title: Accumulation of azithromycin and roxithromycin in tracheal epithelial fetal cell lines expressing wild type or mutated cystic fibrosis transmembrane conductance regulator protein (CFTR).
abstract: Macrolides are accumulated in phagocytes, partially via an active transport system; the membrane carrier is not identified but many data indicate a link with the P-glycoprotein family which includes the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein. We have used two epithelial cell lines which express either wild-type (N cells) or mutated (homozygous deltaF508) (F cells) CFTR to study the cellular accumulation of two macrolides (azithromycin and roxithromycin). Adherent cells were incubated with the radiolabeled drugs before extensive washings and counting. Azithromycin was better (about 2-fold) accumulated in F cells up to 60 min but then plateaued, whereas accumulation continued without saturation over 3 hours in N cells. Roxithromycin was also better (1.5-fold) accumulated in F cells at 15 and 30 min, but there were no differences at further incubation times. Macrolide efflux from loaded N and F cells, and the susceptibilities of the carrier systems (entry and efflux) to various pharmacologic agents were similar to those previously observed with phagocytes. These data suggest that the macrolide carriers (for entry and efflux) are not strictly specific for phagocytes and that the CFTR protein plays a role in macrolide uptake.
authors.affiliation: INSERM U479, CHU X. Bichat, Paris, France. labro@bichat.inserm.fr
authors.forename: M T
authors.initials: MT
authors.lastname: Labro
authors.forename: C
authors.initials: C
authors.lastname: Babin-Chevaye
authors.forename: M
authors.initials: M
authors.lastname: Mergey
mesh_terms: D000704:Analysis of Variance; D017963:Azithromycin / Q000493:pharmacokinetics*; D016022:Case-Control Studies; D003550:Cystic Fibrosis / Q000188:drug therapy / Q000235:genetics; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000187:drug effects* / Q000235:genetics*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005333:Fetus; D006801:Humans; D009154:Mutation; D010597:Pharmacogenetics; D012044:Regression Analysis; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism; D015575:Roxithromycin / Q000493:pharmacokinetics*; D012680:Sensitivity and Specificity; D014132:Trachea / Q000166:cytology
chemical_list: C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D015575:Roxithromycin; D017963:Azithromycin