The Older Antiepileptic Drugs

  • MJ Eadie
  • FJE Vajda


This chapter outlines the pharmacokinetics and clinical pharmacology of the longer established antiepileptic drugs that continue to be reasonably often used in pregnancy, to provide a background to considering the alterations pregnancy and its aftermath produce in these parameters. The four drugs considered, viz. phenobarbitone, phenytoin, carbamazepine and valproate, are cleared from the body mainly by virtue of metabolism, and the clearance values of all increase progressively during pregnancy, though the change for carbamazepine is relatively small unless it is co-administered with another antiepileptic drug that induces the activity of drug-metabolising enzymes. The literature contains information regarding the individual metabolic pathways for phenytoin and carbamazepine biotransformation during pregnancy, indicating that the increased clearances of these drugs are due mainly to the development of increased capacities of already existing metabolic pathways rather than the appearance of new metabolic pathways. Relatively little information has been published concerning the dispositions of these drugs in the neonate, though there are data on their concentration ratios between maternal plasma and breast milk.


Antiepileptic Drug Maternal Plasma Solid Dosage Form Body Weight Basis Plasma Carbamazepine 
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.


  1. Amstutz U, Shear NH, Rieder MJ et al (2014) Recommendations for HLA-B*15:02 and HLA-A*31:01 genetic testing to reduce the risk of carbamazepine-induced hypersensitivity reactions. Epilepsia 55:496–506PubMedCrossRefGoogle Scholar
  2. Ayra R, Gulati S (2012) Phenytoin-induced gingival overgrowth. Acta Neurol Scand 125:149–155CrossRefGoogle Scholar
  3. Bailey DN, Briggs R (2005) Valproic acid binding to human serum and human placenta. Ther Drug Monit 27:375–377PubMedCrossRefGoogle Scholar
  4. Bardy AH, Teramo K, Hiilesmaa VK (1982) Apparent clearances of phenytoin phenobarbitone, primidone and carbamazepine during pregnancy: results of the prospective Helsinski study. In: Janz D, Bossi L, Helge H, Richens A, Schmidt D (eds) Epilepsy, pregnancy, and the child. Raven, New York, pp 141–145Google Scholar
  5. Bar-Oz B, Nulman I, Koren G, Ito S (2000) Anticonvulsants and breast feeding. Paediatr Drugs 2:113–126PubMedCrossRefGoogle Scholar
  6. Battino D, Avanzini G, Bossi L, Croci D, Cusi C, Gomeni C, Moise A (1983) Plasma levels of primidone and its metabolite phenobarbital: effects of age and associated therapy. Ther Drug Monit 5:73–79PubMedCrossRefGoogle Scholar
  7. Battino D, Binelli S, Bossi L, Como ML, Croci D, Cusi C, Avanzini G (1984) Changes in primidone/phenobarbitone ratio during pregnancy and the puerperium. Clin Pharmacokinet 9:252–260PubMedCrossRefGoogle Scholar
  8. Battino D, Binelli S, Bossi L et al (1985) Plasma concentrations of carbamazepine and carbamazepine-10,11-epoxide during pregnancy and after delivery. Clin Pharmacokinet 10:279–284PubMedCrossRefGoogle Scholar
  9. Bauer LA, Blouin RA (1983) Phenytoin Michaelis-Menten pharmacokinetics in Caucasian pediatric patients. Clin Pharmacokinet 8:545–549PubMedCrossRefGoogle Scholar
  10. Bauer J, Jarre A, Klingmuller D, Eiger CE (2000) Polycystic ovary syndrome in patients with focal epilepsy: a study of 93 women. Epilepsy Res 41:163–167PubMedCrossRefGoogle Scholar
  11. Baylis EM, Crowley JM, Preece JM, Sylvester PE, Marks V (1971) Influence of folic acid on blood phenytoin levels. Br Med J 1:62–64Google Scholar
