hERG Serum Shift Assay
In vitro hERG patch clamp assays have become standard components in cardiac safety evaluation during nonclinical drug development. However, prediction of in vivo effects from in vitro measurements of hERG block may be complicated in the case of drugs that are strongly protein bound. The complication arises from the fact that only the free, unbound drug is active against hERG. Thus, accurate estimation of hERG potency in vitro is performed in the absence of serum protein, unlike the in vivo condition where drugs are present in both free and protein-bound forms.
While many clients use the hERG assay to support their preclinical studies, we also recommend their use in discovery studies to support cardiac programs. Large volume screenings of compounds against the most critical cardiac channels (i.e., hERG, Nav1.5, and Cav1.2), conducted in high-throughput formats before lead optimization, can be useful for identifying the potential hazard of hERG-selective compounds. Charles River follows CiPA approaches that are an integral part of lead optimization where a small number of compounds have been identified as potential candidates.
Our experts stay updated on all regulations and guidelines to provide our clients with the highest quality data for their programs. Guidances are available regarding the hERG assay and can be found through the FDA.
Conventional manual patch clamp evaluation of hERG potency in the presence of 100% fetal bovine serum (FBS, dialyzed) evaluates the effect of drug-protein binding on hERG inhibition.
hERG Serum Shift Assay benefits:
- Measures hERG block in the presence and absence of serum proteins
- Conventional manual patch clamp for “gold standard” accuracy
Frequently Asked Questions (FAQs) for hERG Assays
What is a hERG assay?
A hERG (human Ether-a-go-go Related Gene) assay is a laboratory technique that gauges the activity of the hERG channel protein.
How does the hERG assay support cardiac studies?
hERG activity manifests as the movement of potassium ions through a pore present in the hERG channel protein. In the heart, that potassium movement generates one of the major repolarizing currents that bring the excited cardiomyocyte to rest. Any impairment of this repolarizing current may result in life-threatening cardiac arrhythmias. The movement of potassium ions through the hERG channel can be measured using electrophysiological techniques and tracer flux assays. Displacement assays that gauge competition for the hERG channel pore are also used as indication hERG activity.
How does hERG support drug development?
Approximately 60% of all new molecular entities aiming at cardiac or non-cardiac targets interact with hERG channels; thus, hERG channels are considered “promiscuous.” hERG assays are part of the nonclinical testing strategy described in the Regulatory Guideline S7B to assess the effects of pharmaceuticals on ventricular repolarization and proarrhythmic risk.