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The AAPS Journal

, 21:53 | Cite as

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

  • Syedsaoud Zaidi
  • Mong-Jen Chen
  • Daniel T. Lee
  • Elsa Neubart
  • Pär Ewing
  • Anna Miller-Larsson
  • Günther HochhausEmail author
Research Article
  • 51 Downloads

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 [3H]-BUD or a high dose of [3H]-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 [3H]-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.

KEY WORDS

placental drug transporters P-gp budesonide fluticasone propionate 

Abbreviations

BCRP

Breast cancer resistance protein

BUD

Budesonide

CL

Clearance

GBq

Giga becquerel

FP

Fluticasone propionate

fu

Free, protein unbound fraction of drug in plasma or tissue

HPLC

High-performance liquid chromatography

ICS

Inhaled corticosteroid

K(tissue, plasma, u, u)

Free (protein unbound) drug concentration ratio of tissue to maternal blood plasma

K0

Infusion rate

MRP

Multidrug resistance protein

P-gp

P-glycoprotein

USP

US Pharmacopeia

Vdss

Volume of distribution at steady state

v

Volume

w

Weight

Notes

Acknowledgements

The financial support of AstraZeneca to the University of Florida is acknowledged.

Compliance with Ethical Standards

Conflict of Interest

SZ, M-JC, DTL, and EN have no conflicts of interest to disclose. PE is an employee of AstraZeneca. AM-L was an employee of AstraZeneca at the time of the study. GH has no conflict of interest.

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Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Syedsaoud Zaidi
    • 1
  • Mong-Jen Chen
    • 1
  • Daniel T. Lee
    • 1
  • Elsa Neubart
    • 1
  • Pär Ewing
    • 2
  • Anna Miller-Larsson
    • 2
  • Günther Hochhaus
    • 1
    Email author
  1. 1.Departments of Pharmaceutics, JHMHC, P3-33University of FloridaGainesvilleUSA
  2. 2.AstraZeneca GothenburgMölndalSweden

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