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Quantitative Assessment of Pulmonary Targeting of Inhaled Corticosteroids Using Ex Vivo Receptor Binding Studies

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Abstract

The goal of locally acting inhaled corticosteroids is to achieve distinct pulmonary effects with reduced systemic side effects. The present work using an ex vivo receptor binding model in rats was interested in assessing pulmonary targeting for several commercially available corticosteroids by monitoring receptor occupancies in the lung and systemic organs (liver, kidney, spleen, and brain) after intravenous (IV) injection or intratracheal (IT) instillation of a dry powder administration at a dose of 100 μg/kg. Pulmonary targeting, defined as the difference in cumulative receptor occupancies (AUCE) between the lung and kidney after pulmonary delivery, differed across the investigated corticosteroids (ΔAUCE range, 33 ± 46 to 143 ± 52% *h) with the highest degree found for corticosteroids with high systemic clearance and pronounced lipophilicity (presumably allowing a long pulmonary residence time). Additionally, this study demonstrated differences in the receptor occupancies across systemic organs. Using kidney receptor occupancies as the comparator, liver receptor occupancies were reduced (ΔAUCE range: − 157 ± 43 to 178 ± 42% *h) after IV and IT administration for corticosteroids with high intrinsic clearance, while they were increased for corticosteroid prodrugs due to hepatic activation. Spleen receptor occupancies were increased after IT (ΔAUCE range: 33 ± 35 to 135 ± 28% *h), but not after IV administration. This was especially true for slowly dissolving drugs. Reduced brain uptake was also observed for ciclesonide (CIC) and des-ciclesonide (desCIC), two compounds previously not investigated. In summary, ex vivo receptor binding studies represent a powerful tool to assess the fate of ICSs.

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Abbreviations

AMs:

alveolar macrophages

AUCE :

accumulative receptor occupancy

BDP:

beclomethasone dipropionate

BMP:

17-beclomethasone monopropionate

BUD:

budesonide

CIC:

ciclesonide

CL:

systemic clearance

CLint :

hepatic intrinsic clearance

DCs:

dendritic cells

desCIC:

des-ciclesonide

FP:

fluticasone propionate

GR:

glucocorticoid receptor

ICSs:

inhaled corticosteroids

IP:

intraperitoneal

IT:

intratracheal

IV:

intravenous

logP:

log octanol-water partition coefficient

NB:

non-specific binding

PK/PD:

pharmacokinetic and pharmacodynamic

PMSF:

phenylmethylsulphonyl fluoride

P-gp:

P-glycoprotein

RBA:

relative binding affinity

Sol:

solubility in water

TA:

triamcinolone acetonide

TB:

total binding

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Funding

Financial support from 3 M, Takeda (formerly Byk-Gulden), GSK and Astra-Zeneca is acknowledged.

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Authors and Affiliations

  1. Department of Pharmaceutics, JHMHC, P3-33, College of Pharmacy, University of Florida, P.O. Box 100494, Gainesville, FL, 32610, USA

    Jie Shao, Yaning Wang & Guenther Hochhaus

  2. Alchem Laboratories Corp, Alachua, FL, USA

    James Talton

  3. Department of Statistics, University of Florida, Gainesville, FL, USA

    Lawrence Winner

Authors
  1. Jie Shao
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  2. James Talton
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Correspondence to Guenther Hochhaus.

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Electronic Supplementary Material

Figure S1:

% Receptor occupied – time profiles for BDP after systemic (IV) and pulmonary (IT) administration. Receptor occupancy in kidney was used as a reference and displayed in each figure. The mean ± SD is given. (GIF 32 kb)

Figure S2:

% Receptor occupied – time profiles for BMP after systemic (IV) and pulmonary (IT) administration. Receptor occupancy in kidney was used as a reference and displayed in each figure. The mean ± SD is given. (GIF 30 kb)

Figure S3:

% Receptor occupied – time profiles for BUD after systemic (IV) and pulmonary (IT) administration. Receptor occupancy in kidney was used as a reference and displayed in each figure. The mean ± SD is given. (GIF 39 kb)

Figure S4:

% Receptor occupied – time profiles for CIC after systemic (IV) and pulmonary (IT) administration. Receptor occupancy in kidney was used as a reference and displayed in each figure. The mean ± SD is given. (GIF 39 kb)

Figure S5:

% Receptor occupied – time profiles for desCIC after systemic (IV) and pulmonary (IT) administration. Receptor occupancy in kidney was used as a reference and displayed in each figure. The mean ± SD is given. (GIF 39 kb)

Figure S6:

% Receptor occupied – time profiles for TA after systemic (IV) and pulmonary (IT) administration. Receptor occupancy in kidney was used as a reference and displayed in each figure. The mean ± SD is given. (GIF 27 kb)

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Shao, J., Talton, J., Wang, Y. et al. Quantitative Assessment of Pulmonary Targeting of Inhaled Corticosteroids Using Ex Vivo Receptor Binding Studies. AAPS J 22, 39 (2020). https://doi.org/10.1208/s12248-019-0404-0

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