ArticleJournal of cardiovascular pharmacology2009
The organic cation transporter, OCTN1, expressed in the human heart, potentiates antagonism of the HERG potassium channel.
Article in Journal of cardiovascular pharmacology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
What it found
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Who cites it
17 citing papers in PubMed, 36 citations in OpenAlex.
- Pediatric flecainide pharmacogenomics: a roadmap to delivering precision-based care to pediatrics arrhythmias.Frontiers in pharmacology · 2024Review
- MATE1 Deficiency Exacerbates Dofetilide-Induced Proarrhythmia.International journal of molecular sciences · 2022Article
- Solute Carrier Transportome in Chemotherapy-Induced Adverse Drug Reactions.Reviews of physiology, biochemistry and pharmacology · 2022Article
- Expression and Functional Contribution of Different Organic Cation Transporters to the Cellular Uptake of Doxorubicin into Human Breast Cancer and Cardiac Tissue.International journal of molecular sciences · 2021Article
- Targeting OCT3 attenuates doxorubicin-induced cardiac injury.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Organic Cation Transporters in Human Physiology, Pharmacology, and Toxicology.International journal of molecular sciences · 2020Review
- Review
- Overview of the Components of Cardiac Metabolism.Drug metabolism and disposition: the biological fate of chemicals · 2019Review
- Screening genes associated with elevated neutrophil‑to‑lymphocyte ratio in chronic heart failure.Molecular medicine reports · 2018Article
- Pharmacogenetics of Potassium Channel Blockers.Cardiac electrophysiology clinics · 2016Review
- Molecular basis of hERG potassium channel blockade by the class Ic antiarrhythmic flecainide.Journal of molecular and cellular cardiology · 2015Article
- The role of transporters in toxicity and disease.Drug metabolism and disposition: the biological fate of chemicals · 2014Review
- Selective regulation of cardiac organic cation transporter novel type 2 (OCTN2) in dilated cardiomyopathy.The American journal of pathology · 2011Article
- How can we improve our understanding of cardiovascular safety liabilities to develop safer medicines?British journal of pharmacology · 2011Review
- Modulation of drug block of the cardiac potassium channel KCNA5 by the drug transporters OCTN1 and MDR1.British journal of pharmacology · 2010Article
- Drug- and non-drug-associated QT interval prolongation.British journal of clinical pharmacology · 2010Review
- Xenobiotic, bile acid, and cholesterol transporters: function and regulation.Pharmacological reviews · 2010Review
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundVariable 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
resultsReverse 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.
conclusionsCoexpression 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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.