  12. Bensten KD, Gram L, Veje A (1983) Serum thyroid hormones and blood folic acid during monotherapy with carbamazepine or valproate. Acta Neurol Scand 67:235–241CrossRefGoogle Scholar
  13. Berg MJ, Gross RA, Tomaszewski KJ, Zingaro WM, Haskins LS (2008) Generic substitution in the treatment of epilepsy: case evidence of breakthrough seizures. Neurology 71:525–530PubMedCrossRefGoogle Scholar
  14. Bernus I, Dickinson RG, Hooper WD, Eadie MJ (1994) Inhibition of phenobarbitone-N-glucosidation by valproate. Br J Clin Pharmacol 38:411–416PubMedCentralPubMedCrossRefGoogle Scholar
  15. Bernus I, Hooper WD, Dickinson RG, Eadie MJ (1995) Metabolism of carbamazepine and co-administered anticonvulsants during pregnancy. Epilepsy Res 21:65–75PubMedCrossRefGoogle Scholar
  16. Bernus I, Hooper WD, Dickinson RG, Eadie MJ (1997) Effects of pregnancy on various pathways of human antiepileptic drug metabolism. Clin Neuropharmacol 20:13–21PubMedCrossRefGoogle Scholar
  17. Bertilsson L, Tomson T (1986) Clinical pharmacokinetics and pharmacological effects of carbamazepine and carbamazepine-10,11-epoxide: an update. Clin Pharmacokinet 11:177–198PubMedCrossRefGoogle Scholar
  18. Boreus LO, Jalling B, Kallberg N (1975) Clinical pharmacology of phenobarbital in the neonatal period. In: Garrattini S, Sereni F, Morselli PL (eds) Basic and therapeutic aspects of perinatal pharmacology. Raven Press, New York, pp 331–340Google Scholar
  19. Bossi L (1982) Neonatal period including drug disposition in newborns: review of the literature. In: Janz D, Bossi L, Dam M, Helge H, Richens A, Schmidt D (eds) Epilepsy, pregnancy, and the child. Raven, New York, pp 327–341Google Scholar
  20. Bruni J, Wilder BJ, Perschalski RJ, Hammond EJ, Villareal HJ (1980) Valproic acid and plasma levels of phenobarbital. Neurology 30:94–97PubMedCrossRefGoogle Scholar
  21. Chanarin I, Mollin DL, Anderson BB (1958) Folic acid and megaloblastic anaemia. Proc R Soc Med 51:757PubMedCentralPubMedGoogle Scholar
  22. Conney AH (1967) Pharmacological implications of microsomal enzyme induction. Pharmacol Rev 19:317–366PubMedGoogle Scholar
  23. Coradello H (1973) Ueber die Ausscheidung von Antiepileptika in die Muttermilch. Wein Klin Wochenschr 85:695–697Google Scholar
  24. Cotter LM, Eadie MJ, Hooper WD, Lander CM, Smith MT, Tyrer JH (1977) The pharmacokinetics of carbamazepine. Eur J Clin Pharmacol 12:451–456PubMedCrossRefGoogle Scholar
  25. Cramer JA, Mattson RH, Bennett DM, Swick CT (1986) Variable free and total valproic acid concentration in sole- and multi-drug therapy. Ther Drug Monit 8:411–415PubMedCrossRefGoogle Scholar
  26. Crawford P (2009) Managing epilepsy in women of childbearing age. Drug Saf 32:293–307PubMedCrossRefGoogle Scholar
  27. Crawford P, Chadwick D, Cleland P, Tjia J, Cowrie A, Back DJ, Orme M (1986) The lack of effect of sodium valproate on the pharmacokinetics of oral contraceptive steroids. Contraception 33:23–29PubMedCrossRefGoogle Scholar
  28. Critchley EMR, Vakil SD, Hayward HW, Owen VMH (1976) Dupuytren’s contracture in epilepsy: result of prolonged administration of anticonvulsants. J Neurol Neurosurg Psychiatry 39:498–503PubMedCentralPubMedCrossRefGoogle Scholar
  29. Dam M, Mygind KI, Christiansen J (1976) Antiepileptic drugs: plasma clearance during pregnancy. In: Janz D (ed) Epileptology. Thieme, Stuttgart, pp 179–183Google Scholar
