Abstract Understanding how pharmaceuticals cross the placenta is central to balancing effective maternal therapy with fetal safety. Computational and physiologically based pharmacokinetic models are powerful tools for predicting fetal drug exposure, but their accuracy depends on identifying the rate‐limiting determinants of placental transfer. These include placental anatomy, the routes available for paracellular diffusion, and the cellular localisation and membrane polarisation of drug transporters. The placenta both limits and mediates fetal exposure: it clears pharmaceuticals from the fetal circulation yet provides the principal route by which drugs reach the fetus. Transfer depends on a drug's physicochemical properties, especially molecular size and lipid solubility, and the presence of specific transport mechanisms. Net fetal exposure reflects the combined effects of diffusion and transporter‐mediated fluxes, plasma protein affinity, with a smaller contribution from placental metabolism. At the anatomical level recent advances in our understanding of placental ultrastructure have provided new routes allowing fetal exposure via diffusion. At the molecular level, defining transporter expression and polarisation is challenging and the literature is often inconsistent, reflecting methodological limitations. Single‐cell and single‐nucleus transcriptomics provide valuable insights into cell‐specific gene expression, although not necessarily protein localisation. Spatial mass spectrometry offers complementary information on protein abundance and polarity but remains limited by resolution. Effective models require a strong foundation in physiology and anatomy. A key limitation to modelling placental drug transfer is clearly determining the cellular localisation and membrane polarisation of drug transporters, and addressing this question is key to developing more effective predictive models. image
Lewis et al. (Sun,) studied this question.