Active transport across the human placenta: impact on drug efficacy and toxicity

Abstract

The human placenta expresses a large number of transport proteins. The ATP-binding cassette (ABC) family of active efflux pumps, predominantly localised to the maternal-facing syncytial membrane of placental microvilli, comprise the major placental drug efflux transporters. A variety of other transporters are also expressed in the placenta that can facilitate xenobiotic transfer in both the maternal and fetal directions. Many drugs administered in pregnancy are ABC transporter substrates, and many are either teratogenic or fetotoxic. The invitro, invivo and clinical evidence reviewed in this article argues that active efflux of drugs by placental transporters helps to maintain its barrier function, reducing the incidence of adverse fetal effects. ABC transporter polymorphisms may explain the wide variability observed in fetal drug concentrations, incidence of teratogenesis or drug failure in pregnancies exposed to therapeutic agents. Although our understanding of the molecular mechanics and dynamics of placental drug transfer is advancing, much work is needed to fully appreciate the significance of placental drug transporters in the face of increasing drug administration in pregnancy.

Keywords::

• active transport
• ATP-binding cassette
• breast cancer-resistance protein
• drug transport
• efflux pump
• monoamine transporter
• multi-drug resistance protein
• organic anion transporter
• organic anion transporter polypeptide
• organic cation transporter
• P-glycoprotein
• placenta
• polymorphisms
• pregnancy
• syncytiotrophoblast
• teratogenesis

Acknowledgements

The helpful comments of G Reid, Genesis Research and Development Corporation Ltd, are gratefully acknowledged. DEvseenko is a recipient of a Bright Futures Doctoral Scholarship from the Tertiary Education Commission of New Zealand.