  30. Dam M, Christiansen J, Munck O, Mygind KI (1979) Antiepileptic drugs: metabolism in pregnancy. Clin Pharmacokinet 4:53–62PubMedCrossRefGoogle Scholar
  31. Dam M, Christiansen J, Kristensen CB, Helles A, Jaegerskou A, Schmiegelow M (1981) Carbamazepine: a clinical biopharmaceutical study. Eur J Clin Pharmacol 20:59–64PubMedCrossRefGoogle Scholar
  32. Davanzo R, Bo SD, Bua J, Copertino M, Zanelli E (2013) Antiepileptic drugs and breastfeeding. Ital J Pediatr 39:50PubMedCentralPubMedCrossRefGoogle Scholar
  33. Davis RE, Woodliff HJ (1971) Folic acid deficiency in patients receiving anticonvulsant drugs. Med J Aust 2:1070–1072PubMedGoogle Scholar
  34. De Carolis MP, Romagnoli C, Fressa S et al (1992) Placental transfer of phenobarbital: what is new? Dev Pharmacol Ther 19:19–26PubMedGoogle Scholar
  35. Dean M, Stock B, Patterson RJ, Levy R (1980) Serum protein binding and after pregnancy in humans. Clin Pharmacol Ther 28:253–261PubMedCrossRefGoogle Scholar
  36. DeLeacy EA, McLeay CD, Eadie MJ, Tyrer JH (1979) Effect of subjects’ sex and intake of tobacco, alcohol and oral contraceptives on plasma phenytoin levels. Br J Clin Pharmacol 8:33–36CrossRefGoogle Scholar
  37. Dickinson RG, Harland RC, Lynn RK, Smith WB, Gerber N (1979) Transmission of valproic acid (Depakene) across the placenta: half-life of the drug in mother and baby. J Pediatr 94:832–835PubMedCrossRefGoogle Scholar
  38. Dickinson RG, Hooper WD, Wood B, Lander CM, Eadie MJ (1989) The effect of pregnancy in humans on the pharmacokinetics of stable isotope labelled phenytoin. Br J Clin Pharmacol 28:17–27PubMedCentralPubMedCrossRefGoogle Scholar
  39. Eadie MJ, Tyrer JH, Hooper WD (1973) Diphenylhydantoin dosage. Proc Aust Assoc Neurol 10:53–59PubMedGoogle Scholar
  40. Eadie MJ, Lander CM, Hooper WD, Tyrer JH (1976) The effect of phenobarbitone dose on plasma phenobarbitone levels in epileptic patients. Proc Aust Assoc Neurol 13:89–96PubMedGoogle Scholar
  41. Eadie MJ, Lander CM, Hooper WD, Tyrer JH (1977) Factors influencing plasma phenobarbitone levels in epileptic patients. Br J Clin Pharmacol 4:541–547PubMedCentralPubMedCrossRefGoogle Scholar
  42. Eadie MJ, McKinnon GE, Dickinson RG, Hooper WD (1992) Phenytoin metabolism during pregnancy. Eur J Clin Pharmacol 43:389–392PubMedCrossRefGoogle Scholar
  43. Eichelbaum M, Kothe KW, Hoffman F, Von Uruth GE (1982) Use of stable labelled carbamazepine to study its kinetics during chronic carbamazepine treatment. Eur J Clin Pharmacol 23:241–244PubMedCrossRefGoogle Scholar
  44. Elyas AA, Patsalos PN, Agbato OA, Brett EM, Lascelles PT (1986) Factors influencing simultaneous concentrations of total and free carbamazepine and carbamazepine-10,11-epoxide in serum of children with epilepsy. Ther Drug Monit 8:288–292PubMedCrossRefGoogle Scholar
  45. Engel JJ, Pedley T (2008) Epilepsy. A comprehensive textbook, vol 2. Wolters Kluwer, Lippincott Williams and Wilkins, PhiladelphiaGoogle Scholar
  46. Fischer JH, Lockman LA, Zaske D, Kriel R (1981) Phenobarbital maintenance dose requirements in treating neonatal seizures. Neurology 31:1042–1044PubMedCrossRefGoogle Scholar
  47. Fischer JH, Patel TV, Fischer PA (2003) Fosphenytoin: clinical pharmacokinetics and comparative advantage in the acute treatment of seizures. Clin Pharmacokinet 42:33–58PubMedCrossRefGoogle Scholar
  48. Fowler DW, Eadie MJ, Dickinson R (1989) Transplacental transfer and biotransformation studies of valproic acid and its glucuronide(s) in the perfused human placenta. J Pharmacol Exp Ther 249:318–323PubMedGoogle Scholar
