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Abstract 14035: Renal Tubular Secretion and Cardiac Distribution of Dofetilide is based on MATE1 Function

Pharmaceutics and Pharmacology, The Ohio State Univ, Columbus, OH


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Introduction: Dofetilide is a delayed rectifier potassium channel inhibitor utilized to take care of clients with atrial flutter and fibrillation, as well as its usage is connected with a threat of QT prolongation and Torsades de Pointes. The mechanisms tangled up in dofetilide’s renal tubular release and its uptake into cardiomyocytes stay unknown. Formerly reported drug-drug connection (DDI) studies recommend the participation of natural cation transporters. right Here, we investigated the share of natural cation transporters (OCT2 and MATE1) to your pharmacokinetics of dofetilide to get understanding of its DDI potential.

Hypothesis: centered on known DDIs with dofetilide, we hypothesize that OCT2 and/or MATE1 perform an integral part in the inter-individual variability in pharmacokinetics and pharmacodynamics of dofetilide.

Techniques:In vitro and ex vivo transport kinetics of dofetilide had been determined in HEK293 cells stably transfected with OCT2 or MATE1, and in remote cardiomyocytes, correspondingly. In vivo studies had been done in wild-type, OCT2-, and MATE1-deficient mice, with or without a few drugs that are contraindicated. Dofetilide levels in plasma and urine had been based on UPLC-MS/MS.

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