In-vitro respiratory drug absorption models possess nominal functional P-glycoprotein activity.
OBJECTIVE
The P-glycoprotein (P-gp) efflux pump is known to be present within several major physiological barriers including the brain, kidney, intestine and placenta. However, the function of P-gp in the airways of the lung is unclear. The purpose of this study was to use the highly specific P-gp inhibitor GF120918A to investigate the activity of the P-gp transporter in the airways to determine whether P-gp could influence inhaled drug disposition.


METHODS
P-gp activity was measured as a change in digoxin transport in the presence of GF120918A in normal human bronchial epithelial (NHBE) cells, Calu-3 cell layers and the ex-vivo rat lung.


RESULTS
The efflux ratios (ERs) in NHBE and Calu-3 cells were between 0.5 and 2, in contrast to 10.7 in the Caco-2 cell control. These low levels of GF120918A-sensitive polarised digoxin transport were measured in the absorptive direction in NHBE cells (ER = 0.5) and in the secretory direction in Calu-3 cells (ER = 2), but only after 21 days in culture for both cell systems and only in Calu-3 cells at passage > 50. The airspace to perfusate transfer kinetics of digoxin in the ex-vivo rat lung were unchanged in the presence of GF120918A.


CONCLUSIONS
These results demonstrated that although low levels of highly culture-dependent P-gp activity could be measured in cell-lines, these should not be interpreted to mean that P-gp is a major determinant of drug disposition in the airways of the lung.
Madlova
Michaela
M
Pharmaceutical Science Division, King's College London, London, UK.
Bosquillon
Cynthia
C
Asker
Dan
D
Dolezal
Pavel
P
Forbes
Ben
B
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000166:Acridines / Q000494:pharmacology; D000280:Administration, Inhalation; D000818:Animals; D001692:Biological Transport; D001980:Bronchi / Q000166:cytology / Q000378:metabolism; D018938:Caco-2 Cells; D002478:Cells, Cultured; D004077:Digoxin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D051381:Rats; D017208:Rats, Wistar; D044005:Tetrahydroisoquinolines / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D044005:Tetrahydroisoquinolines; D004077:Digoxin; C083501:Elacridar