Fetal Concentrations of Budesonide and Fluticasone Propionate: a Study in Mice

Abstract

The study goal was to evaluate the transplacental transfer of two corticosteroids, budesonide (BUD) and fluticasone propionate (FP), in pregnant mice and investigate whether P-glycoprotein (P-gp) might be involved in reducing BUD transplacental transfer. Pregnant mice (N = 18) received intravenously either low (104.9 μg/kg) or high (1049 μg/kg) dose of [ 3 H]-BUD or a high dose of [ 3 H]-FP (1590 μg/kg). In a separate experiment, pregnant mice (N = 12) received subcutaneously either the P-gp inhibitor zosuquidar (20 mg/kg) or vehicle, followed by an intravenous infusion of [ 3 H]-BUD (104.9 μg/kg). Total and free (protein unbound) corticosteroid concentrations were determined in plasma, brain, fetus, placenta, kidney, and liver. The ratios of free BUD concentrations in fetus versus plasma K (fetus, plasma, u, u) 0.42 ± 0.17 (mean ± SD) for low-dose and 0.38 ± 0.18 for high-dose BUD were significantly different from K = 1 (P < 0.05), contrary to 0.87 ± 0.25 for FP, which was moreover significantly higher than that for matching high-dose BUD (P < 0.01). The BUD brain/plasma ratio was also significantly smaller than K = 1, while these ratios for other tissues were close to 1. In the presence of the P-gp inhibitor, K (fetus, plasma, u, u) for BUD (0.59 ± 0.16) was significantly increased over vehicle treatment (0.31 ± 0.10; P < 0.01). This is the first in vivo study demonstrating that transplacental transfer of BUD is significantly lower than FP's transfer and that placental P-gp may be involved in reducing the fetal exposure to BUD. The study provides a mechanistic rationale for BUD's use in pregnancy.

Benefit:Risk Profile of Budesonide in Obstructive Airways Disease

“…Data from large-scale retrospective studies have shown that treatment with anti-asthmatic medications can increase the risk of pregnancy complications and low infant birth weight [147, 148], although budesonide-specific data have not shown a significant increase in congenital malformations [39, 149]. A study in pregnant mice showed less transplacental transfer of free budesonide than of free FP [150]. This appeared to depend on the lower lipophilicity of budesonide and the fact that, as a substrate for P-glycoprotein, budesonide can be transported out of the placenta and brain.…”