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

Abstract

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 microM, whereas ofloxacin was the least potent compound, with an IC50 value of 1420 microM. Other IC50 values were as follows: grepafloxacin, 50 microM; moxifloxacin, 129 microM; gatifloxacin, 130 microM; levofloxacin, 915 microM; and ciprofloxacin, 966 microM. 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.

Molecular Determinants of Voltage-dependent Human Ether-a-Go-Go Related Gene (HERG) K+ Channel Block

“…Chloroquine blocked HERG current with a potency similar to that of quinidine (13,26,27), mefloquine (28), sparfloxacin (29), and vesnarinone (30,31). All these compounds exhibit increased block with increasing membrane depolarization, and channels fully recover from block in less than a minute at a holding potential of Ϫ80 mV.…”

The antipsychotic drug chlorpromazine inhibits HERG potassium channels

“…Pharmacological inhibition of HERG potassium channels is a property of the class III antiarrhythmic drugs dofetilide (Kiehn et al, 1996), amiodarone , BRL-32872 , or bertosamil (Zitron et al, 2002). In addition, several other nonantiarrhythmic compounds block HERG currents, such as the badrenoceptor antagonist carvedilol (Karle et al, 2001), the tricyclic antidepressants imipramine and amitriptyline (Teschemacher et al, 1999), the selective serotonin reuptake inhibitor fluoxetine , the histamine receptor antagonists terfenadine and astemizole (Suessbrich et al, 1996), and fluoroquinolone-based antibacterial drugs (Kang et al, 2001). Finally, the antipsychotic drugs haloperidol (Suessbrich et al, 1997), thioridazine (Drolet et al, 1999), and sertindole (Lacerda et al, 2001) have been shown to inhibit HERG channels.…”

Moxifloxacina: profilo farmacologico, terapeutico e farmacoeconomico

“…La moxifloxacina è un fluorochinolone dotato di un'eccellente tollerabilità clinica [119][120][121][122][123][124][125][126][127][128][129][130]. L'analisi delle reazioni avverse, registrate nel corso degli studi clinici controllati, condotti in cieco o in aperto, e nel corso della farmacovigilanza post-marketing, evidenzia un profilo di tollerabilità e di sicurezza della moxifloxacina sovrapponibile a quello dei farmaci coi quali è stato confrontato [98].…”

“…Questo effetto, tuttavia, quando si è manifestato nei soggetti trattati con moxifloxacina, non ha mai dato origine a reazioni cardiache avverse clinicamente rilevanti o a casi di morte da torsione di punta [124][125][126][127][128][129].…”