Improved throughput of PatchXpress hERG assay using intracellular potassium fluoride

Area of Science:

• Cardiovascular pharmacology
• Drug safety assessment
• Ion channel electrophysiology

Background:

• Blockade of the human ether-a-go-go-related gene (hERG) potassium channel can lead to QT prolongation and torsade de pointes, causing drug withdrawals.
• Regulatory agencies mandate in vitro hERG screening for drug candidates.
• Automated patch clamp systems offer higher throughput for early-stage hERG screening compared to manual methods.

Purpose of the Study:

• To optimize an automated patch clamp method for hERG screening using potassium fluoride (KF).
• To evaluate the impact of KF on hERG current properties and screening efficiency.
• To improve the throughput and success rate of hERG screening in drug discovery.

Main Methods:

• Optimization of the PatchXpress 7000A automated patch clamp system.
• Utilized potassium fluoride (KF) in the internal recording solution for hERG current measurements.
• Compared biophysical and pharmacological properties of hERG currents recorded with KF versus standard potassium chloride solutions.

Main Results:

• hERG currents recorded with KF exhibited similar biophysical and pharmacological properties to those recorded with standard potassium chloride solutions.
• The use of KF significantly improved the success rate of hERG screening on the PatchXpress system.
• KF utilization led to a significant increase in the throughput of hERG screening without compromising data quality.

Conclusions:

• Optimized automated patch clamp hERG screening using KF enhances efficiency and reliability.
• This method minimizes the risk of late-stage drug development failures due to hERG channel interactions.
• The KF-based approach is valuable for high-throughput functional hERG screening in pharmaceutical research.