The organic cation transporter, OCTN1, expressed in the human heart, potentiates antagonism of the HERG potassium channel.

McBride BF, Yang T, Liu K, Urban TJ, Giacomini KM, Kim RB, Roden DM
J Cardiovasc Pharmacol. 2009 54 (1): 63-71

PMID: 19528813 · PMCID: PMC3745652 · DOI:10.1097/FJC.0b013e3181abc288

BACKGROUND - Variable function and expression of drug transporters have been proposed as mechanisms contributing to variable response to drug therapy. Block of the HERG channel, encoding IKr, can lead to serious arrhythmias, and a key drug-blocking site in HERG has been identified on the intracellular face of the pore. We begin to advance the hypothesis that active drug uptake enhances IKr block.

METHODS AND RESULTS - Reverse transcriptase-polymerase chain reaction identified expression in the human atrium and ventricle of 14 of 31 candidate drug uptake and efflux transporters, including OCTN1 (SLC22A4), a known uptake transporter of the HERG channel blocker quinidine. In situ hybridization and immunostaining localized OCTN1 expression to cardiomyocytes. The IC50 for quinidine block of IKr in CHO cells transfected with HERG alone was significantly higher than cells transfected with HERG + OCTN1 (0.66 +/- 0.15 microM versus 0.14 +/- 0.06 microM [52% absolute increase in drug block; 95% confidence interval, 0.4-0.64 microM]), and this effect was further potentiated by a common genetic variant of OCTN1, L503F. In the absence of OCTN1, quinidine block could be 91% +/- 5% washed out, but with the transporter, washout was incomplete (57% +/- 6%). OCTN1 coexpression also facilitated HERG block by flecainide and ibutilide, but not erythromycin.

CONCLUSIONS - Coexpression of the organic cation transporter, OCTN1, expressed in human cardiac myocytes, intensifies quinidine-induced HERG block. These findings establish a critical hypothesis that variable drug transporter activity may be a potential risk factor for torsade de pointes.

MeSH Terms (18)

Anti-Arrhythmia Agents Arrhythmias, Cardiac Cation Transport Proteins Electrophysiology Ether-A-Go-Go Potassium Channels Flecainide Gene Expression Heart Humans Immunohistochemistry Inhibitory Concentration 50 In Situ Hybridization Myocytes, Cardiac Organic Cation Transport Proteins Patch-Clamp Techniques Potassium Channels Quinidine Sulfonamides

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