  49. French JA (2013) P-glycoprotein expression and antiepileptic drug resistance. Lancet Neurol 12:732–733PubMedCrossRefGoogle Scholar
  50. Garrettson LK, Dayton PG (1970) Disappearance of phenobarbital and diphenylhydantoin from serum of children. Clin Pharmacol Ther 11:674–679PubMedCrossRefGoogle Scholar
  51. Gerardin AP, Abadie FV, Campestrini JA (1976) Pharmacokinetics of carbamazepine in normal humans after single and repeated oral doses. J Pharmacokinet Biopharm 4:521–535CrossRefGoogle Scholar
  52. Gilhus NE, Strandjord RE, Aarli JA (1982) The effect of carbamazepine on serum immunoglobulin concentrations. Acta Neurol Scand 66:172–179PubMedCrossRefGoogle Scholar
  53. Gillette JR (1963) Metabolism of drugs and other foreign compounds by enzymatic mechanisms. Prog Drug Res 6:11–73Google Scholar
  54. Groce JB III, Casto DT, Gal P (1985) Carbamazepine and carbamazepine-epoxide serum protein binding in newborn infants. Ther Drug Monit 7:274–276PubMedCrossRefGoogle Scholar
  55. Guelen PJM, van der Kleijn E, Woudstra U (1975) Statistical analysis of pharmacokinetic parameters in epileptic patients chronically treated with antiepileptic drugs. In: Janz D, Gardner-Thorpe C, Meinardi H, Sherwin AL, Schneider H (eds) Clinical pharmacology of antiepileptic drugs. Springer, Berlin, pp 2–10CrossRefGoogle Scholar
  56. Herzog AG, Blum AS, Farina EL et al (2009) Valproate and lamotrigine level variation with menstrual cycle phase and oral contraceptive use. Neurology 72:911–914PubMedCrossRefGoogle Scholar
  57. Hooper WD, Du Betz DK, Bochner F, Cotter LM, Smith GA, Eadie MJ, Tyrer JH (1975) Plasma protein binding of carbamazepine. Clin Pharmacol Ther 17:433–440PubMedCrossRefGoogle Scholar
  58. Hosokawa K, Takahashi S, Yamamoto M (1984) Plasma concentrations in pregnancy. In: Shinagawa S, Sato T (eds) Antiepileptic drugs and pregnancy. Excerpta Medica, Amsterdam, pp 3–11Google Scholar
  59. Ieiri I, Goto W, Hirata K et al (1995) The effect of 5-(p-hydroxyphenyl)-5-phenylhydantoin (p-HPPH) enantiomers, major metabolites of phenytoin on the occurrence of chronic-gingival hyperplasia: in vivo and in vitro study. Eur J Clin Pharmacol 49:51–56PubMedCrossRefGoogle Scholar
  60. Ishizaki T, Yokochi K, Chiba K, Tabuchi T, Wagatsuma T (1981) Placental transfer of anticonvulsants (phenobarbital, phenytoin valproic acid) and the elimination from neonates. Pediatr Pharmacol 1:291–303Google Scholar
  61. Julien RM, Hollister RP (1975) Carbamazepine: mechanism of action. Adv Neurol 11:263–276PubMedGoogle Scholar
  62. Kaaja E, Kaaja R, Matila R, Hiilesmaa V (2002) Enzyme-inducing antiepileptic drugs in pregnancy and the risk of bleeding in the neonate. Neurology 58:549–553PubMedCrossRefGoogle Scholar
  63. Kamali F, Thomas SH (1994) Effect of flow rate on saliva phenytoin concentrations: implications for therapeutic monitoring. Eur J Clin Pharmacol 46:565–567PubMedCrossRefGoogle Scholar
  64. Kan R, Masubuchi Y, Nikaido T, Yoshijima T, Ono T, Takahashi Y, Kumashiro H (1984) Antiepileptic drug trends during pregnancy. In: Shinagawa S, Sato T (eds) Antiepileptic drugs during pregnancy. Excerpta Medica, Amsterdam, pp 12–19Google Scholar
  65. Kaneko S, Sato T, Suzuki K (1979) The levels of anticonvulsants in breast milk. Br J Clin Pharmacol 7:624–627PubMedCentralPubMedCrossRefGoogle Scholar
  66. Kaneko S, Suzuki K, Sato T, Ogawa Y, Nomura Y (1982) The problem of antiepileptic medication in the neonatal period: is breast feeding advisable? In: Janz D, Bossi L, Dam M, Helge H, Richens A, Schmidt D (eds) Epilepsy, pregnancy, and the child. Raven, New York, pp 343–348Google Scholar
