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

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.