J. W. Scott, and P. C. Rubin. Pharmacokinetics of valproic acid in young and elderly subjects. Br. J. Clin. Pharmacol. 16:104–105 (1983).

    Google Scholar 

  6. L. A. Bauer, R. Davis, A. Wilensky, V. Raisys, and R. H. Levy. Valproic acid clearance: Unbound fraction and diurnal variation in young and elderly adults. Clin. Pharmacol. Ther. 37:697–700 (1985).

    Google Scholar 

  7. K. Hall, N. Otten, B. Johnston, J. Irvine-Meek, M. Leroux, and S. Seshia. A multivariable analysis of factors governing the steady-state pharmacokinetics of valproic acid in 52 young epileptics. J. Clin. Pharmacol. 25:261–268 (1985).

    Google Scholar 

  8. H. Y. Yu, Y. Sugiyama, and M. Hanano. Changes in pharmacokinetics of valproic acid in guinea pigs from birth to maturity. Epilepsia 26:243–251 (1985).

    Google Scholar 

  9. J. W. Van der Laan, T. De Boer, and J. Bruinvels. Di-n-propylacetate and GABA degradation. Preferential inhibition of succinic semialdehyde dehydrogenase and indirect inhibition of GABA-transaminase. J. Neurochem. 32:1769–1780 (1979).

    Google Scholar 

  10. R. Monteleone, M. Iovino, F. Orio, and L. Steardo. Impaired growth hormone response to sodium valproate in normal aging. Psychopharmacology 91:10–13 (1987).

    Google Scholar 

  11. R. A. Voskuyl, J. Dingemanse, and M. Danhof. Determination of the threshold for convulsions by direct cortical stimulation. Epilepsy Res. 3:120–129 (1989).

    Google Scholar 

  12. A. M. Stijnen, M. Danhof, and C. F. A. van Bezooijen. Increased sensitivity to the anesthetic effect of phenobarbital in rats. J. Pharmacol. Exp. Ther. 261:81–87 (1992).

    Google Scholar 

  13. J. Dingemanse, R. A. Voskuyl, M. W. E. Langemeijer, I. Postel-Westra, D. D. Breimer, H. Meinardi, and M. Danhof. Pharmacokinetic-pharmacodynamic modelling of the anticonvulsant effect of oxazepam in individual rats. Br. J. Pharmacol. 99:53–58 (1990).

    Google Scholar 

  14. R. A. Voskuyl, A. Hoogerkamp, and M. Danhof. Properties of the convulsive threshold determined by direct cortical stimulation in rats. Epilepsy Rats. 12:111–120 (1992).

    Google Scholar 

  15. W. Löscher and H. Siemes. Valproic acid increases gamma-aminobutyric acid in CSF of epileptic children. Lancet 2:225 (1984).

    Google Scholar 

  16. S. Liljequist and J. A. Engel. Reversal of the anti-conflict action of valproate by various GABA and benzodiazepine antagonists. Life Sci. 34:2525–2533 (1984).

    Google Scholar 

  17. G. Racagni, J. A. Apud, D. Cocchi, V. Locatelli, and E. E. Müller. GABAergic control of anterior pituitary hormone secretion. Life Sci. 31:823–838 (1982).

    Google Scholar 

  18. W. Löscher, C. P. Fassbender, and B. Nolting. The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. Epilepsy Res. 8:79–94 (1991).

    Google Scholar 

  19. W. Kamphuis and F. H. L. Da Silva. The kindling model of epilepsy: the role of GABA-ergic inhibition. Neurosci. Res. Commun. 6:1–10 (1990).

    Google Scholar 

  20. A. Chapman, P. E. Keane, B. S. Meldrum, J. Simiand, and J. C. Vernieres. Mechanism of anticonvulsant action of valproate. Prog. Neurobiol. 19:315–359 (1982).

    Google Scholar 

  21. M. J. Eadie. Formation of active metabolites of anticonvulsant drugs. A review of their pharmacokinetic and therapeutic significance. Clin. Pharmacokin. 21:27–41 (1991).

    Google Scholar 

  22. J. Li, D. L. Norwood, L.-F. Mao, and H. Schulz. Mitochondrial metabolism of valproic acid. Biochemistry 30:388–394 (1991).

    Google Scholar 

  23. K. Kitani, Y. Masuda, Y. Sato, S. Kanai, M. Ohta, and M. Nokubo. Increased anticonvulsant effect of phenytoin in aging BDF1 mice. J. Pharmacol. Exp. Ther. 229:231–236 (1984).

    Google Scholar 

  24. K. Kitani, Y. Sato, S. Kanai, M. Nokubo, M. Ohta, and Y. Masuda. Increased anticonvulsant effect of phenobarbital with age in mice—a possible pharmacological index for brain aging. Life Sci. 37:1451–1460 (1985).

    Google Scholar 

  25. K. Kitani, Y. Sato, S. Kanai, M. Nokubo, M. Ohta, and Y. Masuda. Increased anticonvulsant effect of AD-810 (zonisamide) in aging BDF1 mice. Life Sci. 41:1339–1344 (1987).

    Google Scholar 

  26. K. Kitani, Y. Sato, S. Kanai, M. Ohta, M. Nokubo, and Y. Masuda. The neurotoxicity of phenobarbital and its effect in preventing pentylenetetrazol-induced maximal seizure in aging mice. Arch. Geront. Geriat. 7:261–271 (1988).

    Google Scholar 

  27. K. Kitani, U. Klotz, S. Kanai, Y. Sato, M. Ohta, and M. Nokubo. Age-related differences in the coordination disturbance and anticonvulsant effect of oxazepam in mice. Arch. Geront. Geriat. 9:31–43 (1989).

    Google Scholar 

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Authors and Affiliations

  1. Center for Bio-Pharmaceutical Sciences, Division of Pharmacology, University of Leiden, Leiden, The Netherlands

    Annemiek M. Stijnen, Suzanne Hovinga, Mariska W. E. Langemeijer, Arendien Hoogerkamp & Meindert Danhof

  2. TNO Institute of Ageing and Vascular Research, Leiden, The Netherlands

    Annemiek M. Stijnen & Cornells F. A. van Bezooijen

Authors
  1. Annemiek M. Stijnen
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  2. Suzanne Hovinga
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  3. Mariska W. E. Langemeijer
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  4. Arendien Hoogerkamp
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  5. Cornells F. A. van Bezooijen
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  6. Meindert Danhof
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Additional information

Suzanne Hovinga: Deceased January 30, 1991.

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Stijnen, A.M., Hovinga, S., Langemeijer, M.W.E. et al. Increased Sensitivity to the Anticonvulsant Effect of Valproate in Aging BN/BiRij Rats. Pharm Res 10, 1046–1051 (1993). https://doi.org/10.1023/A:1018975025417

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