  67. Kaneko S, Fukushima Y, Sato T, Ogawa Y, Nomura Y, Shinagawa S (1984) Breast feeding in epileptic mothers. In: Shinagawa S, Sato T (eds) Antiepileptic drugs and pregnancy. Excerpta Medica, Amsterdam, pp 38–45Google Scholar
  68. Kapetanovic IM, Kupferberg HJ, Porter RJ, Theodore W, Schullmann E, Penry JK (1981) Mechanism of valproate-phenobarbital interaction in epileptic patients. Clin Pharmacol Ther 29:480–486PubMedCrossRefGoogle Scholar
  69. Karoly R, Lenkey N, Juhasz AO, Vizi ES, Mike A (2010) Fast- or slow-inactivated state preference of Na+ channel inhibitors: a simulation and experimental study. PLoS Comp Biol 17:6.e1000818Google Scholar
  70. Kesavan R, Narayan SK, Anithan C (2010) Influence of CYP2C9 and CYP2C19 genetic polymorphisms on phenytoin-induced neurological toxicity in Indian epileptic patients. Eur J Clin Pharmacol 66:689–696PubMedCrossRefGoogle Scholar
  71. Kluck RM, Cannell GR, Hooper WD, Eadie MJ, Dickinson R (1988) Disposition of phenytoin and phenobarbitone in the isolated perfused human placenta. Clin Exp Pharmacol Physiol 15:827–836PubMedCrossRefGoogle Scholar
  72. Kuo CC (1998) A common anticonvulsant binding site for phenytoin carbamazepine and lamotrigine in neuronal Na channels. Mol Pharmacol 54:712–721PubMedGoogle Scholar
  73. Kutt H, Winters W, Kokenge R, McDowell F (1964) Diphenylhydantoin metabolism, blood levels, and toxicity. Arch Neurol 11:642–648PubMedCrossRefGoogle Scholar
  74. Lambie DG, Nanda RN, Johnson RH, Shakir RA (1976) Therapeutic and pharmacokinetic effects of increasing phenytoin in chronic epileptics on multiple drug therapy. Lancet 7:486–489Google Scholar
  75. Lander CM, Eadie MJ (1991) Plasma concentrations of antiepileptic drugs during pregnancy. Epilepsia 32:257–264PubMedCrossRefGoogle Scholar
  76. Lander CM, Edwards VE, Eadie MJ, Tyrer JH (1977) Plasma anticonvulsant concentrations during pregnancy. Neurology 27:128–131PubMedCrossRefGoogle Scholar
  77. Lander CM, Smith MT, Chalk JB, DeWytt C, Symoniw P, Livingstone I, Eadie MJ (1984) Bioavailability and pharmacokinetics of phenytoin during pregnancy. Eur J Clin Pharmacol 27:105–110PubMedCrossRefGoogle Scholar
  78. Lecamwasam DS, Franklin C, Turner P (1975) Effect of phenobarbitone on hepatic drug metabolising enzymes and urinary D-glucaric acid excretion in man. Br J Clin Pharmacol 2:257–262PubMedCentralPubMedCrossRefGoogle Scholar
  79. Levy RH, Pitlick WH, Troupin AS, Green JR, Neal JM (1975) Pharmacokinetics of carbamazepine in normal man. Clin Pharmacol Ther 17:657–668PubMedCrossRefGoogle Scholar
  80. Levy R, Mattson R, Meldrum BS, Perucca E (2002) Antiepileptic drugs, 5th edn. Lippincott Williams & Wilkins, PhiladelphiaGoogle Scholar
  81. Lipkin GM, Fozzard HA (2010) Molecular model of anticonvulsant drug binding to the voltage-gated sodium channel inner pore. Mol Pharmacol 78:631–638CrossRefGoogle Scholar
  82. Loiseau P, Brachet Liermain A, Legroux M, Jogeix M (1977) Interet du dosage des anticonsulsivants dans le traitment des epilepsies. Nouv Presse Med 16:813–817Google Scholar
  83. Loscher W (2007) Drug transporters in the epileptic brain. Epilepsia 48(Suppl 1):8–13PubMedCrossRefGoogle Scholar
  84. MacKichan JJ, Duffner PK, Cohen ME (1981) Salivary concentrations and plasma protein binding of carbamazepine and carbamazepine-10,11-epoxide in epileptic patients. Br J Clin Pharmacol 12:31–37PubMedCentralPubMedCrossRefGoogle Scholar
