Advertisement

Clinical Pharmacokinetics

, Volume 7, Issue 6, pp 508–543 | Cite as

Anticonvulsants during Pregnancy and Lactation Transplacental, Maternal and Neonatal Pharmacokinetics

  • H. Nau
  • W. Kuhnz
  • H.-J. Egger
  • D. Rating
  • H. Helge
Research Review

Summary

Few data are available on placental transfer of anticonvulsants during early pregnancy. Nevertheless, it has been demonstrated that at this early stage of gestation, considerable amounts of Phenytoin, primidone/phenobarbitone and carbamazepine as well as some of their metabolites are already present in fetal tissues. Potentially reactive metabolites of anticonvulsants can be formed by the fetal liver and accumulate in some organs. At term, most anticonvulsants are present in neonatal plasma in concentrations similar to those in maternal plasma. Valproic acid, on the other hand, can accumulate in fetal blood, for still unknown reasons.

Elimination by the neonate is variable and is dependent on several factors, such as clinical state, pre- or perinatal enzyme induction, absorption of the drugs and their plasma protein binding. Neonatal acquisition of anticonvulsants via breast-feeding does not seem to be harmful for the neonate. In the case of phenobarbitone, however, the drug may accumulate in nursing neonates to levels approaching or even exceeding those of their mothers. Significant drug levels can also build up in neonates and infants nursed by carbamazepine-and ethosuximide-treated mothers.

This review contains relevant pharmacokinetic data on anticonvulsant drugs widely used during pregnancy and the neonatal period. The differences between pregnant and non-pregnant adults as well as between neonates and older age groups are emphasised. Some pharmacokinetic data are correlated with clinical manifestations, such as seizure frequency, neonatal depression and withdrawal symptoms.

