MATE1 Deficiency Exacerbates Dofetilide-Induced Proarrhythmia

Uddin ME, Eisenmann ED, Li Y, Huang KM, Garrison DA, Talebi Z, Gibson AA, Jin Y, Nepal M, Bonilla IM, Fu Q, Sun X, Millar A, Tarasov M, Jay CE, Cui X, Einolf HJ, Pelis RM, Smith SA, Radwanski PB, Sweet DH, König J, Fromm M, Carnes CA, Hu S, Sparreboom A (2022)

Publication Type: Journal article

Publication year: 2022

Journal

International Journal of Molecular Sciences MDPI

Book Volume: 23

Journal Issue: 15

DOI: 10.3390/ijms23158607

Abstract

Dofetilide is a rapid delayed rectifier potassium current inhibitor widely used to prevent the recurrence of atrial fibrillation and flutter. The clinical use of this drug is associated with increases in QTc interval, which predispose patients to ventricular cardiac arrhythmias. The mechanisms involved in the disposition of dofetilide, including its movement in and out of cardiomyocytes, remain unknown. Using a xenobiotic transporter screen, we identified MATE1 (SLC47A1) as a transporter of dofetilide and found that genetic knockout or pharmacological inhibition of MATE1 in mice was associated with enhanced retention of dofetilide in cardiomyocytes and increased QTc prolongation. The urinary excretion of dofetilide was also dependent on the MATE1 genotype, and we found that this transport mechanism provides a mechanistic basis for previously recorded drug-drug interactions of dofetilide with various contraindicated drugs, including bictegravir, cimetidine, ketoconazole, and verapamil. The translational significance of these observations was examined with a physiologically-based pharmacokinetic model that adequately predicted the drug-drug interaction liabilities in humans. These findings support the thesis that MATE1 serves a conserved cardioprotective role by restricting excessive cellular accumulation and warrant caution against the concurrent administration of potent MATE1 inhibitors and cardiotoxic substrates with a narrow therapeutic window.

Authors with CRIS profile

Jörg König Lehrstuhl für Klinische Pharmakologie und Klinische Toxikologie Martin Fromm Lehrstuhl für Klinische Pharmakologie und Klinische Toxikologie

Involved external institutions

Ohio State University US United States (USA) (US) Virginia Commonwealth University (VCU) US United States (USA) (US) Novartis AG CH Switzerland (CH)

How to cite

APA:

Uddin, M.E., Eisenmann, E.D., Li, Y., Huang, K.M., Garrison, D.A., Talebi, Z.,... Sparreboom, A. (2022). MATE1 Deficiency Exacerbates Dofetilide-Induced Proarrhythmia. International Journal of Molecular Sciences, 23(15). https://doi.org/10.3390/ijms23158607

MLA:

Uddin, Muhammad Erfan, et al. "MATE1 Deficiency Exacerbates Dofetilide-Induced Proarrhythmia." International Journal of Molecular Sciences 23.15 (2022).

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