Published ahead of print on August 17, 2006, doi:10.1165/rcmb.2006-0230OC
© 2007 American Thoracic Society DOI: 10.1165/rcmb.2006-0230OC Epithelial Organic Cation Transporters Ensure pH-Dependent Drug Absorption in the AirwayDivision of Pulmonary and Critical Care Medicine and Department of Cell Biology and Anatomy, University of Miami Miller School of Medicine, Miami, Florida; and Department of Respiratory Medicine, Semmelweis University School of Medicine, Budapest, Hungary Correspondence and requests for reprints should be addressed to Adam Wanner, M.D., and Gabor Horvath, M.D., Ph.D., Division of Pulmonary and Critical Care Medicine, University of Miami Miler School of Medicine, P.O. Box 016960 (R-47), Miami, FL 33101. E-mail: awanner{at}miami.edu and ghorvath.mail{at}gmail.com
Most inhaled
Key Words: airway epithelia • airway pH • bronchodilators • drug absorption • organic cation transporters
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2-adrenergic agonist and anticholinergic bronchodilators have low lipid solubility because of their transient or permanent positive net charge at physiologic pH. Airway absorption of these cationic drugs is incompletely understood. We examined carrier-mediated mechanisms of cationic drug uptake by human airway epithelia. Airway tissues and epithelial cells, obtained from lung donors without preexisting lung disease, were evaluated for organic cation transporter expression by quantitative RT-PCR and immunofluorescence. For in vitro functional studies on primary airway epithelial cells, uptake of the cationic fluorophore 4-[4-(dimethylamino)-styryl]-N-methylpyridinium (ASP+) was characterized. Quantitative RT-PCR analysis demonstrated high mRNA levels for two polyspecific organic cation/carnitine transporters, OCTN1 and OCTN2, in human airway epithelia. Immunofluorescence of human airway sections confirmed OCTN1/2 protein expression, with a predominant localization to the apical portion of epithelial cells. Primary airway epithelial cells showed a carrier-mediated, temperature-sensitive and saturable uptake of ASP+. Seventy-five to eighty percent of ASP+ uptake was inhibited by L-carnitine, an OCTN2-carried zwitterion. The uptake was pH dependent, with 
3-fold lower rates at acidic (pH 5.7) than at alkaline (pH 8.2) extracellular pH. Albuterol and formoterol inhibited ASP+ uptake, suggesting that all these molecules are carried by the same transport mechanism. These findings demonstrate the existence and functional role of a pH-dependent organic cation uptake machinery, namely OCTN1 and OCTN2, in human airway epithelia. We suggest that epithelial OCTN1/2 are involved in the delivery of inhaled cationic bronchodilators to the airway tissue. 
