At present, atrial fibrillation (AFib) is the most commonly encountered cardiac arrhythmia in clinical practice globally. The prevalence of atrial fibrillation is predicted to affect about 12 million people in the USA and 17 million people in Europe by 2050, and people over the age of 65 are particularly prone to experience atrial fibrillation. The clinical use of dofetilide is associated with increases in the QTc interval, which can exacerbate cardiac arrhythmias. We hypothesize that dofetilide-mediated proarrhythmia is linked to transport mechanisms that regulate uptake of dofetilide in organs of elimination and the heart, and that identification of these mechanisms can contribute to the development of an effective intervention strategy for prevention of QTc prolongation, while retaining therapeutic efficacy. The solute carrier (SLC) superfamily of genes is known to encode membrane proteins that facilitate the transmembrane transport of a broad array of endogenous compounds and clinically relevant drugs, and tissue-specific expression of these transporters significantly contributes to distribution and elimination. Prior studies have suggested on the basis of pharmacokinetic drug-drug interactions that certain renal transporters play a role in the tubular secretion of dofetilide and consequently, elevating drug levels in the systemic circulation may exacerbate the adverse events. Based on this prior knowledge, we will determine the contribution of the organic cation transporters OCT2 (SLC22A2) and MATE1 (SLC47A1) to the pharmacokinetics of dofetilide and evaluate how these processes affect its therapeutic window. Successful completion of these studies will provide further insights into the pharmacological role of organic cation transporters in the handling of dofetilide and their involvement in causing QTc prolongation. Furthermore, this research will help understand the etiology of dofetilide-induced proarrhythmia and provide a rationale for avoiding the use of transporter inhibitors in preventing QTc prolongation without affecting the efficacy of dofetilide.
|Program type||Predoctoral Fellowship|
|Effective start/end date||01/01/2020 → 12/31/2021|