Toward a New Gold Standard for Early Safety: Automated Temperature-Controlled hERG Test on the PatchLiner®

The Patchliner® temperature-controlled automated patch clamp system was evaluated for testing drug effects on potassium currents through human ether-à-go-go related gene (hERG) channels expressed in Chinese hamster ovary cells at 35–37°C. IC50 values for a set of reference drugs were compared with those obtained using the conventional voltage clamp technique. The results showed good correlation between the data obtained using automated and conventional electrophysiology. Based on these results, the Patchliner® represents an innovative automated electrophysiology platform for conducting the hERG assay that substantially increases throughput and has the advantage of operating at physiological temperature. It allows fast, accurate, and direct assessment of channel function to identify potential proarrhythmic side effects and sets a new standard in ion channel research for drug safety testing.

[1]  Martyn P Mahaut-Smith,et al.  Temperature dependence of human ether-a-go-go-related gene K+ currents. , 2006, American journal of physiology. Cell physiology.

[2]  Cristian Ionescu-Zanetti,et al.  IonFlux: a microfluidic patch clamp system evaluated with human Ether-à-go-go related gene channel physiology and pharmacology. , 2011, Assay and drug development technologies.

[3]  A. Brown,et al.  Variability in the measurement of hERG potassium channel inhibition: effects of temperature and stimulus pattern. , 2004, Journal of pharmacological and toxicological methods.

[4]  Jules C Hancox,et al.  Potent inhibition of human cardiac potassium (HERG) channels by the anti-estrogen agent clomiphene-without QT interval prolongation. , 2004, Biochemical and biophysical research communications.

[5]  T J Campbell,et al.  Inhibition of the human ether‐a‐go‐go‐related gene (HERG) potassium channel by cisapride: affinity for open and inactivated states , 1999, British journal of pharmacology.

[6]  Jules C Hancox,et al.  High affinity HERG K(+) channel blockade by the antiarrhythmic agent dronedarone: resistance to mutations of the S6 residues Y652 and F656. , 2004, Biochemical and biophysical research communications.

[7]  D. Swinney.  The role of binding kinetics in therapeutically useful drug action. , 2009, Current opinion in drug discovery & development.

[8]  Mark Slack,et al.  Impact of new technologies for cellular screening along the drug value chain. , 2010, Drug discovery today.

[9]  Jules C Hancox,et al.  Mechanism of hERG K+ channel blockade by the fluoroquinolone antibiotic moxifloxacin , 2006, British journal of pharmacology.

[10]  Michael George,et al.  Port-a-patch and patchliner: high fidelity electrophysiology for secondary screening and safety pharmacology. , 2009, Combinatorial chemistry & high throughput screening.

[11]  M. Sanguinetti,et al.  hERG potassium channels and cardiac arrhythmia , 2006, Nature.

[12]  Heather Guthrie,et al.  A Place for High-Throughput Electrophysiology in Cardiac Safety: Screening hERG Cell Lines and Novel Compounds with the Ion Works HTTM System , 2005, Journal of biomolecular screening.

[13]  J. Hancox,et al.  Clemastine, a conventional antihistamine, is a high potency inhibitor of the HERG K+ channel. , 2006, Journal of molecular and cellular cardiology.

[14]  C. Du,et al.  Pharmacological Inhibition of the hERG Potassium Channel Is Modulated by Extracellular But Not Intracellular Acidosis , 2011, Journal of cardiovascular electrophysiology.

[15]  R. Baker,et al.  Estimation of potency of HERG channel blockers: impact of voltage protocol and temperature. , 2005, Journal of pharmacological and toxicological methods.