Dexmedetomidine disappeared faster than clonidine from the maternal circulation, while even less dexmedetomidine was transported into the fetal circulation. This was due to its greater placental tissue retention, the basis for which probably is the higher lipophilicity of dexmedetomidine.

Summary:Purpose: To study the transfer and metabolism of oxcarbazepine (OCBZ) and 10-hydroxy-10,l l-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, 10,1l-trans-dihydroxy-l0,1 l-dihydrocarbamazepine (l0,ll-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 transIt has been known for some time that the placenta is able to metabolize drugs (1,2). Interspecies differences in the placental structure are so significant that results obtained from animal experiments cannot be directly generalized to apply to humans (3). For ethical reasons, in vitro placental perfusion is the only way for thorough investigation of pharmacokinetics in the human placenta.Pregnant women are frequently treated with carbamazepine (CBZ). CBZ undergoes almost complete biotransformation (4), and it induces its own metabolism (5,6), as do many other antiepileptic drugs (AEDs) (7).CBZ is metabolized mainly (40%) through oxidation into CBZ-10,ll-epoxide (CBZ-E), which is thought to be responsible for the side effects of CBZ, including teratogenicity (8,9). However, this epoxide is not reactive and does not bind significantly to macromolecules (10,ll). The principal catalyst of CBZ-E formation in human liver is cytochrome P-450 (CYP3A4) (12).Accepted October 28, 1996. Address correspondence and reprint requests to Dr. P. Pienimiiki at Department of Pharmacology and Toxicology, University of Oulu, Kajaanintie 52 D, Finland. fer 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. Key Words: Carbamazepine metabolites-Oxcarb...

No abstract