Monitoring the initial pulmonary absorption of two different beclomethasone dipropionate aerosols employing a human lung reperfusion model.
BACKGROUND
The pulmonary residence time of inhaled glucocorticoids as well as their rate and extend of absorption into systemic circulation are important facets of their efficacy-safety profile. We evaluated a novel approach to elucidate the pulmonary absorption of an inhaled glucocorticoid. Our objective was to monitor and compare the combined process of drug particle dissolution, pro-drug activation and time course of initial distribution from human lung tissue into plasma for two different glucocorticoid formulations.


METHODS
We chose beclomethasone dipropionate (BDP) delivered by two different commercially available HFA-propelled metered dose inhalers (Sanasthmax/Becloforte and Ventolair/Qvar). Initially we developed a simple dialysis model to assess the transfer of BDP and its active metabolite from human lung homogenate into human plasma. In a novel experimental setting we then administered the aerosols into the bronchus of an extracorporally ventilated and reperfused human lung lobe and monitored the concentrations of BDP and its metabolites in the reperfusion fluid.


RESULTS
Unexpectedly, we observed differences between the two aerosol formulations Sanasthmax/Becloforte and Ventolair/Qvar in both the dialysis as well as in the human reperfusion model. The HFA-BDP formulated as Ventolair/Qvar displayed a more rapid release from lung tissue compared to Sanasthmax/Becloforte. We succeeded to explain and illustrate the observed differences between the two aerosols with their unique particle topology and divergent dissolution behaviour in human bronchial fluid.


CONCLUSIONS
We conclude that though the ultrafine particles of Ventolair/Qvar are beneficial for high lung deposition, they also yield a less desired more rapid systemic drug delivery. While the differences between Sanasthmax/Becloforte and Ventolair/Qvar were obvious in both the dialysis and lung perfusion experiments, the latter allowed to record time courses of pro-drug activation and distribution that were more consistent with results of comparable clinical trials. Thus, the extracorporally reperfused and ventilated human lung is a highly valuable physiological model to explore the lung pharmacokinetics of inhaled drugs.
Freiwald
Matthias
M
Institut für Pharmazie und Lebensmittelchemie, Bayerische Julius-Maximilians-Universität, Würzburg, Germany. freiwald@pzlc.uni-wuerzburg.de <freiwald@pzlc.uni-wuerzburg.de>
Valotis
Anagnostis
A
Kirschbaum
Andreas
A
McClellan
Monika
M
Mürdter
Thomas
T
Fritz
Peter
P
Friedel
Godehard
G
Thomas
Michael
M
Högger
Petra
P
D000042:Absorption; D000336:Aerosols / Q000008:administration & dosage / Q000493:pharmacokinetics; D001507:Beclomethasone / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D003198:Computer Simulation; D003956:Dialysis; D005938:Glucocorticoids / Q000008:administration & dosage / Q000493:pharmacokinetics; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008168:Lung / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D008991:Monitoring, Physiologic / Q000379:methods; D015424:Reperfusion / Q000379:methods
D000336:Aerosols; D005938:Glucocorticoids; D001507:Beclomethasone
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