GLP Ion Channel & Analytical Support
GLP hERG (IKr)
- Required for IND submission
- Physiologic temperature
- Dose-response assessment
- Dose formulation analysis
Other GLP ion channels:
- Cav1.2 (L-type Ca)
- Nav1.5 (cardiac INa)
- KvLQT1/minK (IKs)
- Kv4.3 (Ito)
- Kir2.1 (IK1)
hERG: Block of this channel can slow repolarization, prolong action potential duration, and lead to early after-depolarizations (EADs). This is manifested on an ECG as QT prolongation and can degenerate into a particular type of ventricular arrhythmia, Torsades de pointes.
Cav1.2: The L-type Ca current is important in contraction of the myocardium and block of this channel can lead to a decreased force of contraction and reduced blood pressure. Block of this channel in the context of pre-existing hERG block can serve to minimize QT prolongation.
Nav1.5: The cardiac Na current consists of 2 components, the peak current which depolarizes the cardiac membrane and is important in cardiac conduction and the late component which plays a role along with Cav1.2 in determining the action potential plateau. Block of the peak component can lead to QRS prolongations and arrhythmias while block of the late component, in the context of pre-existing hERG block, can minimize QT prolongation.
KvLQT1/mink: This current contributes to repolarization of the myocardium. When both KvLQT1 and hERG are blocked, the risk of drug-associated arrhythmias is increased relative to hERG block alone.
Kv4.3: This current (Ito or transient outward current) plays a role in the rapid phase of repolarization of the action potential (phase 1). It is more important in atrial myocytes than ventricular.
Kir2.1: Kir2.1 otherwise known as I K1 plays a role in setting the resting membrane potential in atrial and ventricular myocytes as well as contributing to the terminal phase of repolarization of the action potential.