Abstract
Several macrolides have been reported to cause QT prolongation and ventricular arrhythmias such as torsades de pointes. To clarify the underlying ionic mechanisms, we examined the effects of six macrolides on the human ether-a-go-go-related gene (HERG)-encoded potassium current stably expressed in human embryonic kidney-293 cells. All six drugs showed a concentration-dependent inhibition of the current with the following IC50 values: clarithromycin, 32.9 μM; roxithromycin, 36.5 μM; erythromycin, 72.2 μM; josamycin, 102.4 μM; erythromycylamine, 273.9 μM; and oleandomycin, 339.6 μM. A metabolite of erythromycin, des-methyl erythromycin, was also found to inhibit HERG current with an IC50 of 147.1 μM. These findings imply that the blockade of HERG may be a common feature of macrolides and may contribute to the QT prolongation observed clinically with some of these compounds. Mechanistic studies showed that inhibition of HERGcurrent by clarithromycin did not require activation of the channel and was both voltage- and time-dependent. The blocking time course could be described by a first-order reaction between the drug and the channel. Both binding and unbinding processes appeared to speed up as the membrane was more depolarized, indicating that the drug-channel interaction may be affected by electrostatic responses.
Footnotes
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↵1 These authors contributed equally to this work.
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The abstract of this work was previously presented at the 2002 Biophysical Society Annual Meeting in San Francisco, CA (Volberg et al., 2002).
- Abbreviations:
- TdP
- torsades de pointes
- DME
- des-methyl erythromycin
- HEK
- human embryonic kidney
- HERG
- humanether-a-go-go-related gene
- IKr
- rapidly activating delayed rectifier potassium current
- DDI
- drug-drug interaction
- Rs
- series resistance
- E-4031
- N-[4-[[1-[2-(6-methyl-2-pyridinyl)ethyl]-4-piperidinyl]carbonyl]phenyl]-methanesulfonamide, dihydrochloride
- Received January 24, 2002.
- Accepted March 7, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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