Beta-2 Adrenergic Agonists Are Substrates and Inhibitors of Human Organic Cation Transporter 1.

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Salomon JJ, Hagos Y, Petzke S, Kuhne A, Gausterer JC, Hosoya K, Ehrhardt C

Beta-2 Adrenergic Agonists Are Substrates and Inhibitors of Human Organic Cation Transporter 1.

Mol Pharm. 2015 Aug 3;12(8):2633-41. doi: 10.1021/mp500854e. Epub 2015 Mar 18.

PubMed ID

25751092 [ View in PubMed

]

Abstract

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 beta2-receptors, which are primarily localized on airway smooth muscle cells. Given that beta2-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 beta2-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 beta2-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 beta2-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 beta2-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 beta2-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.

DrugBank Data that Cites this Article

Drugs

Formoterol

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Formoterol	Solute carrier family 22 member 1	Protein	Humans	Unknown	Substrate Inhibitor	Details
Formoterol	Solute carrier family 22 member 3	Protein	Humans	Unknown	Inhibitor	Details
Salmeterol	Solute carrier family 22 member 1	Protein	Humans	Unknown	Substrate Inhibitor	Details
Salmeterol	Solute carrier family 22 member 2	Protein	Humans	Unknown	Inhibitor	Details
Salmeterol	Solute carrier family 22 member 3	Protein	Humans	Unknown	Inhibitor	Details