The endothelin receptor antagonist aprocitentan transfers across the human placental barrier.

The fetal levels of aprocitentan at steady state were insufficient to block endothelin-1-induced constriction.

Since not all aprocitentan could be recovered following cotyledon perfusion when considering tissue and the maternal and fetal perfusion fluids, its presence in the intervillous space should also be taken into account.

The vasoconstrictor endothelin-1 is elevated in preeclampsia, making endothelin receptor antagonists (ERAs) a logical therapeutic strategy. Here we evaluated the placental transfer of the novel ERA aprocitentan, which has recently been approved for hypertension treatment.

Dual-sided placental cotyledon perfusion was used to study transfer of aprocitentan, added maternally at a clinically relevant concentration of 150 ng/mL. Subsequently, these placentas were fetally exposed to endothelin-1. Antipyrine, which freely transfers to the fetal compartment, and fluorescein isothiocyanate [FITC]-dextran, which does not transfer, were used as comparator substances.

After 3 h of perfusion, the fetal-to-maternal ratio for total (free + protein-bound) aprocitentan was 0.25 ± 0.04, while for free aprocitentan it was 0.42 ± 0.08. The fetal aprocitentan concentrations were too low to block the contractile effects of endothelin-1 in the fetal compartment, although experiments in isolated chorionic plate arteries confirmed that aprocitentan can block these effects when given at higher concentrations. After perfusion, 50–60% of aprocitentan was recovered in the maternal and fetal fluid compartments. Around 20–30% was present in tissue, as intact aprocitentan or as its hydrolysis product ACT-080803. Since the recovery of maternally applied antipyrine and FITC-dextran was 85–90%, while fetally applied FITC-dextran was fully recovered, the missing 10–15% is likely present in the intervillous space.

Aprocitentan transfers across the human placental barrier, although its fetal levels following maternal application of 150 ng/mL were insufficient to block endothelin-1. Drug studies in isolated cotyledons should consider the intervillous space when calculating recovery.

Endothelin-receptor antagonist

Aprocitentan

Preeclampsia

Placental perfusion

endothelin receptor antagonist

fluorescein isothiocyanate

concentration–response curve

© 2026 The Author(s). Published by Elsevier B.V. on behalf of International Society for the Study of Hypertension in Pregnancy.