Transplacental transport of paracetamol and its phase II metabolites using the ex vivo placenta perfusion model

In Europe, 50-60% of pregnant women uses paracetamol (PCM), also known as acetaminophen. While it was considered to be safe, recent studies have shown an association between prenatal exposure to PCM and increased incidences of autism, cryptorchidism, asthma and ADHD. In this study the transplacental transfer of PCM and its metabolites was investigated using an ex vivo human placenta perfusion model (closed circuit; n = 38). Maternal-to-foetal (M-F) and foetal-to-maternal (F-M) transplacental transfer was determined at a concentration correlating with the maximum and steady state concentration in normal clinical use. Antipyrine (AP) was added as reference compound. Samples of the foetal and maternal perfusion medium were taken until 210 (PCM) or 360 min (paracetamol sulphate (PCM-S) and paracetamol glucuronide (PCM-G). PCM and AP concentrations reached an equilibrium between foetal and maternal compartments within the duration of the perfusion experiment and irrespective of the transfer direction. The percentage placental transfer of PCM was 45% (M-F and F-M). For PCM-S, transfer was 39% (M-F) and 28% (F-M), while the PCM-G transfer was 34% (M-F) and 25% (F-M). During placenta perfusions with the metabolites slight conversion (3.5-4.1%) to PCM was observed. In conclusion, PCM crosses the placental barrier rapidly via passive diffusion. Differences in flow rate and villous placental structure explain the significantly faster M-F transfer than F-M transfer of PCM. The larger and more hydrophilic molecules PCM-S and PCM-G cross the placenta at a significantly lower rate. Moreover, their F-M transport is about 40% slower than M-F transport, suggesting involvement of a transporter.