TY - JOUR
T1 - Potassium current antagonist properties and proarrhythmic consequences of quinolone antibiotics
AU - Anderson, Mark E.
AU - Mazur, Alexander
AU - Yang, Tao
AU - Roden, Dan M.
PY - 2001
Y1 - 2001
N2 - Quinolones are clinically important antibiotic drugs. One quinolone antibiotic, sparfloxacin (SPX), has been recently reported to increase the QT interval, and another quinolone, grepafloxacin (GRX), was withdrawn because it induced torsade de pointes (TdP), a polymorphic ventricular tachycardia (VT) linked to excessive QT interval prolongation.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, gatifloxacin (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 K+ current (IKr), and second we determined the QT interval prolongation and inducibility 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 ± S.E.) for IKr block: SPX, 0.23 ± 0.07 μM; MOX, 0.75 ± 0.31 μM; GAT, 26.5 ± 13.4 μM; and GRX, 27.2 ± 11.6 μM. All agents also increased the maximum QT interval (mean ± S.E.) from baseline (241 ± 10 ms): SPX, 370 ± 30 ms; MOX, 270 ± 30 ms; GRX, 280 ± 25 ms; and GAT, 255 ± 23 ms. No agents caused TdP during a standard 30-min observation period, but SPX-treated animals developed nonsustained VT (three of six) and TdP (one of six) during an extended 60-min observation period. These findings show that IKr block may be a common feature of many quinolone antibiotics, and that the proarrhythmic consequences vary according to IKr antagonist potency, but are also influenced by additional, unidentified factors.
AB - Quinolones are clinically important antibiotic drugs. One quinolone antibiotic, sparfloxacin (SPX), has been recently reported to increase the QT interval, and another quinolone, grepafloxacin (GRX), was withdrawn because it induced torsade de pointes (TdP), a polymorphic ventricular tachycardia (VT) linked to excessive QT interval prolongation.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, gatifloxacin (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 K+ current (IKr), and second we determined the QT interval prolongation and inducibility 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 ± S.E.) for IKr block: SPX, 0.23 ± 0.07 μM; MOX, 0.75 ± 0.31 μM; GAT, 26.5 ± 13.4 μM; and GRX, 27.2 ± 11.6 μM. All agents also increased the maximum QT interval (mean ± S.E.) from baseline (241 ± 10 ms): SPX, 370 ± 30 ms; MOX, 270 ± 30 ms; GRX, 280 ± 25 ms; and GAT, 255 ± 23 ms. No agents caused TdP during a standard 30-min observation period, but SPX-treated animals developed nonsustained VT (three of six) and TdP (one of six) during an extended 60-min observation period. These findings show that IKr block may be a common feature of many quinolone antibiotics, and that the proarrhythmic consequences vary according to IKr antagonist potency, but are also influenced by additional, unidentified factors.
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M3 - Article
C2 - 11181910
AN - SCOPUS:0035123579
SN - 0022-3565
VL - 296
SP - 806
EP - 810
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 3
ER -