Pharmacokinetics of oxcarbazepine and carbamazepine in human placenta.
OBJECTIVE
To study the transfer and metabolism of oxcarbazepine (OCBZ) and 10-hydroxy-10,11-dihydrocarbamazepine (10-OH-CBZ) and carbamazepine (CBZ) metabolism and its possible induction in human placenta.


METHODS
A dual recirculating human placental perfusion system, blood sampling, high performance liquid chromatography (HPLC), reverse transcriptase-polymerase chain reaction (RT-PCR), and enzyme assays.


RESULTS
OCBZ was metabolized into 10-OH-CBZ in five human placental cotyledons perfused for 2 h in a dual recirculating perfusion system. The same metabolite was found by HPLC in three sample pairs of maternal and cord blood taken during delivery from patients on OCBZ therapy. In all of the clinical samples, 10,11-trans-dihydroxy-10,11-dihydrocarbamazepine (10,11-D) was also found, but not in the perfusions. In addition, 10-OH-CBZ was not metabolized in the placental perfusions. The transfer of OCBZ through the perfused placentas was quicker than the transfer of antipyrine, while the transfer of 10-OH-CBZ was slower. Both OCBZ and 10-OH-CBZ also accumulated in placental tissue. CBZ metabolism was studied in three perfusions using placentas from mothers on CBZ therapy. No metabolism could be detected in the perfused placentas, while metabolites were found in both maternal and cord blood of the same mothers. Another series of placentas of mothers on CBZ therapy did not differ significantly from the placenta of a healthy mother as to CYP activities or the level of CYP3A4 mRNA.


CONCLUSIONS
OCBZ is metabolized into 10-OH-CBZ to some extent in human placenta in vitro, suggesting that the placenta also participates in the metabolism of OCBZ in vivo. On the contrary, the placenta does not participate in the metabolism of CBZ. No induction of placental CBZ metabolism in vitro can be detected after maternal CBZ treatment during pregnancy.
Pienimäki
P
P
Department of Pharmacology and Toxicology, University of Oulu, Finland.
Lampela
E
E
Hakkola
J
J
Arvela
P
P
Raunio
H
H
Vähäkangas
K
K
D000927:Anticonvulsants / Q000378:metabolism / Q000493:pharmacokinetics*; D002220:Carbamazepine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism; D004827:Epilepsy / Q000188:drug therapy; D005260:Female; D005312:Fetal Blood / Q000737:chemistry / Q000201:enzymology; D006801:Humans; D006899:Mixed Function Oxygenases / Q000187:drug effects / Q000378:metabolism; D000078330:Oxcarbazepine; D010920:Placenta / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D011247:Pregnancy; D011248:Pregnancy Complications / Q000188:drug therapy
D000927:Anticonvulsants; D002220:Carbamazepine; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C012227:carbamazepine epoxide; D000078330:Oxcarbazepine