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Vol. 59, Issue 1, 122-126, January 2001

Interactions of a Series of Fluoroquinolone Antibacterial Drugs with the Human Cardiac K+ Channel HERG

Jiesheng Kang, Lin Wang, Xiao-Liang Chen, David J. Triggle, and David Rampe

Aventis Pharmaceuticals, Inc. Bridgewater, New Jersey (J.K., L.W., X.-L.C., D.R.); and State University of New York at Buffalo, Buffalo, New York (D.J.T.)

Administration of certain fluoroquinolone antibacterials has been associated with prolongation of the QT interval on the electrocardiogram and, on rare occasions, ventricular arrhythmia. Blockade of the human cardiac K+ channel HERG often underlies such clinical findings. Therefore, we examined a series of seven fluoroquinolones for their ability to interact with this channel. Using patch-clamp electrophysiology, we found that all of the drugs tested inhibited HERG channel currents, but with widely differing potencies. Sparfloxacin was the most potent compound, displaying an IC50 value of 18 µM, whereas ofloxacin was the least potent compound, with an IC50 value of 1420 µM. Other IC50 values were as follows: grepafloxacin, 50 µM; moxifloxacin, 129 µM; gatifloxacin, 130 µM; levofloxacin, 915 µM; and ciprofloxacin, 966 µM. Block of HERG by sparfloxacin displayed a positive voltage dependence. In contrast to HERG, the KvLQT1/minK K+ channel was not a target for block by the fluoroquinolones. These results provide a mechanism for the QT prolongation observed clinically with administration of sparfloxacin and certain other fluoroquinolones because free plasma levels of these drugs after therapeutic doses approximate those concentrations that inhibit HERG channel current. In the cases of levofloxacin, ciprofloxacin, and ofloxacin, inhibition of HERG occurs at concentrations much greater than those observed clinically. The data indicate that clinically relevant HERG channel inhibition is not a class effect of the fluoroquinolone antibacterials but is highly dependent upon specific substitutions within this series of compounds. HERG channel affinity should be an important criterion for the development of newer fluoroquinolones.

Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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