  85. Majer RV, Green PJ (1987) Neonatal afibrinogenaemia due to sodium valproate. Br Med J 2:740–741Google Scholar
  86. Mantegazza M, Curia G, Biagini G, Ragsdale DS, Avoli M (2010) Voltage-gated sodium channels as therapeutic targets in epilepsy and other neurological disorders. Lancet Neurol 9:413–424PubMedCrossRefGoogle Scholar
  87. Marangos PJ, Patel J, Smith KD, Post RM (1987) Adenosine antagonist properties of carbamazepine. Epilepsia 28:387–394PubMedCrossRefGoogle Scholar
  88. Mattson RH, Gallagher BB, Reynolds EH, Glass D (1973) Folate therapy in epilepsy. A controlled study. Arch Neurol 29:78–81PubMedCrossRefGoogle Scholar
  89. Mattson GF, Mattson RH, Cramer JA (1982) Interaction between valproic acid and carbamazepine: an in vitro study of protein binding. Ther Drug Monit 4:181–184PubMedCrossRefGoogle Scholar
  90. McKauge L, Tyrer JH, Eadie MJ (1981) Factors influencing simultaneous concentrations of carbamazepine and its epoxide in plasma. Ther Drug Monit 3:63–70PubMedCrossRefGoogle Scholar
  91. Melchior JC, Svensmark O, Trolle D (1967) Placental transfer of phenobarbitone in epileptic women, and elimination in newborns. Lancet 2:860–861PubMedCrossRefGoogle Scholar
  92. Meraw SJ, Sheridan PL (1998) Medically induced gingival hyperplasia. Mayo Clin Proc 73:1196–1199PubMedCrossRefGoogle Scholar
  93. Mirkin BL (1971) Diphenylhydantoin: placental transport, fetal localization, neonatal metabolism and possible teratogenic effect. J Pediatr 78:329–337PubMedCrossRefGoogle Scholar
  94. Monaco F, Piredda S, Mutani R, Mastropaolo C, Tondi M (1982) The free fraction of valproic acid in tears, saliva, and cerebrospinal fluid. Epilepsia 23:23–26PubMedCrossRefGoogle Scholar
  95. Morselli PL (1975) Carbamazepine: absorption, distribution and excretion. Adv Neurol 11:279–293PubMedGoogle Scholar
  96. Morselli PL, Rizzo M, Garattini S (1971) Interaction between phenobarbital and diphenylhydantoin in animals and in epileptic patients. Proc N Y Acad Sci 179:88–107CrossRefGoogle Scholar
  97. Mygind KI, Dam M, Christiansen J (1976) Phenytoin and phenobarbitone plasma clearance during pregnancy. Acta Neurol Scand 54:160–166PubMedCrossRefGoogle Scholar
  98. Nakajima M, Sakata N, Ohashi N, Kume T, Yokoi T (2002) Involvement of multiple UDP-glucuronosyltransferase 1A isoforms in glucuronidation of 5-(4′-hydroxyphenyl)-5-phenylhydantoin in human liver microsomes. Drug Metab Dispos 30:1250–1256PubMedCrossRefGoogle Scholar
  99. Nation RL, Evans AM, Milne RW (1990) Pharmacokinetic drug interactions with phenytoin. Clin Pharmacokinet 18(37–60):131–150PubMedCrossRefGoogle Scholar
  100. Nau H, Helge H, Luck W (1984) 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 104:627–634PubMedCrossRefGoogle Scholar
  101. Neuvonen P (1979) Bioavailability of phenytoin: clinical, pharmacokinetic and therapeutic implications. Clin Pharmacokinet 4:91–103PubMedCrossRefGoogle Scholar
  102. Neuvonen PJ (1985) Bioavailability and central side effects of different carbamazepine tablets. Int J Clin Pharmacol Ther Toxicol 23:226–232PubMedGoogle Scholar
  103. O’Brien TJ, Cascino GD, So EL, Hanna DR (1998) Incidence and clinical consequences of the purple glove syndrome in patients receiving intravenous phenytoin. Neurology 51:1034–1039PubMedCrossRefGoogle Scholar
  104. Omtzigt JGC, Los FJ, Grobbee DE et al (1992) The risk of spina bifida aperta after first-trimester exposure to valproate in a prenatal cohort. Neurology 42(Suppl 5):119–125PubMedGoogle Scholar