Keywords

Carbamazepine Valproic Acid Phenobarbitone Maternal Plasma Primidone 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Alexander, F.W.: Sodium valproate and pregnancy. Archives of Disease in Childhood 54: 240–245 (1979).PubMedCrossRefGoogle Scholar
  2. Aymard, P.; Taburet, A.M.; Baudon, J.J.; Blanc, A.M:, Hervé, J. and Costil, J.: Kinetics and metabolism of phenobarbital in the neonate; in Johannessen (Ed.) Antiepileptic Therapy: Advances in Drug Monitoring, pp. 1–8 (Raven Press, New York 1980).Google Scholar
  3. Bardy, A.H.: Plasma clearances of Phenytoin, phenobarbitone, primidone and carbamazepine during pregnancy. A prospective study; in Janz et al. (Eds) Epilepsy, Pregnancy and the Child, pp. 141–145 (Raven Press, New York 1981).Google Scholar
  4. Baughman, F.A. and Randinitis, E.J.: Passage of diphenylhydantoin across the placenta. Journal of the American Medical Association 213: 466 (1970).PubMedCrossRefGoogle Scholar
  5. Boreus, L.O.; Jailing, B. and Kallberg, N.: Clinical pharmacology of phenobarbital in the neonatal period; in Morselli et al. (Eds) Basic and Therapeutic Aspects of the Perinatal Pharmacology, pp.331–340 (Raven Press, New York 1975).Google Scholar
  6. Boréus, L.O.; Jalling, B. and Wallin A.: Plasma concentrations of phenobarbital in mother and child after combined prenatal and postnatal administration for prophylaxis of hyperbilirubinemia. Journal of Pediatrics 93: 695–698 (1978).PubMedCrossRefGoogle Scholar
  7. Bossi, L.: Pharmacokinetics and clinical effects of anticonvulsant drugs in newborns; in Janz et al. (Eds) Epilepsy, Pregnancy and the Child pp.373–381 (Raven Press, New York 1981).Google Scholar
  8. Bossi, L.; Assael, B.M.; Avanzini, G.; Battino, D.; Caccamo, M.L.; Canger, R.; Como, M.L..; Pifarotti, G.; de Giambattista, M.; Franceschetti, S.; Marini, A.; Pardi, G.; Porro, M.G.; Rovei, V.; Sanjuan, M.; Soffientini, M.E.; Spina, S. and Spreafico, R.: Plasma levels and clinical effects of antiepileptic drugs in pregnant epileptic patients and their newborns; in Johannessen (Ed.) Antiepileptic Therapy: Advances in Drug Monitoring, pp.9–18 (Raven Press, New York 1980).Google Scholar
  9. Bowdle, T.A.; Indravadan, H.P.; Levy, R.H. and Wilensky, A.J.: Valproic acid dosage and plasma protein binding and clearance. Clinical Pharmacology and Therapeutics 28: 486–492 (1980).PubMedCrossRefGoogle Scholar
  10. Brachet-Liermain, A. and Demarquez, J.L.: Pharmacokinetics of dipropyl acetate in infants and young children. Pharmaceutisch Weekblad 112: 293–297 (1977).Google Scholar
  11. Brachet-Liermain, A.; Goutieres, F. and Aicardi, J.: Absorption of phenobarbital after the intramuscular administration of single doses in infants. Journal of Pediatrics 87: 624–626 (1975).PubMedCrossRefGoogle Scholar
  12. Canger, R.; Avanzini, G.; Battino, D.; Bossi, L.; Franceschetti, S. and Spina, S.: Modification of seizure frequency in pregnancy: prospective data in 48 patients with epilepsy; in Janz et al. (Eds) Epilepsy, Pregnancy and the Child pp.33–38 (Raven Press, New York 1981).Google Scholar
  13. Chiba, K.; Ishizaki, T.; Miura, H. and Minagawa, K.: Michaelis-Menten pharmacokinetics of diphenylhydantoin and application in the pediatric age group. Journal of Pediatrics 96: 479–484 (1980).PubMedCrossRefGoogle Scholar
  14. Conney, A.H.: Pharmacological implications of microsomal enzyme induction. Pharmacological Reviews 19: 317–366 (1967).PubMedGoogle Scholar
