British journal of clinical pharmacology, 13 2 2025 Pharmacokinetics of betamethasone in pre-eclampsia: An in vivo and ex vivo study. Schoenmakers S, Li L, Kluivers ACM, Broekhuizen M, Harhangi MS, Danser AHJ, Reiss I, Allegaert K, van den Berg SAA, van Zelst BD, van Schaik RHN, DeKoninck PLJ, Ronde E, Sassen SDT, Simons SHP, Koch BCP
Aims
To enhance understanding of betamethasone and its metabolites' pharmacokinetics in pregnancy, specifically early-onset pre-eclampsia, through a population pharmacokinetic model. Additionally, to investigate the placental metabolism and transfer of betamethasone and its main metabolites.
Methods
A prospective, single-centre pharmacokinetic study was conducted in pregnant women (n = 28) with imminent preterm birth treated with intramuscular betamethasone. Betamethasone serum concentrations were determined from serial venous blood samples (n = 194). Placental transfer and metabolism were studied using ex vivo human placental perfusion (healthy term; n = 3) and placental explant experiments (healthy term, n = 4; early-onset pre-eclampsia, n = 4). Additionally, placental mRNA expression of CYP3A4, CYP3A7, 11β-hydroxysteroid dehydrogenase (HSD) 1 and 11β-HSD2 were quantified in healthy and early-onset pre-eclampsia placentas.
Results
The population pharmacokinetic model was best described by a 2-compartment nonlinear mixed effects model. Betamethasone clearance in early-onset pre-eclamptic women was 60% lower of that observed in women without pre-eclampsia (9.35 vs. 15.78 L/h), resulting in a 40% median increase in maternal betamethasone exposure (1567 vs. 1114 ng h/mL). Ex vivo experiments showed placental transfer of betamethasone to the foetal circulation (foetal-to-maternal ratio 0.76 ± 0.05 [in a perfused placental cotyledon]). The placenta only converted betamethasone into 11-ketobetamethasone, with similar ratios in early-onset pre-eclampsia and healthy placental explants (3.0 ± 2.2 vs. 1.4 ± 0.4 per mg tissue, P = .27). The expression of 11β-HSD1 mRNA was lower in early-onset pre-eclampsia placentas (P = .015), while placental CYP3A7 and 11β-HSD2 mRNA expression were similar.
Conclusion
Women with early-onset pre-eclampsia have elevated betamethasone exposure. Betamethasone transfers freely into the foetal circulation, with placental metabolism resulting only in 11-ketobetamethasone. Decreased placental 11β-HSD1 expression may play a role in increased betamethasone exposure in early-onset pre-eclampsia.
