Potassium current antagonist properties and proarrhythmic consequences of quinolone antibiotics.
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(SPX), has been recently reported to increase the QT interval, and another quinolone, grepafloxacin (GRX), was withdrawn because it induced torsade de pointes (TdP), a polymorphic ventricular tachycardia (VT) linked to excessive QT interval prolongation.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 (I(Kr)), 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 I(Kr) antagonists with the following IC(50) values (mean +/- S.E.) for I(Kr) block: SPX, 0.23 +/- 0.07 microM; MOX, 0.75 +/- 0.31 microM; GAT, 26.5 +/- 13.4 microM; and GRX, 27.2 +/- 11.6 microM. 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 I(Kr) block may be a common feature of many quinolone antibiotics, and that the proarrhythmic consequences vary according to I(Kr) antagonist potency, but are also influenced by additional, unidentified factors.
Anderson
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Vanderbilt University Medical Center, Department of Internal Medicine and Pharmacology, Divisions of Clinical Pharmacology and Cardiovascular Medicine, Nashville, Tennessee 37232-6300, USA. mark.anderson@mcmail.vanderbilt.edu
Mazur
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Yang
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Roden
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D042462:4-Quinolones; D000818:Animals; D000890:Anti-Infective Agents / Q000009:adverse effects / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D001372:Aza Compounds; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels; D024841:Fluoroquinolones; D000077734:Gatifloxacin; D008133:Long QT Syndrome / Q000139:chemically induced*; D051379:Mice; D023421:Models, Animal; D000077266:Moxifloxacin; D018408:Patch-Clamp Techniques; D010879:Piperazines / Q000009:adverse effects / Q000494:pharmacology; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D011804:Quinolines; D011817:Rabbits; D015534:Trans-Activators; D014407:Tumor Cells, Cultured
D042462:4-Quinolones; D000890:Anti-Infective Agents; D001372:Aza Compounds; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D024841:Fluoroquinolones; C092509:KCNH6 protein, human; D010879:Piperazines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011804:Quinolines; D015534:Trans-Activators; C075375:grepafloxacin; D000077734:Gatifloxacin; C061363:sparfloxacin; D000077266:Moxifloxacin