Abstract
PurposeTo evaluate the ability of human airway epithelial cell layers and a simple rat isolated perfused lung (IPL) model to predict pulmonary drug absorption in rats in vivo.MethodThe permeability of seven compounds selected to possess a range of lipophilicity was measured in two airway cell lines (Calu-3 and 16HBE14o-), in normal human bronchial epithelial (NHBE) cells and using a simple isolated perfused lungs (IPL) technique. Data from the cell layers and ex vivo lungs were compared to published absorption rates from rat lungs measured in vivo.ResultsA strong relationship was observed between the logarithm of the in vivo absorption half-life and the absorption half-life in the IPL (r = 0.97; excluding formoterol). Good log-linear relationships were also found between the apparent first-order absorption rate in vivo and cell layer permeability with correlation coefficients of 0.92, 0.93, 0.91 in Calu-3, 16HBE14o- and NHBE cells, respectively.ConclusionThe simple IPL technique provided a good prediction of drug absorption from the lungs, making it a useful method for empirical screening of drug absorption in the lungs. Permeability measurements were similar in all the respiratory epithelial cell models evaluated, with Calu-3 having the advantage for routine permeability screening purposes of being readily availability, robust and easy to culture.
Highlights
The rate and extent of absorption of inhaled drugs are determined by the relative rates of the different clearance mechanisms that operate in the lungs [1,2,3]
Methods have been optimized for culturing 16HBE14o- cells [11,12] and Calu-3 cells [13,14,15] such that they exhibit epithelial barrier-like properties, and the permeability of a wide variety of compounds has been measured in these cell layers in different laboratories [4]
The data were analysed using the approach of Tronde et al [19] for simplicity and to enable comparison with the published data. This approach includes an assumption of first order kinetics, the full cumulative absorptive transfer profile is not utilized for compounds which do not reach a plateau in 90 min, the KaIPL parameter may be misleading
Summary
The rate and extent of absorption of inhaled drugs are determined by the relative rates of the different clearance mechanisms that operate in the lungs [1,2,3]. As drug permeability in the lungs has been proposed recently to be a key factor in a biopharmaceutical classification system being developed for inhaled compounds (iBCS; [6]), the validation of screening techniques for predicting absorptive clearance from the lungs is of high importance. The drug permeability in Calu-3 [16] and 16HBE14o- cells [17] has been correlated with absorption from the lungs in vivo and ex vivo, respectively. These models have been evaluated individually, to date the permeability of solutes in the two cell lines has not been compared directly or matched to permeability in primary normal human bronchial epithelial cells
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