  105. Painter MJ, Pippenger C, Carter G, Pitlick W (1977) Metabolism of phenobarbital and phenytoin by neonates with seizures. Neurology 27:370Google Scholar
  106. Panesar S, Orr J, Burton R, Farrell K (1986) Effect of carbamazepine on valproic acid metabolism. Epilepsia 27:591Google Scholar
  107. Patsalos PN (2013) Drug interactions with the newer antiepileptic drugs (AEDs) -Part 1: pharmacokinetic and pharmacodynamic interactions between AEDs. Clin Pharmacokinet 52:927–966PubMedCrossRefGoogle Scholar
  108. Patsalos PN, Perucca E (2003a) Clinically important drug interactions in epilepsy: general features and interactions between antiepileptic drugs. Lancet Neurol 2:347–356PubMedCrossRefGoogle Scholar
  109. Patsalos PN, Perucca E (2003b) Clinically important drug interactions in epilepsy: interactions between antiepileptic drugs and other drugs. Lancet Neurol 2:473–481PubMedCrossRefGoogle Scholar
  110. Patsalos PN, Berry DJ, Bourgeois BF et al (2008) Antiepileptic drugs – best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, I.L.A.E. Commission on Therapeutic Strategies. Epilepsia 49:1239–1276PubMedCrossRefGoogle Scholar
  111. Pennell PB (2003) Antiepileptic drug pharmacokinetics during pregnancy and lactation. Neurology 61(Suppl 2):S35–S42PubMedCrossRefGoogle Scholar
  112. Philbert A, Petersen B, Dam M (1985) Concentration of valproate during pregnancy in the newborn and in breast milk. Acta Neurol Scand 72:460–463PubMedCrossRefGoogle Scholar
  113. Pisani F, Fazio A, Oteri G, Ruello C, Gitto C, Russo F, Perucca E (1986) Sodium valproate and valproamide: differential interactions with carbamazepine in epileptic patients. Epilepsia 27:548–552PubMedCrossRefGoogle Scholar
  114. Pitlick W, Painter M, Pippenger C (1978) Phenobarbital pharmacokinetics in neonates. Clin Pharmacol Ther 23:346–350PubMedCrossRefGoogle Scholar
  115. Pynnonen S, Sillanpaa M (1975) Carbamazepine and mother’s milk. Lancet 3:563CrossRefGoogle Scholar
  116. Qiao X, Sun G, Clare JJ, Werkman TR, Wadman WJ (2014) Properties of human brain sodium channel (alpha)-subunits expressed in HEK293 cells and their modulation by carbamazepine, phenytoin and lamotrigine. Br J Pharmacol 171:1054–1067PubMedCentralPubMedCrossRefGoogle Scholar
  117. Ramsay RE, Strauss RG, Wilder BJ, Willmore LJ (1978) Status epilepticus in pregnancy: effect of phenytoin malabsorption on seizure control. Neurology 28:85–89PubMedCrossRefGoogle Scholar
  118. Rey E, D’Arthis P, DeLautre D, Duklac O, Aicardi J, Olive G (1979) Pharmacokinetics of carbamazepine in the neonate and in the child. Int J Clin Pharmacol Biopharm 17:90–96PubMedGoogle Scholar
  119. Reynolds EH, Travers RD (1974) Serum anticonvulsant concentrations in epileptic patients with mental symptoms. A preliminary report. Br J Psychiatry 124:440–445PubMedCrossRefGoogle Scholar
  120. Richens A (1975) Discussion. In: Schneider H, Janz D, Gardner-Thorpe C, Meinardi H, Sherwin AL (eds) Clinical pharmacology of antiepileptic drugs. Springer, Berlin, pp 46–47Google Scholar
  121. Rościszewska D, Buntner B, Guz I, Zawisza L (1986) Ovarian hormones, anticonvulsant drugs, and seizures during the menstrual cycle in women with epilepsy. J Neurol Neurosurg Psychiatry 49:47–51PubMedCentralPubMedCrossRefGoogle Scholar
  122. Ruprah M, Perucca E, Richens A (1982) Serum protein binding of phenytoin in women: effect of pregnancy and oral contraceptives. In: Janz D, Dam M, Bossi B, Richens A, Helge H, Schmidt D (eds) Epilepsy, pregnancy and the child. Raven, New York, pp 115–120Google Scholar