  15. Conney, A.H.: Pharmacological implications of microsomal enzyme induction. Pharmacological Reviews 19: 317–366 (1967).PubMedGoogle Scholar
  16. Dam, M.; Christiansen, J.; Munck, O. and Mygind, K.I.: Antiepileptic drugs: metabolism in pregnancy. Clinical Pharmacokinetics 4: 53–62 (1979).PubMedCrossRefGoogle Scholar
  17. Davis, M.; Simmons, C.J.; Dordoni, B.; Maxwell, I.D. and Williams, R.: Induction of hepatic enzymes during normal human pregnancy. Journal of Obstetrics and Gynecology 80: 690–694 (1973).Google Scholar
  18. De Wolff, F.A.; Peters, A.C.B. and van Kempen, G.M.J.: Valproate induces urinary D-glucaric acid excretion. Lancet 1: 843 (1981).PubMedCrossRefGoogle Scholar
  19. Dean, M.; Stock, B.; Patterson, R.J. and Levy, G.: Serum protein binding of drugs during and after pregnancy in humans. Clinical Pharmacology and Therapeutics 28: 253–261 (1980).PubMedCrossRefGoogle Scholar
  20. Dickinson, R.G.; Harland, R.C.; Lynn, R.K.; Smith, W.B. and Gerber, N.: Transmission of valproic acid (Dekapene) across the placenta: Half-life of the drug in mother and baby. Journal of Pediatrics 94: 832–835 (1979).PubMedCrossRefGoogle Scholar
  21. Dodson, W.E.: Nonlinear kinetics of phenytoin in children. Neurology 32: 42–48 (1982).PubMedCrossRefGoogle Scholar
  22. Eadie, M.J.; Lander, C.M. and Tyrer, J.H.: Plasma drug level monitoring in pregnancy. Clinical Pharmacokinetics 2: 427–436 (1977).PubMedCrossRefGoogle Scholar
  23. Egger, H.-J.; Wittfoht, W. and Nau, H.: Identification of diphenylhydantoin and its metabolites, including the dihydrodiol and the catechols in maternal plasma, placenta and fetal tissue of man; in Neubert et al. (Eds) Role of Pharmacokinetics in Prenatal and Perinatal Toxicology, pp.483–497 (Georg Thieme Publishers, Stuttgart 1978a).Google Scholar
  24. Egger, H.-J.; Wittfoht, W. and Nau, H.: Metabolism of diphenyl-hydantoin in isolated hepatocyte and liver organ cultures of the human fetus; in Neubert et al. (Eds) Role of Pharmacokinetics in Prenatal and Perinatal Toxicology, pp. 109–121 (Georg Thieme Publishers, Stuttgart 1978b).Google Scholar
  25. Egger, H.-J.; Wittfoht, W. and Nau, H.: Determination of diphenylhydantoin and its metabolites by glass capillary GC-MS. Advances in Mass Spectrometry 8: 1219–1226 (1980).Google Scholar
  26. Ehrnebo, M; Agurell, S.; Jailing, B. and Boreus, L.O.: Age differences in drug binding by plasma proteins: studies on human fetuses, neonates and adults. European Journal of Clinical Pharmacology 3: 189–193 (1971).PubMedCrossRefGoogle Scholar
  27. Eichelbaum, M.; Ekbom, K.; Bertilsson, L.; Ringberger, V.A. and Rane, A.: Plasma kinetics of carbamazepine and its epoxide metabolite in man after single and multiple doses. European Journal of Clinical Pharmacology 8: 337–341 (1975).PubMedCrossRefGoogle Scholar
  28. Friis-Hansen, B.: Body water compartments in children: changes during growth and related changes in body composition. Pediatrics 28: 169–181 (1961).PubMedGoogle Scholar
  29. Fröscher, W.; Niesen, M.; Altmann, D.; Eichelbaum, M; Gugler, R.; Hoffman, F. and Penin, H.: Antiepileptika-Therapie während der Schwangerschaft und Geburt; in Remschmidt et al. (Eds) Epilepsie 1980, pp. 152–163 (Georg Thieme Publishers, Stuttgart 1981).Google Scholar
