title: Characterization of transplacental transfer of paroxetine in perfused human placenta: development of a pharmacokinetic model to evaluate tapered dosing.
abstract: The aim of this study was to determine whether a tapered dosage regimen of paroxetine in pregnant women might be useful to avoid withdrawal syndromes in neonates after delivery. We characterized the transplacental transfer of paroxetine in perfused human placenta, fitting a pharmacokinetic model to the results and applying the model and parameters to evaluate a tapered dosage regimen. Paroxetine was perfused from the maternal or fetal side of an isolated human placental preparation with various perfusion protocols, and paroxetine concentrations in the effluent and placental tissue were determined. The transplacental pharmacokinetic parameters of paroxetine were estimated by simultaneous fitting of a five-compartment transplacental pharmacokinetic model to the set of paroxetine concentration profiles. The developed model and parameters were used to simulate the maternal and fetal concentrations of paroxetine, and the results were compared with reported data. Paroxetine showed a larger distribution volume in placental tissue and a smaller transplacental transfer as compared with antipyrine, a passive diffusion marker. A five-compartment model could well describe the transplacental transfer of paroxetine and could well simulate the maternal and umbilical venous concentrations of paroxetine at delivery. Transplacental transfer kinetic parameters of paroxetine were estimated by fitting a pharmacokinetic model to perfusion study data. The model and parameters appeared to be suitable for simulation of paroxetine kinetics in fetus. The model was also applicable to design a dosage regimen to avoid an abrupt decrease of paroxetine concentration in fetal plasma.
authors.affiliation: Department of Drug Informatics, Graduate School of Pharmaceutical Sciences, the University of Tokyo (M.N., H.S., S.H., Y.S.); Department of Clinical Pharmacy, Faculty of Pharmacy, Keio University (H.O.); Faculty of Pharmaceutical Sciences, University of Tokyo (S.M.); Interfaculty Initiative in Information Studies, the University of Tokyo (S.H.); Department of Obstetrics and Gynecology, Graduate School of Medicine, the University of Tokyo (T.F., Y.T.), Tokyo, Japan.
authors.forename: Marie
authors.initials: M
authors.lastname: Nagai
authors.forename: Hisakazu
authors.initials: H
authors.lastname: Ohtani
authors.forename: Hiroki
authors.initials: H
authors.lastname: Satoh
authors.forename: Sayo
authors.initials: S
authors.lastname: Matsuoka
authors.forename: Satoko
authors.initials: S
authors.lastname: Hori
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Fujii
authors.forename: Yuji
authors.initials: Y
authors.lastname: Taketani
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Sawada
mesh_terms: D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000983:Antipyrine / Q000378:metabolism; D005260:Female; D005333:Fetus / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008431:Maternal-Fetal Exchange / Q000502:physiology*; D008954:Models, Biological; D017374:Paroxetine / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D010477:Perfusion; D010539:Permeability; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy
chemical_list: D018687:Antidepressive Agents, Second-Generation; D017374:Paroxetine; D000983:Antipyrine