Uddin, Erfan Muhammad, Eisenmann, Eric D, Huang, Kevin M, Garrison, Dominique A, Talebi, Zahra, Gibson, Alice A, Jin, Yan, Nepal, Mahesh, Bonilla, Ingrid M, Fu, Qiang, Millar, Alec, Tarasov, Mikhail, Jay, Christopher E, Cui, Xiaoming, Einolf, Heidi, Pelis, Ryan, Smith, Sakima A, Radwanski, Przemyslaw, Sweet, Douglas H, Konig, Jorg, Fromm, Martin F, Carnes, Cynthia A, Hu, Shuiying and Sparreboom, Alex (2022) Contribution of MATE1 to Dofetilide-Induced Proarrhythmia. International journal of molecular sciences, 23. ISSN 1422-0067

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 predisposes 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 an efflux 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 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.

Item Type:	Article
Date Deposited:	20 Jun 2023 00:45
Last Modified:	20 Jun 2023 00:45
URI:	https://oak.novartis.com/id/eprint/47495