Methacholine delays pulmonary absorption of inhaled ß(2)-agonists due to competition for organic cation/carnitine transporters.

BACKGROUND: The aim of the present investigation was to compare the pulmonary absorption of the novel long-acting ß(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 ß(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 ß(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 ß(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.

Comparative permeability and diffusion kinetics of cyclosporine A liposomes and propylene glycol solution from human lung tissue into human blood ex vivo.

Aerolized cyclosporine A (CsA) has been successfully used for prevention of organ rejection in lung transplant recipients. Various formulations of CsA are available and so far no direct comparison of their pharmacokinetics has been performed. Since clinical studies are elaborate, we sought a way to predict the kinetic behaviour of a propylene glycol solution of CsA (CsA-PG) and a liposomal formulation (L-CsA). The permeability across the human bronchial cell line Calu-3 revealed low permeability for CsA with the apparent permeability for CsA-PG being twice as high as for L-CsA. Employing a previously described dialysis model, the diffusion of CsA from human lung tissue into human blood was determined ex vivo. Consistent with the cell culture model results, we observed that the degree and rate of drug transfer into human blood was more pronounced for CsA-PG than for L-CsA with the area under the curve (AUC) of CsA-PG being about 1.6 times higher than for the L-CsA formulation. The diffusion rate was more than 50% higher from CsA-PG than from the liposomes. To conclude, both model systems consistently revealed that L-CsA displayed clearly a prolonged release effect and favourable longer tissue retention than CsA-PG.

Comparison of the bronchodilating effects of inhaled ß2-agonists after methacholine challenge in a human lung reperfusion model.

The aim of the present investigation was to compare the onset of action and intrinsic activity of the long-acting ß(2)-agonist GW597901 with the fast- and short-acting salbutamol as model compounds using an isolated human lung reperfusion model. Twelve resected human lung lobes were challenged with methacholine (MCh) and subsequently nebulised with either GW597901 or salbutamol. Prostaglandin E(2) (PGE(2)) concentrations in the perfusion fluid were compared with the dose of MCh that was required to induce a bronchoconstriction. After successful MCh provocation, nebulisation of GW597901 and salbutamol fully reversed any observed bronchoconstriction. The bronchodilating effect was more pronounced for GW597901. Salbutamol revealed an immediate onset of action while the effect of GW597901 was observed with an approximate delay of 6 min. Higher doses of MCh were required for a successful bronchial challenge in the presence of elevated PGE(2) levels (r=0.8171, p ≤ 0.05). For the first time, an isolated perfused human lung model has been established for comparing the onset of action and potency of a short- and long-acting ß(2)-agonist. We therefore conclude that it is an alternative for determination of drug effect characteristics and suitable for supplementing or predicting clinical data.