Published ahead of print on August 17, 2006, doi:10.1165/rcmb.2006-0230OC Am. J. Respir. Cell Mol. Biol., Volume 36, Number 1, January 2007, 53-60 A more recent version of this article appeared on January 1, 2007
Submitted on June 27, 2006 Epithelial Organic Cation Transporters Ensure pH Dependent Drug Absorption in the AirwayGabor Horvath1*,1 Division of Pulmonary and Critical Care Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA; Department of Respiratory Medicine, Semmelweis University School of Medicine, Budapest, Hungary, 2 Division of Pulmonary and Critical Care Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA, 3 Department of Cell Biology and Anatomy, University of Miami Miller School of Medicine, Miami, Florida, USA, 4 Division of Pulmonary and Critical Care Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA; Department of Cell Biology and Anatomy, University of Miami Miller School of Medicine, Miami, Florida, USA * To whom correspondence should be addressed. E-mail: ghorvath.mail{at}gmail.com.
Most inhaled
This article has been cited by other articles:
|
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2-adrenergic agonist and anticholinergic bronchodilators have low lipid solubility because of their transient or permanent positive net charge at physiological 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 reverse transcription-polymerase chain reaction (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 80% of ASP+ uptake was inhibited by L-carnitine, an OCTN2-carried zwitterion. The uptake was pH dependent, with about 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.
