Purpose: Inhaled corticosteroids (ICSs) are widely used for the treatment of asthma. Through the inhalation route glucocorticoids are directly delivered to the target organ with the aim to achieve distinct pulmonary effect while reducing systemic side effects. Although the efficacy and safety of ICSs have been widely investigated, no studies have evaluated and compared their pulmonary selectivity with systemic organs throughout the body. The present research was to evaluate the pulmonary selectivity of fluticasone propionate (FP), which is widely used as a dry powder inhaler for the treatment of asthma. FP possesses favorable pharmacokinetic properties for pulmonary targeting, such as low oral bioavailability and high systemic clearance. In the present study we quantified pulmonary targeting of FP using the ex-vivo receptor binding assay after systemic and pulmonary delivery in rats.
Methods: FP were given to rats via intravenous (IV) injection of a solution or by intratracheal (IT) instillation of a suspension of micronized powders at doses of 100 µg/kg. Free glucocorticoid receptors were monitored over time in lung, liver, kidney, spleen and brain using an ex-vivo receptor binding assay. The accumulative receptor occupancy change from baseline (AUCE) was calculated to assess differential receptor occupancy between lung and systemic organs. Pulmonary targeting was defined as AUCE difference between lung and a reference systemic organ. Statistical analysis were performed to compare the receptor occupancy differences between organs after IV or IT administration of FP.
Results: After intravenous administration, the receptor occupancies across tissues were not identical (Figure A). Significantly lower receptor occupancy in brain than that in lung was observed, indicating transporters played a role in modulating the permeability of FP. Surprisingly, hepatic receptor occupancy was significantly smaller, which was not expected. So when the high intrinsic hepatic clearance of FP is considered, the observed lower liver receptor occupancy is understandable. Upon intratracheal administration of FP (Figure B), higher pulmonary receptor occupancy than other systemic organs could be expected because of slow absorption of pulmonary - delivered FP. A clear pulmonary targeting was shown when lung receptor occupancy was compared with that of kidney. Interestingly, similar levels of receptor occupancy were observed in lung and spleen, suggesting FP was moved from lung to spleen through the migration of macrophages after IT instillation of the FP suspension. Considering all the results above, kidney is suggested as a proper reference organ in the system. Thus, FP is a pulmonary targeted drug after IT administration.
Conclusion: Our study could show that receptor occupancies vary in tissues because of pharmacokinetic events, such as transporter, enzymes, and cell trafficking. Furthermore, the present study provides a quantitative assessment of pulmonary targeting of inhaled corticosteroids.