  30. Glatt, H.R.; Oesch, F.; Frigerio, A. and Garattini, S.: Epoxides metabolically produced from some known carcinogens and from some clinically used drugs. 1. Differences in mutagenicity. International Journal of Cancer 16: 787–797 (1975).CrossRefGoogle Scholar
  31. Gugler, R. and von Unruh, G.E.: Clinical pharmacokinetics of valproic acid. Clinical Pharmacokinetics 5: 67–83 (1980).PubMedCrossRefGoogle Scholar
  32. Hamar, C. and Levy, G.: Serum protein binding of drugs and bilirubin in newborn infants and their mothers. Clinical Pharmacology and Therapeutics 28: 58–63 (1980).PubMedCrossRefGoogle Scholar
  33. Heimann, G. and Gladtke, E.: Pharmacokinetics of phenobarbital in childhood. European Journal of Clinical Pharmacology 12: 305–310 (1977).PubMedCrossRefGoogle Scholar
  34. Helge, H. and Jäger, E.: Pharmacokinetics in the human neonate; in Neubert et al. (Eds) Role of Pharmacokinetics in Prenatal and Perinatal Toxicology, pp. 167–182 (Georg Thieme Publishers, Stuttgart 1978).Google Scholar
  35. Helge, H.; Gregg, B.; Jäger, E.; Knies, S.; Bochert, G. and Nigam, S.: N-demethylation of 13C-dimethylaminopyrine in children; in Klein et al. (Eds) Stable Isotopes: Proceedings of the Third International Conference pp.495–505 (Academic Press, New York 1979).Google Scholar
  36. Horning, M.G.; Butler, C.M.; Nowlin, J. and Hill, R.M.: Drug metabolism in the human neonate. Life Sciences 16: 651–672 (1975).PubMedCrossRefGoogle Scholar
  37. Ischizaki, T.; Yokochi, K.; Chiba, K.; Tabuchi, T. and T. Wagatsuma: Placental transfer of anticonvulsants (phenobarbital, Phenytoin, valproic acid) and the elimination from neonates. Pediatric Pharmacology 1: 291–303 (1981).Google Scholar
  38. Jailing, B.; Boréus, L.O.; Kallberg, N. and Agurell, S.: Disappearance from the newborn of circulating prenatally administered phenobarbital. European Journal of Clinical Pharmacology 6: 234–238 (1973).CrossRefGoogle Scholar
  39. Juchau, M.R.; Chao, S.T. and Omiecinski, C.J.: Drug metabolism by the human fetus. Clinical Pharmacokinetics 5: 320–339 (1980).PubMedCrossRefGoogle Scholar
  40. Kaneko, S.; Sato, T. and Suzuki, K.: The levels of anticonvulsants in breast milk. British Journal of Clinical Pharmacology 7: 624–626 (1979).PubMedCrossRefGoogle Scholar
  41. Kaneko, S.; Suzuki, K.; Sato, T.; Ogawa, Y. and Nomura, Y.: The problems of anticonvulsant medication at the neonatal period: Is breast feeding advisable? in Janz et al. (Eds) Epilepsy, Pregnancy and the Child, pp.343–347 (Raven Press, New York 1981).Google Scholar
  42. Kochenour, N.K.; Emlky, M.G. and Sawchuk, R.J.: Phenytoin metabolism in pregnancy. Obstetrics and Gynecology 56: 577–582 (1980).PubMedGoogle Scholar
  43. Koup, J.R.; Rose, J.Q. and Cohen, M.E.: Ethosuximide pharmacokinetics in a pregnant patient and the newborn. Epilepsia 19: 535–539 (1978).PubMedCrossRefGoogle Scholar
  44. Krauer, B.; Krauer, F. and Hytten, F.E.: Drug disposition and pharmacokinetics in the maternal placental fetal unit. Pharmacology and Therapeutics 10: 301–328 (1980).PubMedCrossRefGoogle Scholar
  45. Kurz, H.; Mauser-Ganshorn, A. and Stickel, H.H.: Differences in the binding of drugs to plasma proteins from newborn and adult man. I. European Journal of Clinical Pharmacology 11: 463–467 (1977).PubMedCrossRefGoogle Scholar
  46. Lander, C.M.; Edwards, V.E.; Eadie, M.J. and Tyrer, J.H.: Plasma anticonvulsant concentrations during pregnancy. Neurology 27: 128–131 (1977).PubMedCrossRefGoogle Scholar
