Drug Absorption from the Isolated Perfused Rat Lung–Correlations with Drug Physicochemical Properties and Epithelial Permeability

Abstract

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 10 000 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 (kalung) was found to correlate to the apparent permeability (Papp) 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 kalung) from the descriptors log Papp, %PSA and cLog D(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.