Permeability characteristics of calu-3 human bronchial epithelial cells: in vitro-in vivo correlation to predict lung absorption in rats.
The goal of this study was to evaluate the permeability characteristics of Calu-3, human bronchial epithelial cells to passive and actively transported drugs and to correlate the data with other in vitro models and rat lung absorption in vivo. Air-interface cultured Calu-3 cells grown on collagen-coated permeable filter supports formed "tight" polarized and well differentiated cell monolayers with apical microvilli and tight-junctional complexes. Within 8-10 days, cell monolayers developed trans-epithelial electrical resistance (TEER) > 1000 ohm cm2 and potential difference about 11-16 mV. Solute permeability was dependent on lipophilicity, and inversely related to molecular size. Calu-3 cells actively transported amino acids, nucleosides and dipeptide analogs, but not organic anions, organic cations or efflux pump substrates. The permeability characteristics of Calu-3 cells correlated well with primary cultured rabbit tracheal epithelial cells in vitro (r2 = 0.91), and the rate of drug absorption from the rat lung in vivo (r2 = 0.94). The absorption predicted from the regression equation correlated well with observed values. In conclusion, in vitro-in vivo correlation studies indicate that the Calu-3 cell culture model is a potentially useful model to predict absorption of inhalation delivery drug candidates.
Mathia
Neil R
NR
Department of Exploratory Biopharmaceutics and Drug Delivery, Bristol-Myers, New Brunswick, NJ 08903-0191, USA. neil.mathias@bms.com
Timoszyk
Julita
J
Stetsko
Paul I
PI
Megill
John R
JR
Smith
Ronald L
RL
Wall
Doris A
DA
D000042:Absorption; D000280:Administration, Inhalation; D000465:Algorithms; D000818:Animals; D001692:Biological Transport; D001980:Bronchi / Q000166:cytology* / Q000502:physiology / Q000648:ultrastructure; D002460:Cell Line; D002463:Cell Membrane Permeability / Q000502:physiology*; D002478:Cells, Cultured; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004847:Epithelial Cells / Q000502:physiology* / Q000648:ultrastructure; D006207:Half-Life; D006801:Humans; D008168:Lung / Q000378:metabolism*; D008854:Microscopy, Electron; D018408:Patch-Clamp Techniques; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism; D051381:Rats
D004364:Pharmaceutical Preparations