Drug Transporters Expressed in the Human Placenta and Models for Studying Maternal-Fetal Drug Transfer

Abstract

Tremendous efforts have been directed to investigate the ontogeny of drug transporters in fetuses, neonates, infants, and children based on their importance for understanding drug pharmacokinetics. During development (ie, in the fetus and newborn infant), there is special interest in transporters expressed in the placenta that modulate placental drug transfer. Many of these transporters can decrease or increase drug concentrations in the fetus and at birth, stressing the relevance of elucidating expression in the placenta and potential gestational age-dependent changes therein. Hence, the main objective of this review was to summarize the current knowledge about expression and ontogeny of transporters in the human placenta in healthy pregnant women. In addition, various in vitro, ex vivo, and in silico models that can be used to investigate placental drug transfer, namely, placental cancer cell lines, ex vivo cotyledon perfusion experiments, and physiologically based pharmacokinetic (PBPK) models, are discussed together with their advantages and shortcomings. A particular focus was placed on PBPK models because these models can integrate different types of information, such as expression data, ontogeny information, and observations obtained from the ex vivo cotyledon perfusion experiment. Such a mechanistic modeling framework may leverage the available information and ultimately help to improve knowledge about the adequacy and safety of pharmacotherapy in pregnant women and their fetuses.

Keywords: PBPK; fetal medicine; modeling and simulation; obstetrics; transporters.

Figure 1.

Expression and localization of drug transporters in the placenta. Transporters are shown as green symbols, and the arrows indicate the direction of the transport, if reported.BCRP, breast cancer resistance protein; MATE, multidrug and toxin extrusion; MRP, multidrug resistance-associated protein; OAT, organic anion transporter; OATP, organic anion transporting polypeptide; OCT, organic cation transporter; OCTN, organic cation/carnitine transporter; P-gp, P-glycoprotein.