Beta-2 Adrenergic Agonists Are Substrates and Inhibitors of Human Organic Cation Transporter 1.
Beta-2-adrenergic agonists are first line therapeutics in the treatment of asthma and chronic obstructive pulmonary disease (COPD). Upon inhalation, bronchodilation is achieved after binding to β2-receptors, which are primarily localized on airway smooth muscle cells. Given that β2-adrenergic agonists chemically are bases, they carry net positive charge at physiologic pH value in the lungs (i.e., pH 7.4). Here, we studied whether β2-agonists interact with organic cation transporters (OCT) and whether this interaction exerted an influence on their passage across the respiratory epithelium to their target receptors. [14C]-TEA uptake into proximal (i.e., Calu-3) and distal (i.e., A549 and NCI-H441) lung epithelial cells was significantly reduced in the presence of salbutamol sulfate, formoterol fumarate, and salmeterol xinafoate in vitro. Expression of all five members of the OCT/N family has been confirmed in human pulmonary epithelial cells in situ and in vitro, which makes the identification of the transporter(s) responsible for the β2-agonist interaction challenging. Thus, additional experiments were carried out in HEK-293 cells transfected with hOCT1-3. The most pronounced inhibition of organic cation uptake by β2-agonists was observed in hOCT1 overexpressing HEK-293 cells. hOCT3 transfected HEK-293 cells were affected to a lesser extent, and in hOCT2 transfectants only marginal inhibition of organic cation uptake by β2-agonists was observed. Bidirectional transport studies across confluent NCI-H441 cell monolayers revealed a net absorptive transport of [3H]-salbutamol, which was sensitive to inhibition by the OCT1 modulator, verapamil. Accordingly, salbutamol uptake into hOCT1 overexpressing HEK-293 cells was time- and concentration-dependent and could be completely blocked by decynium-22. Taken together, our data suggest that β2-agonists are specific substrates and inhibitors of OCT1 in human respiratory epithelial cells and that this transporter might play a role in the pulmonary disposition of drugs of this class.
†School of Pharmacy and Pharmaceutical Sciences and Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
Johanna J
JJ
Salomon
‡Zentrum für Physiologie und Pathophysiologie, Georg-August-Universität, 37073 Göttingen, Germany.|§PortaCellTec Biosciences GmbH, 37073 Göttingen, Germany.
Yohannes
Y
Hagos
‡Zentrum für Physiologie und Pathophysiologie, Georg-August-Universität, 37073 Göttingen, Germany.
Sören
S
Petzke
§PortaCellTec Biosciences GmbH, 37073 Göttingen, Germany.
Annett
A
Kühne
†School of Pharmacy and Pharmaceutical Sciences and Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
Julia C
JC
Gausterer
∥Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 930-0887 Toyama, Japan.
Ken-ichi
K
Hosoya
†School of Pharmacy and Pharmaceutical Sciences and Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
Carsten
C
Ehrhardt
D058666:Adrenergic beta-2 Receptor Agonists / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000420:Albuterol / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D001692:Biological Transport; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D000068759:Formoterol Fumarate / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D027702:Organic Cation Transporter 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism; D065589:Respiratory Tract Absorption; D000068299:Salmeterol Xinafoate / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D014162:Transfection
D058666:Adrenergic beta-2 Receptor Agonists; D027702:Organic Cation Transporter 1; D000068299:Salmeterol Xinafoate; D000420:Albuterol; D000068759:Formoterol Fumarate
bronchodilators; competitive inhibition; inhalation biopharmaceutics; pulmonary drug disposition; respiratory epithelium