European Journal of Clinical Pharmacology

, Volume 58, Issue 10, pp 677–682 | Cite as

Transplacental passage of lamotrigine in a human placental perfusion system in vitro and in maternal and cord blood in vivo

  • Päivi K. Myllynen
  • Päivi K. Pienimäki
  • Kirsi H. Vähäkangas
Pharmacokinetics and Disposition

Abstract

Objective

We studied transplacental passage of lamotrigine (3,5-diamino-6-[2,3-dichlorophenyl]-1,2,4-triazine; LTG) using an ex vivo human placental perfusion method and in in vivo samples.

Methods

Term placentas from healthy mothers without medications were perfused in a recirculating dual perfusion system. LTG (2.5 μg/ml, n=4; 10 μg/ml, n=4) and reference compound antipyrine (100 μg/ml) were added into the maternal circulation. The disappearance of drugs from the maternal circulation and appearance into the foetal circulation was followed every 15 min up to 2 h. Drug concentrations were analysed using high-performance liquid chromatography. In addition to human placental perfusions, we analysed LTG concentrations in maternal vein and cord blood samples after delivery from two epileptic mothers receiving LTG therapy during pregnancy.

Results

LTG was detectable in the foetal circulation at 15 min in all of the perfusions, indicating rapid transfer. Maternal and foetal concentrations reached equilibrium at 60 min with both concentrations used. The feto–maternal ratio was 1.26±0.20 with 10 μg/ml LTG and 0.83±0.41 with 2.5 μg/ml LTG at the end of the perfusion. The transfer of LTG from the maternal to the foetal compartment at 120 min was 28.9±10.7% with 2.5 μg/ml LTG and 37.8±3.2% with 10 μg/ml LTG (p>0.05). In the serum samples from epileptic mothers, the cord blood maternal concentration ratio was 1.02 in one pair and 1.55 in the other.

Conclusions

LTG crossed the placenta easily and rapidly, indicating that the maternal treatment leads to a considerable foetal exposure.

