The pulmonary absorption of nine low-molecular-weight (225-430 Da) drugs (atenolol, budesonide, enalaprilat, enalapril, formoterol, losartan, metoprolol, propranolol and terbutaline) and one high-molecular-weight membrane permeability marker compound (FITC-dextran 10000 Da) was investigated using the isolated, perfused and ventilated rat lung (IPL). The relationships between pulmonary transport characteristics, epithelial permeability of Caco-2 cell monolayers and drug physicochemical properties were evaluated using multivariate data analysis. Finally, an in vitro-in vivo correlation was made using in vivo rat lung absorption data. The absorption half-life of the investigated drugs ranged from 2 to 59 min, and the extent of absorption from 21 to 94% in 2 h in the isolated perfused rat lung model. The apparent first-order absorption rate constant in IPL (ka(lung)) was found to correlate to the apparent permeability (P(app)) of Caco-2 cell monolayers (r = 0.87), cLog D(7.4) (r = 0.70), cLog P, and to the molecular polar surface area (%PSA) (r = -0.79) of the drugs. A Partial Least Squares (PLS)-model for prediction of the absorption rate (log ka(lung)) from the descriptors log P(app), %PSA and cLogD(7.4) was found (Q2 = 0.74, R2 = 0.78). Furthermore, a strong in vitro-in vivo correlation (r = 0.98) was found for the in vitro (IPL) drug absorption half-life and the pulmonary absorption half-life obtained in rats in vivo, based on a sub-set of five compounds.

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The actions of and interaction between formoterol and salmeterol were studied on guinea-pig trachea in vitro. Tracheal strip preparations were contracted by 1 mumol/l carbachol giving a near maximal contraction. Salmeterol in concentrations from 0.1 to 3 mumol/l relaxed the tracheal smooth muscle by about 30 per cent of the maximum relaxation produced by theophylline. Formoterol caused a concentration-dependent and almost complete relaxation with a pD2 of 8.56. In the presence of salmeterol there was a rightward shift of the concentration-response curve for formoterol. The pA2 for salmeterol was estimated to 7.42. Similar experiments with isoprenaline indicated that salmeterol has a low affinity for beta 1-adrenoceptors. Formoterol and salmeterol both inhibited in a concentration-dependent manner the contractions evoked by stimulation of the vagus nerve in a tracheal tube preparation. The degree of inhibition decreased with increasing stimulation frequency. Complete inhibition was attained with salmeterol, but not with formoterol, at the highest frequency employed (45 Hz). The inhibiting effect of 10 mumol/l salmeterol was not blocked by 10 mumol/l sotalol, a beta-adrenoceptor antagonist. It is concluded that salmeterol, in comparison to formoterol, is a partial beta 2-adrenoceptor agonist and has, at high concentrations, an additional unspecific inhibitory action.

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