Placental Drug Transfer and Fetal Drug Exposure: Emerging Pharmacokinetic Approaches for Rational Pharmacotherapy in Pregnancy

Abstract

Medication use during pregnancy is common, yet pregnancy-specific pharmacokinetic and fetal exposure data remain limited. Placental drug transfer is often described as a barrier phenomenon, but the placenta is better understood as a dynamic interface that integrates passive diffusion, transporter-mediated influx and efflux, placental metabolism, maternal and fetal blood flow, and fetal distribution and elimination. Maternal physiological changes alter systemic drug exposure and therefore the amount of drug presented to the placenta, while gestational maturation changes placental structure, transporter localization, and fetal clearance. Recent studies have strengthened quantitative approaches to fetal exposure prediction, particularly through integration of ex vivo human placental perfusion with maternal–fetal physiologically based pharmacokinetic (PBPK) models. Transporter-informed approaches using relative expression factors have also demonstrated the potential to predict fetal exposure for selected P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrates. At the same time, microphysiological placenta models and placenta-on-a-chip systems are being developed to address limitations of conventional trophoblast models and term placental tissue. Important uncertainties remain, including limited direct fetal concentration data, incomplete characterization of gestational-age-dependent transporter function, variability in ex vivo perfusion methodology, and uncertainty in transplacental clearance parameters. This review summarizes current evidence on the determinants of placental drug transfer, pregnancy-associated pharmacokinetic changes, placental transport and metabolism, experimental models, and computational approaches, with emphasis on how recent advances can improve mechanistic interpretation and support rational maternal pharmacotherapy while avoiding overinterpretation of predicted fetal exposure.