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

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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.

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Abbreviations

BCRP:

Breast cancer resistance protein

BUD:

Budesonide

CL:

Clearance

GBq:

Giga becquerel

FP:

Fluticasone propionate

f u :

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

K 0 :

Infusion rate

MRP:

Multidrug resistance protein

P-gp:

P-glycoprotein

USP:

US Pharmacopeia

Vdss :

Volume of distribution at steady state

v :

Volume

w :

Weight

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Acknowledgements

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

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Author notes

  1. Syedsaoud Zaidi and Mong-Jen Chen contributed equally to this work.

Authors and Affiliations

  1. Departments of Pharmaceutics, JHMHC, P3-33, University of Florida, 100494, Gainesville, Florida, 32610, USA

    Syedsaoud Zaidi, Mong-Jen Chen, Daniel T. Lee, Elsa Neubart & Günther Hochhaus

  2. AstraZeneca Gothenburg, 431 83, Mölndal, Sweden

    Pär Ewing & Anna Miller-Larsson

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  1. Syedsaoud Zaidi
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Correspondence to Günther Hochhaus.

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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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Zaidi, S., Chen, MJ., Lee, D.T. et al. Fetal Concentrations of Budesonide and Fluticasone Propionate: a Study in Mice. AAPS J 21, 53 (2019). https://doi.org/10.1208/s12248-019-0313-2

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