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Pharmaceutisch Weekblad

, Volume 14, Issue 3, pp 114–117 | Cite as

Pharmacokinetics of valproate in pregnancy: Mother-foetus-newborn

  • Svein I. Johannessen
Recent Developments on Valproate and its Metabolites

Abstract

An increased risk of seizures during and immediately after labour has been observed in epileptic women, and it is recognized that serum levels of antiepileptic drugs may decrease in pregnancy. Several studies have suggested that total valproate levels fall, but that free fractions increase during pregnancy. Recent findings suggest that the actual metabolism of valproate is not altered by pregnancy and that the changes of the plasma clearance are due primarily to decreased protein binding. The levels of free drug will not change significantly as pregnancy advances. However, dose reduction after delivery may be necessary to avoid toxicity. Valproate and its metabolites undergo placental transfer. In the foetus the plasma level of valproate and the protein binding are higher than in maternal plasma, and the halflife of valproate following placental transfer is considerably longer than in adults. Only small amounts of valproate appear in breast milk and those are not likely to cause any problems. During pregnancy and the first month after delivery preferably both total and free valproate serum levels should be closely monitored to determine the lowest effective dose.

Keywords

Biological availability Fetus Lactation Metabolism Pharmacokinetics Placental transfer Protein binding 

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References

  1. 1.
    Schmidt D, Beck-Mannagetta G, Janz D, Koch S. The effect of pregnancy on the course of epilepsy: a prospective study. In: Janz D, Bossi L, Dam M, Helge H, Richens A, Schmidt D, eds. Epilepsy, pregnancy, and the child. New York: Raven Press, 1982:39–49.Google Scholar
  2. 2.
    Yerby M. Problems and management of the pregnant woman with epilepsy. Epilepsia 1987;28 Suppl 3:S29–37.PubMedGoogle Scholar
  3. 3.
    Philbert A, Dam M. Antiepileptic drug disposition during pregnancy: review of the litterature. In: Janz D, Bossi L, Dam M, Helge H, Richens A, Schmidt D, eds. Epilepsy, pregnancy, and the child. New York: Raven Press, 1982:109–14.Google Scholar
  4. 4.
    Levy RH, Yerby MS. Effects of pregnancy on antiepileptic drug utilization. Epilepsia 1985;26 Suppl 1:S52–7.PubMedGoogle Scholar
  5. 5.
    Robert E. Valproic acid and spina bifida: a preliminary report — France. MMRR 1982;31:565–6.Google Scholar
  6. 6.
    Bourgeois B, Beaumanoir A, Blajev B, De la Cruz N, Despland PA, Egli M, et al. Monotherapy with valproate in primary generalized epilepsies. Epilepsia 1987;28 Suppl 2:S8–11.PubMedGoogle Scholar
  7. 7.
    Nau H, Kuhnz W, Egger H-J, Rating D, Helge H. Anticonvulsants during pregnancy and lactation. Transplacental, maternal and neonatal pharmacokinetics. Clin Pharmacokinet 1982;7:508–43.PubMedGoogle Scholar
  8. 8.
    Krauer B, Krauer F. Drug kinetics in pregnancy. In: Gibaldi M, Prescott L, eds. Handbook of clinical pharmacokinetics. Balgowlah: Adis Press, 1983:1–17.Google Scholar
  9. 9.
    Zaccara G, Messori A, Moroni F. Clinical pharmacokinetics of valproic acid — 1988. Clin Pharmacokinet 1988;15:367–89.PubMedGoogle Scholar
  10. 10.
    Sabers A, Dam M. Pregnancy, delivery, and puerperium. In: Dam M, Gram L, eds. Comprehensive epileptology. New York: Raven Press, 1991:299–307.Google Scholar
  11. 11.
    Leppik IE. Pharmacokinetics of antiepileptic drugs during pregnancy. Semin Neurol 1988;8(3):240–6.PubMedGoogle Scholar
  12. 12.
    Wittfodt W, Nau H, Rating D, Helge H.13C-labeled valproic acid pulse dosing during steady state antiepileptic therapy for pharmacokinetic studies during pregnancy. In: Schmidt HL, Förstel H, Heinzinger K, eds. Stable isotopes. Amsterdam: Elsevier, 1982:265–70.Google Scholar
  13. 13.
    Notarianni LJ. Plasma protein binding of drugs in pregnancy and in neonates. Clin Pharmacokinet 1990; 18(1):20–36.PubMedGoogle Scholar
  14. 14.
    Nau H, Schmidt-Gollwitzer M, Kuhnz W, Koch S, Helge H, Rating D. Antiepileptic disposition, protein binding, and estradiol/progesterone serum concentration ratios during pregnancy. In: Porter R, Mattson R, Ward A, Dam M, eds. Advances in epileptology. New York: Raven Press, 1984:239–49.Google Scholar
