RESUMO
Lidoflazine is an antianginal calcium channel blocker that carries a significant risk of QT interval prolongation and ventricular arrhythmia. We investigated whether or not lidoflazine inhibits current through the rapid delayed rectifier K(+) channel alpha subunit (encoded by HERG - human ether-a-go-go-related gene), since this channel has been widely linked to drug-induced QT-prolongation. Lidoflazine inhibited potently HERG current (I(HERG)) recorded from HEK 293 cells stably expressing wild-type HERG (IC(50) of approximately 16 nM). It was approximately 13-fold more potent against HERG than was verapamil under similar conditions. On membrane depolarization, I(HERG) inhibition developed gradually, ruling out closed-channel state dependent inhibition. The effect of command voltage on the drug's action suggested that lidoflazine preferentially inhibits activated/open HERG channels. The S6 mutation Y652A largely eliminated the inhibitory action of lidoflazine, whilst the F656A mutation also reduced blocking potency. We conclude: first, that lidoflazine produces high affinity blockade of the alpha subunit of the HERG channel by binding to aromatic amino acid residues within the channel pore and, second, that this is likely to represent the molecular mechanism of QT interval prolongation by this drug.
Assuntos
Lidoflazina/metabolismo , Lidoflazina/farmacologia , Bloqueadores dos Canais de Potássio/metabolismo , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/antagonistas & inibidores , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Linhagem Celular , Canal de Potássio ERG1 , Eletrofisiologia , Canais de Potássio Éter-A-Go-Go , Humanos , Lidoflazina/química , Mutação/genética , Fenilalanina/genética , Fenilalanina/metabolismo , Bloqueadores dos Canais de Potássio/química , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Tirosina/genética , Tirosina/metabolismoRESUMO
Lidoflazine was metabolized very rapidly by 16000 g supernatant fractions of rat and dog liver. The rate and the extent of metabolism were considerably superior for rat liver. Lidoflazine metabolites were purified by extraction and thin-layer chromatography and identified by mass spectrometry. The main pathways of the in vitro metabolism by rat and dog liver fractions were the same. Oxidative N-dealkylation was the most important. An incubation of major metabolite 1-[4,4-bis(4-fluorophenyl)-butyl]piperazine, with rat liver fraction was performed. A hydroxylated metabolite and a ketopiperazine metabolite were detected only in the dog experiments.
