RESEARCH PAPERA Comparison of Drug Transport in Pulmonary AbsorptionModels: Isolated Perfused rat Lungs, Respiratory EpithelialCell Lines and Primary Cell CultureCynthia Bosquillon 1 & Michaela Madlova 2,3 & Nilesh Patel 4 & Nicola Clear 5 & Ben Forbes 2Received: 7 April 2017 /Accepted: 24 August 2017 /Published online: 18 September 2017# The Author(s) 2017. This article is an open access publicationABSTRACTPurpose To evaluate the ability of human airway epithelialcell layers and a simple rat isolated perfused lung (IPL) modelto predict pulmonary drug absorption in rats in vivo.Method The permeability of seven compounds selected topossess a range of lipophilicity was measured in two airwaycell lines (Calu-3 and 16HBE14o-), in normal human bron-chial epithelial (NHBE) cells and using a simple isolated per-fused lungs (IPL) technique. Data from the cell layers andex vivo lungs were compared to published absorption ratesfrom rat lungs measured in vivo.Results A strong relationship was observed between the log-arithm of the in vivo absorption half-life and the absorptionhalf-life in the IPL (r = 0.97; excluding formoterol). Goodlog-linear relationships were also found between the apparentfirst-order absorption rate in vivo and cell layer permeabilitywith correlation coefficients of 0.92, 0.93, 0.91 in Calu-3,16HBE14o- and NHBE cells, respectively.Conclusion The simple IPL technique provided a good pre-diction of drug absorption from the lungs, making it a usefulmethod for empirical screening of drug absorption in thelungs. Permeability measurements were similar in all the re-spiratory epithelial cell models evaluated, with Calu-3 havingthe advantage for routine permeability screening purposes ofbeing readily availability, robust and easy to culture.KEY WORDS 16HBE14o- . biopharmaceutics . calu-3 .inhalation . isolatedperfusedlungs(IPL) . NHBE . permeability .pulmonaryABBREVIATIONSAAPS American association of pharmaceutical scientistsP app Apparent permeability coefficientBEGM Bronchial epithelial cell growth mediumDMEM Dulbecco’s modified eagle’s mediumFDA Food and drug administrationHBSS Hank’s balanced salt solutionIPL Isolated perfused lungsiBCS Inhalation biopharmaceutical classification systemMEM Minimum essential mediumMW Molecular weightNHBE Normal human bronchial epithelialQSAR Quantitative structure activity relationshipTER Transepithelial electrical resistanceUSP United States pharmacopoeiaINTRODUCTIONThe rate and extent of absorption of inhaled drugs are deter-mined by the relative rates of the different clearance mecha-nisms thatoperateinthe lungs[1–3].Clearance byabsorptivetransfer from the lung lumen is predominately controlled bythe epithelial permeability of free (unbound) drug. Althoughin vitro epithelial cell culture [4] and ex vivo lung methods [5]are available to screen the permeability of drug candidates fordevelopment as orally inhaled products, there is no standardexperimental method for measuring drug permeability orpredicting lung absorption [2]. As drug permeability in the* Ben Forbesben.forbes@kcl.ac.uk1School of Pharmacy, University of Nottingham, Boots ScienceBuilding, University Park, Nottingham NG7 2RD, UK2King′s College London, Pharmaceutical Science Division, Franklin-WilkinsBuilding, 150 Stamford Street, London SE1 9NH, UK3Faculty of Pharmacy, Charles University in Prague, HradecKralove, Czech Republic4School of Pharmacy, University of Reading, Whiteknights, Reading RG66AP, UK5Pfizer R&D, Sandwich, Kent CT13 9NJ, UKPharm Res (2017) 34:2532–2540DOI 10.1007/s11095-017-2251-y