  47. Landon, M.J. and Kirkley, M.: Metabolism of diphenylhydantoin (Phenytoin) during pregnancy. British Journal of Obstetrics and Gynaecology 86: 125–132 (1979).PubMedCrossRefGoogle Scholar
  48. Liddiard, C.; Brendel, K. and Nau, H.: Drug metabolism in cultures of isolated hepatocytes of the human fetus, the newborn pig and the adult rat; in Neubert et al. (Eds) Role of Pharmacokinetics in Prenatal and Perinatal Toxicology, pp.91–108 (Georg Thieme Publishers, Stuttgart 1978).Google Scholar
  49. Liddiard, C.; Merker, H.-J. and Nau, H.: An improved method for the preparation of human fetal and adult hepatocytes. Advances in Toxicology 44: 107–112 (1980).CrossRefGoogle Scholar
  50. Loughnan, P.M.; Greenwald, A.; Purton, W.W.; Aranda, J.V.; Watters, G. and Neims, A.H.: Pharmacokinetic observations of Phenytoin disposition in the newborn and young infant. Archives of Disease in Childhood 52: 302–309 (1977).PubMedCrossRefGoogle Scholar
  51. Martinez, G. and Snyder, R.D.: Transplacental passage of primidone. Neurology 23: 381–383 (1973).PubMedCrossRefGoogle Scholar
  52. Melchior, J.C.; Svensmark, O. and Trolle, D.: Placental transfer of phenobarbitone in epileptic women, and elimination in newborns. Lancet 2: 860–861 (1967).PubMedCrossRefGoogle Scholar
  53. Mirkin, B.L.: Placental transfer and neonatal elimination of diphenylhydantoin. American Journal of Obstetrics and Gynecology 109: 930–933 (1971a).PubMedGoogle Scholar
  54. Mirkin, B.L.: Diphenylhydantoin: Placental transport, fetal localization, neonatal metabolism, and possible teratogenic effects. Pediatric Pharmacology and Therapeutics 78: 329–337 (1971b).Google Scholar
  55. Morselli, P.L.: Clinical pharmacokinetics in neonates. Clinical Pharmacokinetics 1(2): 81–98 (1976).PubMedCrossRefGoogle Scholar
  56. Morselli, P.L.: Antiepileptic drugs; in Morselli (Ed.) Drug Disposition During Development, pp.311–360 (Spectrum Publications, New York 1977).Google Scholar
  57. Morselli, P.L. and Francc-Morselli, R.: Clinical pharmacokinetics of antiepileptic drugs in adults. Pharmacological Therapeutics 10: 65–101 (1980).CrossRefGoogle Scholar
  58. Morselli, P.L.; Franco-Morselli, R. and Bossi, L.: Clinical pharmacokinetics in newborns and infants. Clinical Pharmacokinetics 5: 485–527 (1980).PubMedCrossRefGoogle Scholar
  59. Mygind, K.I.; Dam, M. and Christiansen, J.: Phenytoin and phenobarbitone plasma clearance during pregnancy. Acta Neurologica Scandinavica 54: 160–166 (1976).PubMedCrossRefGoogle Scholar
  60. Nau, H. and Liddiard, C.: Liver organ culture as a long term viable system for the study of drug metabolism in the human fetus; in Neubert et al. (Eds) Role of Pharmacokinetics in Prenatal and Perinatal Toxicology, pp.77–90 (Georg Thieme Publishers, Stuttgart 1978).Google Scholar
  61. Nau, H.; Liddiard, C; Egger, H.-J. and Wittfoht, W.: Drug metabolism and lipid peroxidation in various hepatic in vitro systems of the human fetus; in Olive (Ed.) Advances in Pharmacology and Therapeutics 8, pp.91–100 (Pergamon Press, Oxford and New York 1978).Google Scholar
  62. Nau, H.; Rating, D.; Häuser, I.; Jäger, E.; Koch, S. and Helge, H.: Placental transfer and pharmacokinetics of primidone and its metabolites phenobarbital, PEMA and hydroxyphenobarbital in neonates and infants of epileptic mothers. European Journal of Clinical Pharmacology 18: 31–42 (1980a).PubMedCrossRefGoogle Scholar
