Transplacental passage of lamotrigine in a human placental perfusion system in vitro and in maternal and cord blood in vivo.
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 microg/ml, n=4; 10 microg/ml, n=4) and reference compound antipyrine (100 microg/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 microg/ml LTG and 0.83+/-0.41 with 2.5 microg/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 microg/ml LTG and 37.8+/-3.2% with 10 microg/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.
Myllynen
Päivi K
PK
Department of Pharmacology and Toxicology, University of Oulu, PO Box 5000, FIN-90014, Oulu, Finland. paivi.k.myllynen@oulu.fi
Pienimäki
Päivi K
PK
Vähäkangas
Kirsi H
KH
D000927:Anticonvulsants / Q000097:blood*; D000983:Antipyrine / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005260:Female; D005312:Fetal Blood / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D000077213:Lamotrigine; D008431:Maternal-Fetal Exchange; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy / Q000097:blood*; D013997:Time Factors; D014227:Triazines / Q000097:blood*
D000927:Anticonvulsants; D014227:Triazines; D000983:Antipyrine; D000077213:Lamotrigine