TY - JOUR T1 - Characterization of Transplacental Transfer of Paroxetine in Perfused Human Placenta: Development of a Pharmacokinetic Model to Evaluate Tapered Dosing JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 2124 LP - 2132 DO - 10.1124/dmd.113.052332 VL - 41 IS - 12 AU - Marie Nagai AU - Hisakazu Ohtani AU - Hiroki Satoh AU - Sayo Matsuoka AU - Satoko Hori AU - Tomoyuki Fujii AU - Yuji Taketani AU - Yasufumi Sawada Y1 - 2013/12/01 UR - http://dmd.aspetjournals.org/content/41/12/2124.abstract N2 - 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. ER -