The influence of MDR1 transporters on antiarrhythmic safety and efficacy

Loyola University Chicago, Maywood IL

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Abstract

DESCRIPTION (provided by applicant): Interpatient variability is an accepted consequence of human drug administration including medications to control cardiac rhythm. A key determinant of the magnitude of any drug effect in patients is the drug concentration achieved at the molecular effector site, and so variable drug metabolism is one well-recognized determinant of variable drug action in patients. More recently, delivery of drug to and removal from intracellular molecular effector sites by xenobiotic transporters has become increasingly well recognized as a modulator of intracellular drug concentration. Voltage gated ion channels (including calcium, potassium, and sodium channels) represent a class of molecular targets where a key site of drug action has been identified at the intracellular face of the pore region. Accordingly, I propose the novel hypothesis that modulation of intracellular drug concentration by drug transport molecules is a key modulator of patient response to drugs that block cardiac ion channels. Ion channel blockers display considerable interpatient variability in clinical response ranging from suppression of arrhythmia to life-threatening proarrhythmia. One of the most well studied examples is exaggerated prolongation of the QT interval and the development of Torsade des Pointes through antagonism of the Human Ether a go-go-Related (HERG) potassium channel by antiarrhythmic medications and medications with "non-cardiovascular" indications. Our preliminary data shows that multiple xenobiotic transporters are expressed in the heart and that the organic cation/carnitine uptake transporter, OCTN1, and the drug efflux transporter P-glycoprotein (encoded by ABCB1/MDR1) contribute to variable HERG block by a number of ion channel blocking antiarrhythmics. Investigation of this novel hypothesis will begin with two Specific Aims: Specific Aim I: To examine the effect of MDR1 drug transport expression on HERG block in HL-1 cardiomyocytes. Specific Aim II: To determine the influence of altered atrial electrophysiology on regulation and expression of the MDR1 transporter. PUBLIC HEALTH RELEVANCE: Patient response to drugs controlling cardiac rhythm is highly variable in terms of the drug's ability to suppress abnormal heart rhythms and worsen heart rhythm. The research proposed here seeks to understand if proteins in the heart known as drug transporters are responsible for some of this variability because these transporters can deliver and remove drug from heart cells. This understanding will help scientist design safer drugs to better control abnormal heart rhythms