title: Monitoring the initial pulmonary absorption of two different beclomethasone dipropionate aerosols employing a human lung reperfusion model.
abstract: 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.
authors.affiliation: Institut für Pharmazie und Lebensmittelchemie, Bayerische Julius-Maximilians-Universität, Würzburg, Germany. freiwald@pzlc.uni-wuerzburg.de <freiwald@pzlc.uni-wuerzburg.de>
authors.forename: Matthias
authors.initials: M
authors.lastname: Freiwald
authors.forename: Anagnostis
authors.initials: A
authors.lastname: Valotis
authors.forename: Andreas
authors.initials: A
authors.lastname: Kirschbaum
authors.forename: Monika
authors.initials: M
authors.lastname: McClellan
authors.forename: Thomas
authors.initials: T
authors.lastname: Mürdter
authors.forename: Peter
authors.initials: P
authors.lastname: Fritz
authors.forename: Godehard
authors.initials: G
authors.lastname: Friedel
authors.forename: Michael
authors.initials: M
authors.lastname: Thomas
authors.forename: Petra
authors.initials: P
authors.lastname: Högger
mesh_terms: 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
chemical_list: D000336:Aerosols; D005938:Glucocorticoids; D001507:Beclomethasone
references.citation: Curr Opin Pulm Med. 2003 Jan;9(1):1-8
references.pmid: 12476077
references.citation: J Aerosol Med. 2002 Fall;15(3):283-96
references.pmid: 12396416
references.citation: Int J Pharm. 2003 Apr 14;255(1-2):175-87
references.pmid: 12672613
references.citation: J Pharm Sci. 2003 Jun;92(6):1216-33
references.pmid: 12761811
references.citation: J Allergy Clin Immunol. 2003 Sep;112(3):469-78; quiz 479
references.pmid: 13679801
references.citation: J Clin Pharmacol. 2004 Jan;44(1):37-47
references.pmid: 14681340
references.citation: Treat Respir Med. 2004;3(1):35-44
references.pmid: 15174892
references.citation: Pulm Pharmacol Ther. 2004;17(4):233-8
references.pmid: 15219268
references.citation: BMC Clin Pharmacol. 2003 Mar 19;3:1
references.pmid: 12659643
references.citation: Biopharm Drug Dispos. 1990 Jul;11(5):381-94
references.pmid: 2207292
references.citation: Biopharm Drug Dispos. 1993 Jul;14(5):455-9
references.pmid: 8218963
references.citation: Thorac Cardiovasc Surg. 1996 Jun;44(3):140-6
references.pmid: 8858797
references.citation: Cancer Res. 1997 Jun 15;57(12):2440-5
references.pmid: 9192823
references.citation: Eur Respir J. 1997 Jul;10(7):1496-9
references.pmid: 9230236
references.citation: Drug Metab Dispos. 1998 Jul;26(7):623-30
references.pmid: 9660844
references.citation: J Allergy Clin Immunol. 1998 Oct;102(4 Pt 2):S36-51
references.pmid: 9798722
references.citation: Respir Med. 1998 Jun;92 Suppl A:9-15
references.pmid: 9850358
references.citation: Eur Respir J. 1998 Dec;12(6):1346-53
references.pmid: 9877489
references.citation: Br J Clin Pharmacol. 1999 Dec;48(6):866-8
references.pmid: 10594492
references.citation: J Pharm Pharmacol. 1999 Nov;51(11):1235-40
references.pmid: 10632080
references.citation: J Control Release. 2000 Mar 1;65(1-2):43-7
references.pmid: 10699268
references.citation: Pharm Res. 2000 Aug;17(8):1007-12
references.pmid: 11028949
references.citation: J Allergy Clin Immunol. 2000 Dec;106(6):1209-26
references.pmid: 11112914
references.citation: Br J Clin Pharmacol. 2001 May;51(5):400-9
references.pmid: 11421996
references.citation: J Aerosol Med. 2001;14 Suppl 1:S9-17
references.pmid: 11424896
references.citation: Arzneimittelforschung. 2001 Oct;51(10):825-31
references.pmid: 11715635
references.citation: J Pharmacol Exp Ther. 2002 Apr;301(1):223-8
references.pmid: 11907177
references.citation: Eur J Clin Pharmacol. 2002 Jun;58(3):197-201
references.pmid: 12107606
references.citation: Chest. 2002 Aug;122(2):510-6
references.pmid: 12171824
references.citation: Respir Med. 2002 Aug;96 Suppl D:S9-15
references.pmid: 12201080
references.citation: Pediatr Pulmonol. 2003 Mar;35(3):192-9
references.pmid: 12567387