Interplay of drug transporters P-glycoprotein (MDR1), MRP1, OATP1A2 and OATP1B3 in passage of maraviroc across human placenta

Special attention is required when pharmacological treatment is indicated for a pregnant woman. P-glycoprotein (MDR1) is a well-known transporter localized in the maternal blood-facing apical membrane of placental syncytiotrophoblast and is considered to play an important role in protecting the developing fetus. Maraviroc, a MDR1 substrate that is registered for treatment of HIV infection, shows a low toxicity profile, suggesting favorable tolerability also if administered to pregnant women. Nevertheless, there is only poor understanding to date regarding the extent to which it permeates across the placental barrier and what are the transport mechanisms involved. Endeavoring to clarify the passage of maraviroc across placenta, we used in this study the method of closed-circuit perfusion of maraviroc across human placental cotyledon. The data obtained confirmed slight involvement of MDR1, but they also suggest possible interaction with other transport system(s) working in the opposite direction from that of MDR1. Complementary in vitro studies, including cellular experiments on choriocarcinoma BeWo cells as well as transporter-overexpressing MDCKII and A431 cell lines and accumulation in placental fresh villous fragments, revealed maraviroc transport by MRP1, OATP1A2, and OATP1B3 transporters. Based on mRNA expression data in the placental tissue, isolated trophoblasts, and fetal endothelial cells, especially MRP1 and OATP1A2 seem to play a crucial role in cooperatively driving maraviroc into placental tissue. By the example of maraviroc, we show here the important interplay of transporters in placental drug handling and its possibility to overcome the MDR1-mediated efflux. © 2020 The Author

Road users rarely use explicit communication when interacting in today’s traffic: Implications for Automated Vehicles

To be successful, automated vehicles (AVs) need to be able to manoeuvre in mixed traffic in a way that will be accepted by road users, and maximises traffic safety and efficiency. A likely prerequisite for this success is for AVs to be able to communicate effectively with other road users in a complex traffic environment. The current study, conducted as part of the European project interACT, investigates the communication strategies used by drivers and pedestrians while crossing the road at six observed locations, across three European countries. In total, 701 road user interactions were observed and annotated, using an observation protocol developed for this purpose. The observation protocols identified 20 event categories, observed from the approaching vehicles/drivers and pedestrians. These included information about movement, looking behaviour, hand gestures, and signals used, as well as some demographic data. These observations illustrated that explicit communication techniques, such as honking, flashing headlights by drivers, or hand gestures by drivers and pedestrians, rarely occurred. This observation was consistent across sites. In addition, a follow-on questionnaire, administered to a sub-set of the observed pedestrians after crossing the road, found that when contemplating a crossing, pedestrians were more likely to use vehicle-based behaviour, rather than communication cues from the driver. Overall, the findings suggest that vehicle-based movement information such as yielding cues are more likely to be used by pedestrians while crossing the road, compared to explicit communication cues from drivers, although some cultural differences were observed. The implications of these findings are discussed with respect to design of suitable external interfaces and communication of intent by future automated vehicles