Keywords

Lamotrigine Pregnancy Human placental perfusion 

References

  1. 1.
    Reiff-Eldridge R, Heffner CR, Ephross SA, Tennis PS, White AD, Andrews EB (2000) Monitoring pregnancy outcomes after prenatal drug exposure through prospective pregnancy registries: a pharmaceutical company commitment. Am J Obstet Gynecol 182:159–163PubMedGoogle Scholar
  2. 2.
    Morrell MJ (1996) The new antiepileptic drugs and women: efficacy, reproductive health, pregnancy, and fetal outcome. Epilepsia 37[Suppl 6]:S34–S44Google Scholar
  3. 3.
    Marchi NS, Azoubel R, Tognola WA (2001) Teratogenic effects of lamotrigine on rat fetal brain: a morphometric study. Arq Neuropsiquiatr 59:362–364PubMedGoogle Scholar
  4. 4.
    Richens A (1995) Lamotrigine. Toxicity. In: Levy RH, Mattson RH, Meldrum BS (eds) Antiepileptic drugs. Raven Press, New York, pp 897–902Google Scholar
  5. 5.
    Audus KL (1999) Controlling drug delivery across the placenta. Eur J Pharm Sci 8:161–165PubMedGoogle Scholar
  6. 6.
    Sastry BV (1999) Techniques to study human placental transport. Adv Drug Deliv Rev 38:17–39CrossRefPubMedGoogle Scholar
  7. 7.
    Ala-Kokko TI, Myllynen P, Vähäkangas K (2000) Ex vivo perfusion of human placental cotyledon implications for anesthetic pharmacology. International Journal of Obstetric Anesthesia 9:26–38CrossRefGoogle Scholar
  8. 8.
    Tuntland T, Odinecs A, Pereira CM, Nosbisch C, Unadkat JD (1999) In vitro models to predict the in vivo mechanism, rate, and extent of placental transfer of dideoxynucleoside drugs against human immunodeficiency virus. Am J Obstet Gynecol 180:198–206PubMedGoogle Scholar
  9. 9.
    Bourget P, Roulot C, Fernandez H (1995) Models for placental transfer studies of drugs. Clin Pharmacokinet 28:161–180PubMedGoogle Scholar
  10. 10.
    Omarini D, Pistotti V, Bonati M (1992) Placental perfusion. An overview of the literature. J Pharmacol Toxicol Methods 28:61–66PubMedGoogle Scholar
  11. 11.
    Rurak DW, Wright MR, Axelson JE (1991) Drug disposition and effects in the fetus. J Dev Physiol 15:33–44PubMedGoogle Scholar
  12. 12.
    Ohman I, Vitols S, Tomson T (2000) Lamotrigine in pregnancy: pharmacokinetics during delivery, in the neonate, and during lactation. Epilepsia 41:709–713PubMedGoogle Scholar
  13. 13.
    Tomson T, Ohman I, Vitols S (1997) Lamotrigine in pregnancy and lactation: a case report. Epilepsia 38:1039–1041PubMedGoogle Scholar
  14. 14.
    Rambeck B, Kurlemann G, Stodieck SR, May TW, Jurgens U (1997) Concentrations of lamotrigine in a mother on lamotrigine treatment and her newborn child. Eur J Clin Pharmacol 51:481–484CrossRefPubMedGoogle Scholar
  15. 15.
    Lampela ES, Nuutinen LH, Ala-Kokko TI, Parikka RM, Laitinen RS, Jouppila PI, Vähäkangas KH (1999) Placental transfer of sulindac, sulindac sulfide, and indomethacin in a human placental perfusion model. Am J Obstet Gynecol 180:174–180PubMedGoogle Scholar
  16. 16.
    Pienimäki P, Lampela E, Hakkola J, Arvela P, Raunio H, Vähäkangas K (1997) Pharmacokinetics of oxcarbazepine and carbamazepine in human placenta. Epilepsia 38:309–316PubMedGoogle Scholar
  17. 17.
    Pienimäki P, Hartikainen AL, Arvela P, Partanen T, Herva R, Pelkonen O, Vähäkangas K (1995) Carbamazepine and its metabolites in human perfused placenta and in maternal and cord blood. Epilepsia 36:241–248PubMedGoogle Scholar
  18. 18.
    Pienimäki P, Fuchs S, Isojarvi J, Vähäkangas K (1995) Improved detection and determination of carbamazepine and oxcarbazepine and their metabolites by high-performance liquid chromatography. J Chromatogr B Biomed Appl 673:97–105CrossRefPubMedGoogle Scholar
  19. 19.
    Challier JC, Guerre-Millo M, Nandakumaran M, Gerbaut L, d'Athis P (1985) Clearance of compounds of different molecular size in the human placenta in vitro. Biol Neonate 48:143–148PubMedGoogle Scholar
  20. 20.
    Pacifici GM, Nottoli R (1995) Placental transfer of drugs administered to the mother. Clin Pharmacokinet 28:235–269Google Scholar
  21. 21.
    Ganapathy V, Prasad PD, Ganapathy ME, Leibach FH (2000) Placental transporters relevant to drug distribution across the maternal-fetal interface. J Pharmacol Exp Ther 294:413–420PubMedGoogle Scholar
  22. 22.
    Uchino H, Kanai Y, Kim dK, Wempe MF, Chairoungdua A, Morimoto E, Anders MW, Endou H (2002) Transport of amino acid-related compounds mediated by L-type amino acid transporter 1 (LAT1): insights into the mechanisms of substrate recognition. Mol Pharmacol 61:729–737PubMedGoogle Scholar
  23. 23.
    Ritchie JW, Taylor PM (2001) Role of the system L permease LAT1 in amino acid and iodothyronine transport in placenta. Biochem J 356:719–725PubMedGoogle Scholar
  24. 24.
    Nulman I, Laslo D, Koren G (1999) Treatment of epilepsy in pregnancy. Drugs 57:535–544PubMedGoogle Scholar
  25. 25.
    Tran TA, Leppik IE, Blesi K, Sathanandan ST, Remmel R (2002) Lamotrigine clearance during pregnancy. Neurology 59:251–255PubMedGoogle Scholar
  26. 26.
    Myllynen P, Pienimäki P, Jouppila PI, Vähäkangas K (2001) Transplacental passage of oxcarbazepine and its metabolites. Epilepsia 42:1482–1485CrossRefPubMedGoogle Scholar
  27. 27.
    Bulau P, Paar WD, von Unruh GE (1988) Pharmacokinetics of oxcarbazepine and 10-hydroxy-carbazepine in the newborn child of an oxcarbazepine-treated mother. Eur J Clin Pharmacol 34:311–313PubMedGoogle Scholar
  28. 28.
    Nau H, Rating D, Koch S, Hauser I, Helge H (1981) Valproic acid and its metabolites: placental transfer, neonatal pharmacokinetics, transfer via mother's milk and clinical status in neonates of epileptic mothers. J Pharmacol Exp Ther 219:768–777PubMedGoogle Scholar
  29. 29.
    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 (New York ) 1:291–303Google Scholar
  30. 30.
    Omarini D, Barzago MM, Bortolotti A, Lucchini G, Stellari F, Efrati S, Bonati M (1993) Placental transfer of theophylline in an in vitro closed perfusion system of human placenta isolated lobule. Eur J Drug Metab Pharmacokinet 18:369–374PubMedGoogle Scholar
  31. 31.
    Ching MS, Mihaly GW, Morgan DJ, Date NM, Hardy KJ, Smallwood RA (1987) Low clearance of cimetidine across the human placenta. J Pharmacol Exp Ther 241:1006–1009PubMedGoogle Scholar
  32. 32.
    Qvist N, Storm K, Holmskov A (1985) Cimetidine as pre-anesthetic agent for cesarean section: perinatal effects on the infant, the placental transfer of cimetidine and its elimination in the infants. J Perinat Med 13:179–183PubMedGoogle Scholar
  33. 33.
    Henderson GI, Hu ZQ, Johnson RF, Perez AB, Yang Y, Schenker S (1992) Acyclovir transport by the human placenta. J Lab Clin Med 120:885–892PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Päivi K. Myllynen
    • 1
  • Päivi K. Pienimäki
    • 1
  • Kirsi H. Vähäkangas
    • 1
    • 2
  1. 1.Department of Pharmacology and ToxicologyUniversity of OuluOuluFinland
  2. 2.Department of Pharmacology and ToxicologyUniversity of KuopioKuopioFinland

Personalised recommendations