  123. Schmidt D, Einicke I, Haenel F (1986) The influence of seizure type on the efficacy of plasma concentrations of phenytoin, phenobarbital, and carbamazepine. Arch Neurol 43:263–265PubMedCrossRefGoogle Scholar
  124. Shavit G, Lerman P, Korczyn AD, Kivity S, Bechar M, Gitter S (1984) Phenytoin pharmacokinetics in catamenial epilepsy. Neurology 34:959–961PubMedCrossRefGoogle Scholar
  125. Sherwin AL, Lloynd JS, Bock GW, Sokolowski CD (1974) Effect of age, sex, obesity and pregnancy on plasma diphenylhydantoin levels. Epilepsia 15:507–521PubMedCrossRefGoogle Scholar
  126. Shorvon SD, Reynolds EH (1982) Anticonvulsant peripheral neuropathies. A clinical and electrophysiological study of patients on single drug treatment with phenytoin, carbamazepine, or barbiturates. J Neurol Neurosurg Psychiatry 47:621–626Google Scholar
  127. Shorvon S, Perucca E, Engel JJ (2009) The treatment of epilepsy, 3rd edn. Wiley Blackwell, OxfordCrossRefGoogle Scholar
  128. Thomas EA, Petrou S (2013) Network-specific mechanisms may explain the paradoxical effects of carbamazepine and phenytoin. Epilepsia 54:1195–1202PubMedCrossRefGoogle Scholar
  129. Tomson T, Tybring G, Bertilsson L (1983) Single-dose kinetics and metabolism of carbamazepine-10,11-epoxide. Clin Pharmacol Ther 33:58–65PubMedCrossRefGoogle Scholar
  130. Tomson T, Landmark CJ, Battino D (2013) Antiepileptic drug treatment in pregnancy: changes in drug disposition and their clinical implications. Epilepsia 54:405–414PubMedCrossRefGoogle Scholar
  131. Travers RD, Reynolds EH, Gallagher BB (1972) Variations in response to anticonvulsants in a group of epileptic patients. Arch Neurol 27:29–33PubMedCrossRefGoogle Scholar
  132. Vakil SD, Critchley EMR, Phillips JC, Fahim Y, Haydock C, Cocks A, Dyer T (1976) The effect of sodium valproate (Epilim) on phenytoin and phenobarbitone blood levels. In: Legg NJ (ed) Clinical and pharmacological aspects of sodium valproate (Epilim) in the treatment of epilepsy. MCS Consultants, Tunbridge Wells, pp 75–77Google Scholar
  133. Westenberg HGM, Van Der Kleijn E, Oei TT, De Zeeuw RA (1978) Kinetics of carbamazepine and carbamazepine-epoxide determined by use of plasma and saliva. Clin Pharmacol Ther 23:320–328PubMedCrossRefGoogle Scholar
  134. Wilder BJ, Willmore LJ, Bruni J, Villareal HJ (1978) Valproic acid: interaction with other anticonvulsant drugs. Neurology 28:892–896PubMedCrossRefGoogle Scholar
  135. Windorfer AJ, Sauer W (1977) Drug interactions during anticonvulsant therapy in childhood: diphenylhydantoin, primidone, phenobarbitone, clonazepam, nitrazepam, carbamazepine and dipropylacetate. Neuropediatrie 8:29–41CrossRefGoogle Scholar
  136. Yerby MS, Friel P, Miller DQ (1985) Carbamazepine protein binding and disposition in pregnancy. Ther Drug Monit 7:269–273PubMedCrossRefGoogle Scholar
  137. Yerby MS, Friel PN, McCormick K et al (1990) Pharmacokinetics of anticonvulsants in pregnancy: alterations in plasma protein binding. Epilepsy Res 5:223–228PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • MJ Eadie
    • 1
  • FJE Vajda
    • 2
  1. 1.Clinical Neurology and NeuropharmacologyUniversity of Queensland, and Honorary Consultant Neurologist, Royal Brisbane and Women’s HospitalBrisbaneAustralia
  2. 2.Department of Medicine and Neurology Director of the Australian Epilepsy and Pregnancy RegisterUniversity of Melbourne and Royal Melbourne HospitalMelbourneAustralia

Personalised recommendations