  15. 15.
    Riva R, Albani F, Contin M, Baruzzi A, Altomare M, Merlini GP, et al. Mechanism of altered drug binding to serum proteins in pregnant women: studies with valproic acid. Ther Drug Monit 1984;6:25–30.PubMedGoogle Scholar
  16. 16.
    Patel IH, Levy RH. Valproic acid binding to human serum albumin and determination of free fraction in the presence of anticonvulsants and free fatty acids. Epilepsia 1979;20:85–90.PubMedGoogle Scholar
  17. 17.
    Hunter J. Enzyme induction and inhibition in human pregnancy. In: Richens A, Woodford FP, eds. Anticonvulsant drugs and enzyme induction. Amsterdam: Elsevier, 1976:131–3.Google Scholar
  18. 18.
    Nau H, Löscher W. Valproic acid and metabolites. Pharmacological and toxicological studies. Epilepsia 1984;25 Suppl 1:S14–22.PubMedGoogle Scholar
  19. 19.
    Schobben F, Van der Kleijn E, Gabreels PJM. Pharmacokinetics of di-N-propylacetate in epileptic patients. Eur J Clin Pharmacol 1975;8:97–105.CrossRefPubMedGoogle Scholar
  20. 20.
    Sackellares C, Sato S, Dreifuss FE, Penry JK. Reduction of steady-state valproate levels by other antiepileptic drugs. Epilepsia 1981;22:437–41.PubMedGoogle Scholar
  21. 21.
    Oxley J, Hedges A, Makki KA, Monks A, Richens A. Lack of enzyme inducing effects of sodium valproate. Br J Clin Pharmacol 1979;8:189–90.PubMedGoogle Scholar
  22. 22.
    Henriksen O, Johannessen SI. Clinical and pharmacokinetic observations on sodium valproate. A five-year follow-up study of 100 children with epilepsy. Acta Neurol Scand 1982;65:504–23.PubMedGoogle Scholar
  23. 23.
    Philbert A, Dam M. The epileptic mother and her child. Epilepsia 1982;23:85–99.PubMedGoogle Scholar
  24. 24.
    Nau H, Helge H, Luck W. Valproic acid in the perinatal period: decreased maternal serum protein binding results in fetal accumulation and neonatal displacement of the drug and some metabolites. J Pediatr 1984;104:627–34.PubMedGoogle Scholar
  25. 25.
    Koerner M, Yerby M, Friel P, McCormick K. Valproic acid disposition and protein binding in pregnancy. Ther Drug Monit 1989;11:228–30.PubMedGoogle Scholar
  26. 26.
    Bardy AH, Hiilesmaa VK, Teramo K, Neuvonen PJ. Protein binding of antiepileptic drugs during pregnancy, labor, and puerperium. Ther Drug Monit 1990;12:40–6.PubMedGoogle Scholar
  27. 27.
    Atkinson HC, Begg EJ, Darlow BA. Drugs in human milk. Clinical pharmacokinetic considerations. Clin Pharmacokinet 1988;14:217–40.PubMedGoogle Scholar
  28. 28.
    Knott C, Reynolds F. Therapeutic drug monitoring in pregnancy. Rationale and current status. Clin Pharmacokinet 1990;19(6):425–33.PubMedGoogle Scholar
  29. 29.
    Choonara IA, Rane A. Therapeutic drug monitoring of anticonvulsants. State of art. Clin Pharmacokinet 1990;18(4):318–28.PubMedGoogle Scholar
  30. 30.
    Cramer JA, Matsson RH. Valproic acid:in vitro plasma protein binding and interaction with phenytoin. Ther Drug Monit 1979;23:307–13.Google Scholar
  31. 31.
    Levy RH, Bowdle TA, Patel IH, Wilensky AJ. Variability in valproate binding and clearance: implications in therapeutic monitoring. Epilepsia 1981;22:240–1.Google Scholar
  32. 32.
    Levy RH. Monitoring of free valproic acid levels? Ther Drug Monit 1980;2:199–201.PubMedGoogle Scholar
  33. 33.
    Farrell K, Abbott FS, Orr JM, Applegarth A, Jan JE, Wong PK. Free and total serum valproate concentrations: their relationship to seizure control, liver enzymes and plasma ammonia in children. Can J Neurol Sci 1986;13:252–5.PubMedGoogle Scholar
  34. 34.
    Kilpatrick CJ, Fullinfaw RO, Burg RW, Moulds RFW. Plasma concentrations of unbound valproate and management of epilepsy. Aust NZ J Med 1987;17:574–7.Google Scholar
  35. 35.
    Barre J, Didey F, Delion F, Tillement J-P. Problems in therapeutic monitoring. Free drug level monitoring. Ther Drug Monitor 1988;10:133–43.Google Scholar
  36. 36.
    Johannessen SI, Løyning Y, Munthe-Kaas AW. IX. Medical treatment. General aspects. In: Dam M, Gram L, eds. Comprehensive epileptology. New York: Raven Press, 1991:505–24.Google Scholar

Copyright information

© Royal Dutch Association for Advancement of Pharmacy 1992

Authors and Affiliations

  • Svein I. Johannessen
    • 1
  1. 1.The National Centre for EpilepsySandvikaNorway

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