An update on expression and function of P-gp/ABCB1 and BCRP/ABCG2 in the placenta and fetus

Abstract

P-glycoprotein (P-gp)/ABCB1 and breast cancer resistance protein (BCRP)/ABCG2 are highly expressed in the placenta and fetus throughout gestation and can modulate exposure and toxicity of drugs and xenobiotics to the vulnerable fetus during the sensitive times of growth and development. We aim to provide an update on current knowledge on placental and fetal expressions of the two transporters in different species, and to provide insight on interpreting transporter expression and fetal exposure relative to the concept of fraction of drug transported. Areas covered: Comprehensive literature review through PubMed (primarily from July 2010 to February 2018) on P-gp and BCRP expression and function in the placenta and fetus of primarily human, mouse, rat, and guinea pig. Expert opinion: While there are many commonalities in the expression and function of P-gp and BCRP in the placenta and fetal tissues across species, there are distinct differences in expression levels and temporal changes. Further studies are needed to quantify protein abundance of these transporters and functionally assess their activities at various gestational stages. Combining the knowledge of interspecies differences and the concept of fraction of drug transported, we may better predict the magnitude of impact these transporters have on fetal drug exposure.

Preclinical Transplacental Transfer and Pharmacokinetics of Fipronil in Rats

“…According to previous report, fipronil binds to fatty acid site 1 (FA1) of human serum albumin (HSA) in humans (Ascenzi et al, 2018). Moreover, the ATP-binding cassette transporters (ABC transporters) of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are abundantly expressed in the syncytiotrophoblast layers of placenta and in the fetal brain, liver, spleen and intestine throughout gestation to protect the fetus from drugs in the maternal circulation (Han et al, 2018). In the fipronil-resistant strain of Plutella xylostella larvae, ABCG2 gene is up-regulated but ABCB1 gene is down-regulated (Qi et al, 2016).…”

Placental transfer of xenobiotics in pregnancy physiologically-based pharmacokinetic models: Structure and data

“…Animal-based experimental methods are the main information supplier of placental diffusional transfer rates in pPBPK modeling studies (Tables 1 and 2), mainly as they are easy to operate with low inter-individual variation because of inbred animals, they offer to study placental transfer at different gestation ages and are whole body system which integrate the physiological changes due to pregnancy. In vivo animal data were used both in animal [50,58,79,86,128,129] and human [73,130] [131]. In humans, the structure of tissue layers which separate maternal and fetal bloods, defined by Grosser classification [132], is haemomonochorial.…”

Usage of Tacrolimus and Mycophenolic Acid During Conception, Pregnancy, and Lactation, and Its Implications for Therapeutic Drug Monitoring: A Systematic Critical Review

“…47 P-gp is highly expressed in the placenta during early gestation, and it might actively transport Tac back into the maternal circulation. 58 Zheng et al reported a venous umbilical cord Tac concentration of 6.6 ng/mL, which corresponded with 71 6 18% of the maternal blood concentration (9.0 ng/mL). The venous umbilical cord plasma to maternal plasma Tac concentration and the venous cord unbound to maternal plasma Tac concentration ratios were 0.23 (0.09 ng/mL versus 0.40 ng/mL) and 0.19 (0.003 ng/ mL versus 0.017 ng/mL), respectively.…”