On the relationship between block of the cardiac XXXX    channel and drug-induced prolongation of the QRS complex.

@entity1 @entity6500 @entity4024 @entity65
BACKGROUND AND PURPOSE: Inhibition of the @entity1 cardiac @entity4024 channel ( @entity6500 ) can prolong the QRS complex and has been associated with increased mortality in @entity1 with underlying @entity65 . The safety implications of blocking @entity6500 channels suggest the need to test for this activity early in drug discovery in order to design out any potential liability. However, interpretation of @entity6500 blocking potency requires knowledge of how @entity6500 block translates into prolongation of the QRS complex. EXPERIMENTAL APPROACH: We tested Class I anti-arrhythmics, other known QRS prolonging drugs and drugs not reported to prolong the QRS complex. Their block of @entity6500 channels (as IC(50) values) was measured in an automated electrophysiology-based assay. These IC(50) values were compared with published reports of the corresponding unbound (free) plasma concentrations attained during clinical use (fC(max)) to provide an IC(50) : fC(max) ratio. KEY RESULTS For 42 Class I anti-arrhythmics and other QRS prolonging drugs, 67% had IC(50) : fC(max) ratios <30. For 55 non-QRS prolonging drugs tested, 72% had ratios >100. Finally, we determined the relationship between the IC(50) value and the free drug concentration associated with prolongation of the QRS complex in @entity1 . For 37 drugs, QRS complex prolongation was observed at free plasma concentrations that were about 15-fold lower than the corresponding IC(50) at @entity6500 channels. CONCLUSIONS AND IMPLICATIONS: A margin of 30- to 100-fold between @entity6500 IC(50) and fC(max) appears to confer an acceptable degree of safety from QRS prolongation. QRS prolongation occurs on average at free plasma levels 15-fold below the IC(50) at @entity6500 channels. LINKED ARTICLE: This article is commented on by Gintant et al., pp. 254-259 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2011.01433.x.
