Methacholine delays pulmonary absorption of inhaled β2-agonists due to competition for organic cation/carnitine transporters

BackgroundThe aim of the present investigation was to compare the pulmonary absorption of the novel long-acting β2-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.MethodsIn an initial study with six lung perfusions the pharmacokinetic properties of the β2-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 β2-agonists.ResultsAs 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 β2-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.ConclusionsNebulised 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.