title: Lack of difference in pulmonary absorption of digoxin, a P-glycoprotein substrate, in mdr1a-deficient and mdr1a-competent mice.
abstract: Although in-vitro experiments have suggested that P-glycoprotein (P-gp) may have an important influence on the disposition of inhaled drugs, the effect of P-gp on absorption from the lung in-vivo has not been reported previously. The aim of this study was to compare the pulmonary absorption of digoxin, a well-characterised substrate for P-gp, in mdr1a (-/-) (P-gp-deficient) and mdr1a (+/+) (P-gp-competent) mice. Digoxin was administered by intratracheal instillation over 3-4 s, a method demonstrated to result in dispersion of the dose to all regions of the lung. Drug distribution was determined in the lungs, plasma, brain, heart, liver and kidney of individual mice after 5, 10, 30, 60 and 90 min. Digoxin was cleared rapidly from the lung after intratracheal administration. No differences were observed in the maximum serum concentrations between mdr1a (+/+) and mdr1a (-/-) mice (37.8 +/- 6.9 and 38.8 +/- 15.8 ng mL(-1), respectively). The serum concentration versus time profiles were similar in both strains; the area under the drug serum concentration versus time curve (AUC) was 2010 and 1812 ng mL(-1) min in mdr1a (-/-) and mdr1a (+/+) mice, respectively. For organs harvested at the end of the experiment (90 min), the only significant difference between the strains was the markedly elevated concentration of digoxin in the brains of mdr1a (-/-) mice. In conclusion, digoxin is rapidly absorbed from the mouse lung following tracheal instillation, with no difference in the rate or extent of absorption between mdr1a-deficient and -competent mice. This suggests that, in contrast to the scenario suggested by in-vitro data, P-gp in the respiratory epithelium may have little influence on the disposition of drugs that are well absorbed from the lung.
authors.affiliation: King's College London, Pharmaceutical Science Division, 150 Stamford Street, London, UK.
authors.forename: Fergus
authors.initials: F
authors.lastname: Manford
authors.forename: Yanira
authors.initials: Y
authors.lastname: Riffo-Vasquez
authors.forename: Domenico
authors.initials: D
authors.lastname: Spina
authors.forename: Clive P
authors.initials: CP
authors.lastname: Page
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Hutt
authors.forename: Vanessa
authors.initials: V
authors.lastname: Moore
authors.forename: Fredrik
authors.initials: F
authors.lastname: Johansson
authors.forename: Ben
authors.initials: B
authors.lastname: Forbes
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019540:Area Under Curve; D001921:Brain / Q000378:metabolism; D002250:Carbon Radioisotopes; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D004077:Digoxin / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D005260:Female; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism; D020545:Respiratory Mucosa / Q000378:metabolism; D013997:Time Factors; D014316:Tritium
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D002250:Carbon Radioisotopes; D002316:Cardiotonic Agents; D014316:Tritium; D004077:Digoxin; C095122:multidrug resistance protein 3