Glucocorticoids modulate drug transporter function in human fetal brain endothelial cells

Synthetic glucocorticoid (sGC) may be administered to women throughout gestation. Animal studies have shown that sGC can modulate the function of key blood–brain barrier (BBB) drug transporters P‐glycoprotein (P‐gp; encoded by ABCB1 ) and breast cancer resistance protein (BCRP; ABCG2 ). The endogenous glucocorticoid cortisol is also key to fetal BBB maturation. The effect of sGC and cortisol on drug transporter function in the developing human BBB is not known. We aimed to determine the effect of exposure to sGC (dexamethasone) and cortisol on drug transporter function and expression in the fetal human BBB. We isolated primary human fetal brain endothelial cells (hfBECs) at early and mid‐gestation for culture and treatment with glucocorticoids, in vitro . P‐gp and BCRP efflux activity were increased by dexamethasone and cortisol exposure, in a time‐ and dose‐dependent manner, with greater relative increases in mid‐gestation than in early gestation hfBECs. Dexamethasone had a greater positive effect on transporter activity than cortisol. Dexamethasone exposure increased P‐gp and BCRP protein levels in early gestation hfBECs but not in mid‐gestation hfBECs. Selective activation of the xenobiotic sensor pregnane X receptor (a receptor for sGC) by hyperforin did not completely recapitulate the effect of dexamethasone on transporter activity. We conclude that glucocorticoid increases the activity of P‐gp and BCRP in hfBECs in a time‐, dose‐ and age‐dependent manner, possibly via a non‐genomic pathway. Our findings highlight the potential for aberrant glucocorticoid levels during gestation to dysregulate P‐gp and BCRP substrate passage across the BBB and into the developing brain, which may disrupt neurodevelopment. image Key points We have previously shown that glucocorticoids modify the function of key drug transporters P‐glycoprotein and breast cancer resistance protein at the fetal blood–brain barrier in animal models. In this study, we used a novel model of the human fetal blood–brain barrier to show that cortisol and the synthetic glucocorticoid dexamethasone cause age‐specific increases in P‐glycoprotein and breast cancer resistance protein efflux activity. Changes in efflux activity were not accompanied by changes in mRNA levels, suggesting a non‐genomic mechanism by which glucocorticoids modify transporter function. The effect of dexamethasone on drug transporter efflux activity is mediated through a combination of glucocorticoid receptor and pregnane X receptor signalling. Our findings highlight the potential for glucocorticoid exposure to alter the transport of key substrates across the fetal blood–brain barrier.