O-17 Transplacental transport of paracetamol and its metabolites using the ex-vivo human placenta perfusion model

Abstract

Background In Europe, 50%–60% of pregnant women uses paracetamol (Dafalgan). While its use in pregnan-cy was considered safe, recent studies show an associ-ation between prenatal exposure to paracetamol and increased incidences of autism, cryptorchidism, asthma and attention deficit hyperactivity disorder in a dose and duration dependent manner1-3. Data on transplacental transfer and metabolism of paracetamol are limited. Methods In an ex vivo placenta perfusion model (closed circuit) (n=38), maternal-to-fetal and fetal-to-maternal transplacental transfer of paracetamol (PCM) and its me-tabolites, paracetamol sulfate (PCM-S) and paracetamol glucuronide (PCM-G), was determined at a concentration corresponding to the maximum (PCM: 30 µg/ml; PCM-S: 10 µg/ml; PCM-G: 25 µg/ml) and steady state (PCM: 10 µg/ml; PCM-S: 5 µg/ml; PCM-G: 12.5 µg/ml) plasma con-centrations in normal clinical use. Antipyrine 100 µg/mL was added as internal control. PCM, PCM-S, PCM-G and antipyrine concentrations in perfusion medium and pla-cental tissue were determined using HPLC and LC-MS. Samples were taken at 0, 3, 6, 10, 15, 20, 30 min then ev-ery 15 min until 150 min followed by every 30 min until 210 (PCM) or 360 min (PCM-S and PCM-G). Fetal-to-ma-ternal and maternal-to-fetal ratios were normalised for antipyrine for each time point. Tissue accumulation and recovery of the compounds was calculated. Statistical dif-ferences were assessed using ANOVA. Results The maternal-to-fetal as fetal-to-maternal trans-port of PCM was 44%–48%. For PCM-S, transplacental trans-fer was 38%–40% for maternal-to-fetal transfer and 28% for fetal-to-maternal transfer. PCM-G had a transfer of 31%–36% for maternal-to-fetal and 25% for fetal-to-maternal transfer. An equilibrium between the maternal and fetal concentrations was reached for PCM after 210 min for perfusion from maternal-to-fetal circulation. Fetal-to-ma-ternal transport of PCM-S and PCM-G was significantly slower then maternal-to-fetal transport. Extrapolation of maternal-to-fetal transport data till 360 min predict-ed equilibrium at 7.5 hour (PCM-S) and 9.5 hour (PCM-G). For fetal-to-maternal transport extrapolation of data till 210 min (PCM) and 360 min (PCM-S and PCM-G) predict-ed equilibrium for PCM after 270 min, PCM-S 36 hour and PCM-G 44 hour. PCM-S and PCM-G were converted to PCM by the placenta during the perfusions. Conclusion This study shows that PCM rapidly crosses the placental barrier via passive diffusion for both mater-nal-to-fetal and fetal-to-maternal transplacental transfer. PCM-S and PCM-G, larger and more hydrophilic mole-cules, cross the placenta at a significantly lower rate. For PCM-S and PCM-G fetal-to-maternal transport is signifi-cantly slower than maternal-to-fetal transport.