Interactions of the antimalarial drug mefloquine with the human cardiac potassium channels KvLQT1/minK and HERG.
Mefloquine is a quinoline antimalarial drug that is structurally related to the antiarrhythmic agent quinidine. Mefloquine is widely used in both the treatment and prophylaxis of Plasmodium falciparum malaria. Mefloquine can prolong cardiac repolarization, especially when coadministered with halofantrine, an antagonist of the human ether-a-go-go-related gene (HERG) cardiac K+ channel. For these reasons we examined the effects of mefloquine on the slow delayed rectifier K+ channel (KvQT1/minK) and HERG, the K+ channels that underlie the slow (I(Ks)) and rapid (I(Kr)) components of repolarization in the human myocardium, respectively. Using patch-clamp electrophysiology we found that mefloquine inhibited KvLQT1/minK channel currents with an IC50 value of approximately 1 microM. Mefloquine slowed the activation rate of KvLQT1/minK and more block was evident at lower membrane potentials compared with higher ones. When channels were held in the closed state during drug application, block was immediate and complete with the first depolarizing step. HERG channel currents were about 6-fold less sensitive to block by mefloquine (IC50 = 5.6 microM). Block of HERG displayed a positive voltage dependence with maximal inhibition obtained at more depolarized potentials. In contrast to structurally related drugs such as quinidine, mefloquine is a more effective antagonist of KvLQT1/minK compared with HERG. Block of KvLQT1/minK by mefloquine may involve an interaction with the closed state of the channel. Inhibition by mefloquine of KvLQT1/minK in the human heart may in part explain the synergistic prolongation of QT interval observed when this drug is coadministered with the HERG antagonist halofantrine.
Kang
J
J
Drug Safety Evaluation, Aventis Pharmaceuticals, Inc., Bridgewater, New Jersey 08807-0800, USA.
Chen
X L
XL
Wang
L
L
Rampe
D
D
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D016466:CHO Cells; D027682:Cation Transport Proteins; D006224:Cricetinae; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels; D006801:Humans; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D015767:Mefloquine / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects*; D024642:Potassium Channels, Voltage-Gated; D011802:Quinidine / Q000494:pharmacology; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG
D000962:Antimalarials; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D011802:Quinidine; D015767:Mefloquine