MATE1 Deficiency Exacerbates Dofetilide-Induced Proarrhythmia

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.

N1‐Methylnicotinamide as Biomarker for MATE‐Mediated Renal Drug–Drug Interactions: Impact of Cimetidine, Rifampin, Verapamil, and Probenecid

“…15,16 For example, the drugs metformin, dofetilide, pramipexole, and lamivudine, and also the endogenous sub stance creatinine are substrates for OCT2/ MATE. [17][18][19][20] Co-administration of MATE inhibitors, such as cimetidine, trimethoprim, and pyrimethamine, with renally secreted OCT2/MATE substrates lead to a reduced renal clearance (CL R ) and to some extent increased systemic exposure of the victim drugs. 21 Shim et al 22 as well as Ito et al 23 proposed N 1 methylnicotinamide (NMN) as possible biomarker for renal secretion of organic cations.…”

“…Organic cation transporter 2 works in coordinated fashion with the MATE proteins (MATE1 ( SLC47A1 ) and MATE2‐K ( SLC47A2 )), which are localized in the apical membrane of renal proximal tubular cells due to their overlapping substrate spectrum 15,16 . For example, the drugs metformin, dofetilide, pramipexole, and lamivudine, and also the endogenous substance creatinine are substrates for OCT2/MATE 17–20 . Co‐administration of MATE inhibitors, such as cimetidine, trimethoprim, and pyrimethamine, with renally secreted OCT2/MATE substrates lead to a reduced renal clearance (CL R ) and to some extent increased systemic exposure of the victim drugs 21 …”

Overcoming Biological Barriers: Importance of Membrane Transporters in Homeostasis, Disease and Disease Treatment

“…They found species-dependent differences for 2 and substrate-dependent differences for 3 out of 22 investigated compounds, showing that species-dependent differences should be considered when extrapolating data from mice to humans. In the paper “MATE1 Deficiency Exacerbates Dofetilide-Induced Proarrhythmia”, Uddin et al [ 13 ] found that Dofetilide, a class III antiarrhythmic drug, is a substrate of the multidrug and toxin extrusion protein 1 (MATE1). Dofetilide transport in cardiomyocytes and renal tubular cells is mediated by MATE1 and is highly sensitive to pharmacological inhibition, suggesting that these findings are important for optimizing polypharmacy regimens.…”