Potassium current antagonist properties and proarrhythmic consequences of quinolone antibiotics

Quinolones are clinically important antibiotic drugs. One quin-olone antibiotic, sparfloxacin (SPX), has been recently reported to increase the QT interval, and another quinolone, grepafloxa-cin (GRX), was withdrawn because it induced torsade de pointes (TdP), a polymorphic ventricular tachycardia (VT) linked to excessive QT interval prolongation. To determine whether SPX, GRX, and other recently developed quinolones, gatifloxa-cin (GAT) and moxifloxacin (MOX), have similar, potentially deleterious, properties we compared these agents in two ways. First, we measured their relative antagonist potency against the rapid component of the delayed rectifier K1 current (IKr), and second we determined the QT interval prolongation and induc-ibility of VT and TdP using a well established in vivo rabbit arrhythmia model. All of these agents are IKr antagonists with the following IC50 values (mean 6 S.E.) for IKr block: SPX, 0.23 6 0.07 mM; MOX, 0.75 6 0.31 mM; GAT, 26.5 6 13.4 mM; and GRX, 27.2 6 11.6 mM. All agents also increased the max