Effect of macrolides on in vivo ion transport across cystic fibrosis nasal epithelium.
Fourteen- and 15-member macrolide antibiotics are under investigation as potential therapeutic agents for cystic fibrosis (CF). The nonantibiotic mechanisms of action of these compounds in CF are not understood. We used nasal potential difference (NPD) measurements to test the effect of macrolides on airway epithelial ion (chloride, sodium) transport of CF mice and humans. We tested clarithromycin and azithromycin in mice, and clarithromycin in patients with CF. Baseline and post-treatment NPD was measured in two strains (C57Bl6 and BalbC) of CF transmembrane regulator "knockout" and littermate control mice, and in DeltaF508/DeltaF508 mice. In addition, NPD was measured in 18 human subjects with CF (17 DeltaF-508/DeltaF-508 and 1 DeltaF-508/other) who were undergoing a 12-month, randomized, double-blind crossover study of the effects of clarithromycin on pulmonary outcome in CF. Neither clarithromycin nor azithromycin affected ion transport characteristics of normal or CF nasal epithelium in either mouse or humans. We conclude that the apparent beneficial effects of macrolides on pulmonary outcome in CF are not mediated by their modulation of ion transport.
Barker
Pierre M
PM
Department of Pediatrics, University of North Carolina at Chapel Hill, 200 Mason Farm Road, Chapel Hill, NC 27599-7220, USA. pbarker@med.unc.edu
Gillie
Daniel J
DJ
Schechter
Michael S
MS
Rubin
Bruce K
BK
D000293:Adolescent; D000328:Adult; D000818:Animals; D017963:Azithromycin / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D002648:Child; D017291:Clarithromycin / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D018592:Cross-Over Studies; D003550:Cystic Fibrosis / Q000188:drug therapy / Q000503:physiopathology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D004311:Double-Blind Method; D006801:Humans; D017136:Ion Transport / Q000187:drug effects*; D018942:Macrolides / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018181:Mice, Inbred CFTR; D018345:Mice, Knockout; D009297:Nasal Mucosa / Q000187:drug effects* / Q000503:physiopathology
D018942:Macrolides; C093349:cystic fibrosis transmembrane conductance regulator delta F508; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D017963:Azithromycin; D017291:Clarithromycin