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


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.
McBride
Brian F
BF
Loyola University Schools of Nursing and Medicine, Maywood, IL, USA.
Yang
Tao
T
Liu
Kai
K
Urban
Thomas J
TJ
Giacomini
Kathleen M
KM
Kim
Richard B
RB
Roden
Dan M
DM
D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000378:metabolism; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005424:Flecainide / Q000494:pharmacology; D015870:Gene Expression; D006321:Heart / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020128:Inhibitory Concentration 50; D032383:Myocytes, Cardiac / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000378:metabolism / Q000502:physiology*; D011802:Quinidine / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D027981:Symporters
D000889:Anti-Arrhythmia Agents; D027682:Cation Transport Proteins; D051638:Ether-A-Go-Go Potassium Channels; D027701:Organic Cation Transport Proteins; D015221:Potassium Channels; C109807:SLC22A4 protein, human; D013449:Sulfonamides; D027981:Symporters; C067192:ibutilide; D011802:Quinidine; D005424:Flecainide