  63. Nau, H. and Neubert, D.: Development of drug-metabolizing monooxygenase systems in various mammalian species including man. Its significance for transplacental toxicity; in Neubert et al. (Eds) Role of Pharmacokinetics in Prenatal and Perinatal Toxicology, pp. 13–44 (Georg Thieme Publishers, Stuttgart 1980b).Google Scholar
  64. Nau, H.; Schmidt, D.; Beck-Mannagetta, G.; Rating, D.; Koch, S. and Helge, H.: Pharmacokinetics of primidone and metabolites during human pregnancy; in Janz et al. (Eds) Epilepsy, Pregnancy and the Child, pp. 121–130 (Raven Press, New York 1981a).Google Scholar
  65. Nau, H.; Rating, D.; Häuser, I.; Jäger, E.; Göpfert-Geyer, I. and Helge, H.: Placental transfer at birth and postnatal elimination of primidone and metabolites in neonates of epileptic mothers; in Janz et al. (Eds) Epilepsy, Pregnancy and the Child, pp.361–366 (Raven Press, New York 1981b).Google Scholar
  66. Nau, H.; Wittfoht, W.; Rating, D.; Jakobs, C.; Schäfer, H. and Helge, H.: Pharmacokinetics of valproic acid and its metabolites in a pregnant patient: stable isotope methodology; in Janz et al. (Eds) Epilepsy, Pregnancy and the Child, pp. 131–144 (Raven Press, New York 1981c).Google Scholar
  67. Nau, H.; Rating, D.; Koch, S.; Häuser, I. and Helge, H.: Valproic acid and its metabolites: placental transfer, neonatal pharmacokinetics, transfer via mother’s milk and clinical status in neonates of epileptic mothers. Journal of Pharmacology and Experimental Therapeutics 219: 768–777 (1981d).PubMedGoogle Scholar
  68. Nau, H.; Schäfer, H.; Rating, D.; Jakobs, C. and Helge, H.: Placental transfer and neonatal pharmacokinetics of valproic acid and some of its metabolites; in Janz et al. (Eds) Epilepsy, Pregnancy and the Child, pp.367–372 (Raven Press, New York 1981e).Google Scholar
  69. Nau, H.; Wittfoht, W.; Schäfer, H.; Jakobs, C. and Helge, H.: Valproic acid and several metabolites: quantitative determination in serum, urine, breast milk and tissues by GC-MS selected ion monitoring. Journal of Chromatography 226: 69–78 (1981f).PubMedCrossRefGoogle Scholar
  70. Niebyl, J.R.; Blake, D.A.; Freeman, J.M. and Luff, R.D.: Carbamazepine levels in pregnancy and lactation. Obstetrics and Gynecology 53: 139–140 (1979).PubMedGoogle Scholar
  71. Painter, M.J.; Pippenger, C.; MacDonald, H. and Pitlick, W.: Phenobarbital and diphenylhydantoin levels in neonates with seizures. Journal of Pediatrics 92: 315–319 (1978).PubMedCrossRefGoogle Scholar
  72. Pelkonen, O.: Biotransformation of xenobiotics in the fetus. Pharmacological Therapeutics 10: 261–281 (1980).CrossRefGoogle Scholar
  73. Perez, V.; Gorodisch, S.; Casavilla, F. and Maruffo, C: Ultra-structure of human liver at the end of normal pregnancy. American Journal of Obstetrics and Gynecology 110: 428–431 (1971).PubMedGoogle Scholar
  74. Persson, B.H.: Studies on the accumulation of certain barbiturates in the brain of the human fetus. Acta Obstetrica Gynecologica Scandinavica 39: 88–99 (1960).CrossRefGoogle Scholar
  75. Perucca, E.; Ruprah, M. and Richens, A.: Altered drug binding to serum proteins in pregnant women: therapeutic relevance. Journal of the Royal Society of Medicine 74: 422–426 (1981).PubMedGoogle Scholar
  76. Philbert, A. and Dam, M.: The epileptic mother and her child. Epilepsia 23: 85–99 (1982).PubMedCrossRefGoogle Scholar
