An update on placental drug transport and its relevance to fetal drug exposure

Abstract

Pregnant women are often complicated with diseases that require treatment with medication. Most drugs administered to pregnant women are off-label without the necessary dose, efficacy, and safety information. Knowledge concerning drug transfer across the placental barrier is essential for understanding fetal drug exposure and hence drug safety and efficacy to the fetus. Transporters expressed in the placenta, including adenosine triphosphate (ATP)-binding cassette efflux transporters and solute carrier uptake transporters, play important roles in determining drug transfer across the placental barrier, leading to fetal exposure to the drugs. In this review, we provide an update on placental drug transport, including in vitro cell/tissue, ex vivo human placenta perfusion, and in vivo animal studies that can be used to determine the expression and function of drug transporters in the placenta as well as placental drug transfer and fetal drug exposure. We also describe how the knowledge of placental drug transfer through passive diffusion or active transport can be combined with physiologically based pharmacokinetic modeling and simulation to predict systemic fetal drug exposure. Finally, we highlight knowledge gaps in studying placental drug transport and predicting fetal drug exposure and discuss future research directions to fill these gaps.

Changes in Expression and Function of Placental and Intestinal P-gp and BCRP Transporters during Pregnancy

“…Those Abcg2 knock-out mice which are treated with glyburide and nitrofurantoin also have higher fetal exposure than the wild-type mice. Furthermore, giving P-gp or BCRP inhibitors to the mother, the placental P-gp or BCRP activity is suppressed [91,94,95]. Lankas et al exposed P-gp (−/−) knock-out pregnant mice to an 8,9 Z photoisomer of avermectin (L-652,280), which is a teratogen.…”

Fetus Exposure to Drugs and Chemicals: A Holistic Overview on the Assessment of Their Transport and Metabolism across the Human Placental Barrier

“…During recent decades, there has been increased research refuting the theory that the uterus provides a protected environment for the fetus, which is mainly attributed to the placental barrier [ 10 , 11 ]. The above process requires enhanced caution worldwide, as pregnant women and their developing fetuses are at risk of exposure to diverse drugs and chemicals like environmental pollutants and pesticides [ 12 ]. In this aspect, developmental toxicology data are systematically utilized for the prioritization and screening of drugs and chemicals, for the assessment and labeling of drugs, and for describing hazards and risks of exposure to industrial and environmental chemicals [ 12 , 13 ].…”

“…The above process requires enhanced caution worldwide, as pregnant women and their developing fetuses are at risk of exposure to diverse drugs and chemicals like environmental pollutants and pesticides [ 12 ]. In this aspect, developmental toxicology data are systematically utilized for the prioritization and screening of drugs and chemicals, for the assessment and labeling of drugs, and for describing hazards and risks of exposure to industrial and environmental chemicals [ 12 , 13 ]. Notably, during the initial weeks of gestation, women do not necessarily know they are pregnant and therefore do not worry about their gestational state; however, this may result in unintended exposure to diverse toxic xenobiotic compounds.…”

“…There are also additional risk factors of exposure, including certain lifestyle factors, such as smoking, the use of daily care products, alcohol intake, and recreational drugs, together with environmental pollutants, pesticides, heavy metals, and other synthetic compounds [ 10 , 11 ]. Moreover, fetal treatment through maternal drug administration is even more frequently employed, such as the retroviral treatment received by pregnant women with HIV [ 12 , 13 ]. Notably, nanomedicine constitutes an exceptional opportunity to target and support drug delivery to the reproductive system and other relevant organs in both the mother and fetus, and it can effectively improve xenobiotics’ safety profile and minimize side effects [ 15 ].…”

Efflux Transporters in Drug Disposition During Pregnancy

“…Equally important, the in vitro and in vivo models and assays developed in his lab and utilized in his work serve as a guide enabling other labs and young investigators to set up reproducible methodologies for conducting transporter research. Dr. Mao also wrote several critical and comprehensive reviews to summarize the knowledge gaps and better assist other researchers to pursue further research in this field(Mao and Unadkat, 2015;Mao and Chen, 2022).Dr. Mao was an avid, enthusiastic, and devoted researcher with an incredible work ethic.…”