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Antiepileptic Drug Disposition in Pregnancy

  • MJ Eadie
  • FJE Vajda

Abstract

The progressive physiological changes that occur in the female body during pregnancy, and their reversal in the weeks after the delivery of the foetus and placenta at the time of childbirth, have consequences for the body’s handling of drugs. The physiological changes have little effect on the absorption of the orally administered drugs, but the expanded extracellular fluid volume of pregnancy and the increasing bulk of the uterus and its contents have a diluting effect on circulating drug concentrations. Also, in later pregnancy, plasma protein concentrations decrease, resulting in a relative increase in plasma-unbound drug concentrations relative to total drug concentrations. Overall, the magnitude of these effects is small relative to the effects of pregnancy on drug elimination. Increased glomerular filtration during pregnancy increases the excretion of antiepileptic drugs that are cleared from the body predominantly as unchanged molecules, while the increasing circulating steroidal sex hormone concentrations of pregnancy induce formation of the liver enzymes that metabolise antiepileptic drugs that are cleared from the body by biotransformation. The overall result of these two processes is for circulating concentrations of antiepileptic drugs to fall relative to drug dose during pregnancy, potentially compromising the control of the seizure disorders for which the drugs have been prescribed.

After childbirth, antiepileptic drugs seem to enter maternal milk by a process of passive transfer along concentration gradients, with factors such as the fat and protein content of the milk affecting the drugs’ concentrations in that fluid. These concentrations are generally lower than those simultaneously present in maternal plasma.

Keywords

Antiepileptic Drug Maternal Plasma Dose Ratio Maternal Body Plasma Water 
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.

References

  1. Anderson GD (2006) Using pharmacokinetics to predict the effects of pregnancy and maternal-infant transfer of drugs during lactation. Clin Pharmacokinet 2:947–960Google Scholar
  2. Choi SY, Koh KH, Jeong H (2013) Isoform-specific regulation of cytochrome P450 expression by estradiol and progesterone. Drug Metab Dispos 41:263–269PubMedCentralCrossRefPubMedGoogle Scholar
  3. Collier AC, Tingle MD, Paxton JW, Mitchell MD, Keelan JA (2002) Metabolizing enzyme localization and activities in the first trimester human placenta: the effects of maternal gestational age, smoking and alcohol consumption. Hum Reprod 17:2564–2572CrossRefPubMedGoogle Scholar
  4. Dam M, Mygind KI, Christiansen J (1976) Antiepileptic drugs: plasma clearance during pregnancy. In: Janz D (ed) Epileptology. Thieme, Stuttgart, pp 179–183Google Scholar
  5. Davanzo R, Bo SD, Bua J, Copertine M, Zanelli E, Matarazzo L (2013) Antiepileptic drugs and breast feeding. Ital J Pediatr 39:50PubMedCentralCrossRefPubMedGoogle Scholar
  6. Dill WA, Kazenko A, Wolf LM, Glazko AJJ (1956) Studies on 5-5′-diphenylhydantoin (Dilantin) in animals and man. J Pharmacol Exp Ther 118:270–279PubMedGoogle Scholar
  7. Eadie MJ, Lander CM, Tyrer JH (1977) Plasma drug level monitoring in pregnancy. Clin Pharmacokinet 2:427–436CrossRefPubMedGoogle Scholar
  8. Fahmi OA, Kish M, Boldt S, Obach RS (2010) Cytochrome P450 3A4 mRNA is a more reliable marker than CYP 3A4 activity for detecting pregnane X receptor-activated induction of drug-metabolizing enzymes. Drug Metab Dispos 38:1605–1611CrossRefPubMedGoogle Scholar
  9. Fokina VM, Patrikeeva SL, Zharikova OL, Nanovskaya TN, Hankins GV, Ahmed MS (2011) Transplacental transfer and metabolism of buprenorphine in preterm human placenta. Am J Perinatol 28:25–32CrossRefPubMedGoogle Scholar
  10. Heidemann BH, McClure JH (2003) Changes in maternal physiology during pregnancy. Br J Anaesth CEPD Rev 3:65–68Google Scholar
  11. Lander CM, Edwards VE, Eadie MJ, Tyrer JH (1977) Plasma anticonvulsant concentrations during pregnancy. Neurology 27:128–131CrossRefPubMedGoogle Scholar
  12. Maezawa K, Matsunaga T, Takezawa T, Kanai M, Ohira S, Ohmori S (2010) Cytochrome P450 3As gene expression and testosterone 6 beta-hydroxylase activity in human fetal membranes and placenta at full term. Biol Pharm Bull 33:249–254CrossRefPubMedGoogle Scholar
  13. Meijer JWA, Meinardi H, Gardner-Thorpe C, van der Kleijn E (1973) Methods of analysis of anti-epileptic drugs. Excerpta Medica, AmsterdamGoogle Scholar
  14. Mygind KI, Dam M, Christiansen J (1976) Phenytoin and phenobarbitone plasma clearance during pregnancy. Acta Neurol Scand 54:160–166CrossRefPubMedGoogle Scholar
  15. Myllynen P, Pasanen M, Vakakangas K (2007) The fate and effects of xenobiotics in the human placenta. Expert Opin Drug Metab Toxicol 3:331–346CrossRefPubMedGoogle Scholar
  16. Papageorgiou I, Grepper S, Unadkat JD (2013) Induction of hepatic CYP3A enzymes by pregnancy-related hormones: studies in human hepatocytes and hepatic cell lines. Drug Metab Dispos 41:281–290CrossRefPubMedGoogle Scholar
  17. Pippenger CE, Penry JK, Kutt H (1978) Antiepileptic drugs: quantitative analysis and interpretation. Raven, New YorkGoogle Scholar
  18. Plaa GL, Hine CC (1956) Hydantoin and barbiturate blood levels observed in epileptics. Arch Int Pharmacodyn Ther 128:375–382Google Scholar
  19. Reddy DS (2010) Clinical pharmacokinetic interactions between antiepileptic drugs and hormonal contraceptives. Expert Rev Clin Pharmacol 3:183–192PubMedCentralCrossRefPubMedGoogle Scholar
  20. Reimers A, Osttby L, Struen I, Sundby E (2011) Expression of UDP glucuronosyltransferase 1A4 in human placenta at term. Eur J Drug Metab Pharmacokinet 35:79–82PubMedCentralCrossRefPubMedGoogle Scholar
  21. Syme MR, Paxton JW, Keelan JA (2004) Drug transfer and metabolism by the human placenta. Clin Pharmacokinet 43:387–514CrossRefGoogle Scholar
  22. Tracy TS, Venkataramanan R, Glover DD, Cariris SN (2005) Temporal changes in drug metabolism (CYP1A2, CYP2D6 and CYP3A activity) during pregnancy. Am J Obstet Gynecol 192:633–639CrossRefPubMedGoogle Scholar
  23. Wang H, Ping J, Peng RX et al (2008) Changes of multiple phase I and phase II enzyme activities in human fetal adrenals during fetal development. Acta Pharmacol Sin 29:231–238CrossRefPubMedGoogle Scholar
  24. Wloch S, Palasz A, Kaminski M (2009) Active and passive transport of drugs in the human placenta. Ginekol Pol 80:772–777PubMedGoogle 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

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