  77. Philbert, A.; Dam, M. and Pedersen, B.: Serum levels of valproic acid during pregnancy. Scandinavian Epilepsy Conference (1981).Google Scholar
  78. Piafsky, K.M. and Rane, A.: Formation of carbamazepine epoxide in human fetal liver. Drug Metabolism and Disposition 6: 502 (1978).PubMedGoogle Scholar
  79. Pitlick, W.; Painter, M. and Pippenger, C.: Phenobarbital pharmacokinetics in neonates. Clinical Pharmacology and Therapeutics 23: 346–350 (1978).PubMedGoogle Scholar
  80. Plasse, J.C.; Revol, M.; Chabert, G. and Ducerf, F.: Neonatal pharmacokinetics of valproic acid; in Schaaf and van der Kleijn (Eds) Progress in Clinical Pharmacy, pp.247–252 (Elsevier North Holland, Amsterdam 1979).Google Scholar
  81. Plomann, L. and Persson, B.H.: On the transfer of barbiturates to the human fetus and their accumulation in some of its vital organs. Journal of Obstetrics and Gynecology 64: 706–711 (1957).Google Scholar
  82. Pynnönen, S.; Kanto, J.; Sillanpää, M. and Erkkola, R.: Carbamazepine: placental transport, tissue concentrations in foetus and newborn, and level in milk. Acta Pharmacologica et Toxicologica 41: 244–253 (1977).PubMedCrossRefGoogle Scholar
  83. Ramsay, R.E.; Strauss, R.G.; Wilder, J. and Willmore, J.: Status epilepticus in pregnancy: effect of Phenytoin malabsorption on seizure control. Neurology 28: 85–96 (1978).PubMedCrossRefGoogle Scholar
  84. Rane, A.: Urinary excretion of diphenylhydantoin metabolites in newborn infants. Journal of Pediatrics 85: 543–545 (1974).PubMedCrossRefGoogle Scholar
  85. Rane, A.; Bertilsson, L. and Palmer, L.: Disposition of placentally transferred carbamazepine (Tegretol) in the newborn. European Journal of Clinical Pharmacology 8: 283–284 (1975).PubMedCrossRefGoogle Scholar
  86. Rane, A.; Garle, M.; Borgå, O. and Sjöqvist, F.: Plasma disappearance of transplacentaly transferred diphenylhydantoin in the newborn studied by mass fragmentography. Clinical Pharmacology and Therapeutics 15: 39–45 (1974).PubMedGoogle Scholar
  87. Rane, A.; Hoppel, C. and Hojer, B.: Kinetics of placentally transferred Phenytoin and its p-hydroxylated metabolites in newborn infants. British Journal of Clinical Pharmacology 8: 465–468 (1979).PubMedCrossRefGoogle Scholar
  88. Rane, A.; Lunde, P.K.M.; Jalling, B.; Yaffe, S.J. and Sjöqvist, F.: Plasma protein binding of diphenylhydantoin in normal and hyperbilirubinemic infants. Journal of Pediatrics 78: 877–882 (1971).PubMedCrossRefGoogle Scholar
  89. Rane, A.; Sundwall, A. and Tomson, G.: Oxidative and synthetic drug-metabolic pathways in the newborn infant. Studies on the neonatal kinetics of oxazepam; In Neubert et al. (Eds) Role of Pharmacokinetics in Prenatal and Perinatal Toxicology, pp. 183–191 (Georg Thieme Publishers, Stuttgart 1978).Google Scholar
  90. Rane, A. and Tunell, R.: Ethosuximide in human milk and in plasma of a mother and her nursed infant. British Journal of Clinical Pharmacology 12: 855–858 (1981).PubMedCrossRefGoogle Scholar
  91. Rating, D.; Jäger-Roman, E.; Koch, S.; Nau, H. and Helge, H.: Enzyme induction in neonates due to antiepileptic therapy during pregnancy; in Janz et al. (Eds) Epilepsy, Pregnancy and the Child, pp.349–355 (Raven Press, New York 1981a).Google Scholar
