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

Abstract

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.

Outcomes:In vitro studies demonstrated that dofetilide is just a good substrate of mate1 not OCT2. Lack of MATE1 had been related to increased plasma concentrations of dofetilide in accordance with a notably paid down excretion that is urinary in females and 5-fold in men, correspondingly). Dofetilide accumulation in cardiomyocytes ended up being increased by 2-fold in MATE1-deficient females, and pre-incubation with all the MATE1 inhibitor cimetidine notably paid off dofetilide uptake in wild-type cardiomyocytes. Several contraindicated medications listed into the dofetilide prescribing information, including cimetidine, ketoconazole, increased dofetilide plasma visibility in wild-type mice by >2.8-fold.

Conclusion: Renal release of dofetilide is mediated by MATE1 and it is extremely responsive to inhibition by numerous popular prescription drugs that may cause DDIs that is clinically relevant. Scarcity of MATE1 additionally increases accumulation into the heart which could play a role in variation that is individual a reaction to dofetilide.

Footnotes

Author Disclosures: For writer disclosure information, please look at the AHA Scientific Sessions Online Program Planner and seek out the abstract title.

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