title: Methacholine delays pulmonary absorption of inhaled β(2)-agonists due to competition for organic cation/carnitine transporters.
abstract: BACKGROUND
  The aim of the present investigation was to compare the pulmonary absorption of the novel long-acting β(2)-agonist GW597901 with salbutamol and to determine the influence of an induced bronchoconstriction on the pharmacokinetics of the compounds using a human lung reperfusion model.
  
  
  METHODS
  In an initial study with six lung perfusions the pharmacokinetic properties of the β(2)-agonists were determined. We then investigated the influence of an induced bronchoconstriction on the pulmonary absorption in six lung lobes for each drug. Therefore, methacholine (MCh) challenge agent was nebulised prior to administration of the β(2)-agonists.
  
  
  RESULTS
  As expected, the extent of pulmonary absorption of salbutamol into the perfusate was more pronounced than for the more lipophilic GW597901. Although the observed differences were not statistically significant they were further supported by analysis of tissue concentrations. In contrast, we observed a statistically significant influence of the bronchoprovocation with MCh on the pulmonary absorption of both β(2)-agonists, but this effect was not limited to a successfully induced bronchoconstriction. A prominent decline of salbutamol distribution into perfusion fluid was also observed when the organic cation transporter substrate carnitine was nebulised prior to the bronchodilator.
  
  
  CONCLUSIONS
  Nebulised methacholine had a significant influence on the pharmacokinetics of bronchodilators. Since we observed this effect independently of a successfully induced bronchoconstriction and also after nebulisation of carnitine we suggest a significant delay of pulmonary absorption of inhaled salbutamol and GW597901 due to competition for a cation/carnitine drug transporter, most likely OCTN2.
authors.affiliation: Universität Würzburg, Institut für Pharmazie und Lebensmittelchemie, Am Hubland, 97074 Würzburg, Germany.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Gnadt
authors.forename: Beatrice
authors.initials: B
authors.lastname: Trammer
authors.forename: Matthias
authors.initials: M
authors.lastname: Freiwald
authors.forename: Boris
authors.initials: B
authors.lastname: Kardziev
authors.forename: Martin K
authors.initials: MK
authors.lastname: Bayliss
authors.forename: Chris D
authors.initials: CD
authors.lastname: Edwards
authors.forename: Michael
authors.initials: M
authors.lastname: Schmidt
authors.forename: Godehard
authors.initials: G
authors.lastname: Friedel
authors.forename: Petra
authors.initials: P
authors.lastname: Högger
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000493:pharmacokinetics*; D000328:Adult; D000336:Aerosols; D000368:Aged; D000420:Albuterol / Q000493:pharmacokinetics; D000465:Algorithms; D019540:Area Under Curve; D001667:Binding, Competitive / Q000187:drug effects; D016084:Bronchoconstriction / Q000187:drug effects; D016085:Bronchoconstrictor Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002331:Carnitine / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D016210:Methacholine Chloride / Q000008:administration & dosage / Q000494:pharmacology*; D008875:Middle Aged; D027701:Organic Cation Transport Proteins / Q000187:drug effects / Q000378:metabolism*; D010477:Perfusion; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D000336:Aerosols; D016085:Bronchoconstrictor Agents; D007202:Indicators and Reagents; D027701:Organic Cation Transport Proteins; D016210:Methacholine Chloride; D000420:Albuterol; D002331:Carnitine