  92. Rating, D.; Jäger-Roman, G.; Koch, S.; Nau, H.; Klein, P.D. and Helge, H.: Minor anomalies in the offspring of epileptic parents (prospective study); in Janz et al. (Eds) Epilep’sy, Pregnancy and the Child, pp.282–288 (Raven Press, New York 1981b).Google Scholar
  93. Rating, D.; Nau, H.; Jäger-Roman, E.; Göpfert-Geyer, I.; Koch, S.; Beck-Mannagetta, G.; Schmidt, D. and Helge, H.: Teratogenic and pharmacokinetic studies of primidone during pregnancy and in the offspring of epileptic women. Acta Paediatrica Scandinavica 71: 301–311 (1982).PubMedCrossRefGoogle Scholar
  94. Reith, A. and Schäfer, H.: Antiepileptika Während Schwangerschaft und Stillzeit. Deutsche Medizinsche Wochenschrift 104: 818–823 (1979).CrossRefGoogle Scholar
  95. Rey, E.; D’Athis, P.; de Lauture, D.; Dulac, O.; Aicardi, J. and Olive, G.: Pharmacokinetics of carbamazepine in the neonate and in the child. International Journal of Clinical Pharmacology and Biopharmacology 17: 90–96 (1979).Google Scholar
  96. Reynolds, J.W. and Mirkin, B.L.: Urinary corticosteroid and diphenylhydantoin metabolite patterns in neonates exposed to anticonvulsant drugs in utero. Clinical Pharmacology and Therapeutics 14: 891–897 (1973).PubMedGoogle Scholar
  97. Ruprah, M.; Perucca, E. and Richens, A.: Phenytoin binding in pregnancy. Lancet 1: 97 (1981).PubMedCrossRefGoogle Scholar
  98. Schmidt, D.: The effect of pregnancy on the natural history of epilepsy; in Janz et al. (Eds) Epilepsy, Pregnancy and the Child, pp.39–49 (Raven Press, New York 1981).Google Scholar
  99. Similä, S.; von Wendt, L.; Hartikainen-Sorri, A.-L.; Kääpä, P. and Sankkonen, A.-L.: Sodium valproate, pregnancy and neonatal hyperglycinaemia. Archives of the Disabled Child 54: 985–986 (1979).CrossRefGoogle Scholar
  100. Spielberg, S.P.; Gordon, G.B.; Blake, D.A.; Meilits, E.D. and Brass, D.S.: Anticonvulsant toxicity in vitro; possible role of arene oxides. Journal of Pharmacology and Experimental Therapeutics 217: 386–389 (1981).PubMedGoogle Scholar
  101. Stock, B.H.: Drug disposition in pregnancy. Pharmacy International 2: 60–63 (1981).Google Scholar
  102. Urein, S.; Albengers, E. and Tillement, J.-P.: Serum protein binding of valproic acid in healthy subjects and patients with liver disease. International Journal of Clinical Pharmacology, Therapy and Toxicology 19: 319–325 (1981).Google Scholar
  103. Van der Kleijn, E.; Vree, T.B.; Guelen, P.; Schobten, F.; Westenberg, H. and Knop, H.: Kinetics of drug interactions in the treatment of epilepsy; in Meinardi (Ed.) Advances in Epileptology —1977, pp. 197–210 (Swets and Zeitlinger Verlag, Amsterdam 1978).Google Scholar
  104. Windorfer, A.: Stillen und Medikamente. Medizinische Monatszeitschrift für Pharmazie 7: 193–198 (1979).Google Scholar
  105. Wittfoht, W.; Nau, H., Rating, D. and Helge, H.: 13C-labelled valproic acid pulse dosing during steady state antiepileptic therapy for pharmacokinetic studies during pregnancy; in Schmidt et al. (Eds) Stable Isotopes, pp.265–270 (Elselvier, Amsterdam 1982).Google Scholar

Copyright information

© ADIS Press Australasia Pty Ltd (Inc. NSW). 1982

Authors and Affiliations

  • H. Nau
    • 1
    • 2
  • W. Kuhnz
    • 1
    • 2
  • H.-J. Egger
    • 1
    • 2
  • D. Rating
    • 1
    • 2
  • H. Helge
    • 1
    • 2
  1. 1.Institut für Toxikologie und Embryonalpharmakologie and KinderklinikFreie Universität BerlinBerlin 33West Germany
  2. 2.Hoffmann La RocheBaselSwitzerland

Personalised recommendations