Effects of common antitussive drugs on the hERG potassium channel current.
A common over-the-counter (OTC) non-opioid antitussive drug, clobutinol, was recently withdrawn from the market due to its potential to induce cardiac arrhythmias by a blockade of the potassium channel coded by the human ether-à-go-go-related gene (hERG). In this study, we investigated the effects of a number of antitussive compounds on the hERG ion channel current using patch-clamp electrophysiology, and compared the effects to that of clobutinol. The compounds clobutinol, pentoxyverine, dextromethorphan, and codeine inhibited the outward current in hERG transfected cells with half-maximal inhibition concentrations (IC50) of 1.9 microM, 3.0 microM, 5.1 microM, and 97 microM, respectively. For theobromine, no significant effect on the hERG current at a concentration up to 100 microM was detected. Safety margins between the effects of the drugs on the hERG ion channel current and their calculated maximal free therapeutic plasma concentration were calculated. These results were compared to assess potential risks of the compounds to induce torsade de pointes-type arrhythmias.
Deisemann
Heike
H
Evotec AG, Hamburg, Germany.
Ahrens
Nadine
N
Schlobohm
Irene
I
Kirchhoff
Christian
C
Netzer
Rainer
R
Möller
Clemens
C
D000605:Amino Alcohols / Q000633:toxicity; D000818:Animals; D000996:Antitussive Agents / Q000633:toxicity*; D016466:CHO Cells; D003061:Codeine / Q000633:toxicity; D006224:Cricetinae; D003412:Cricetulus; D003517:Cyclopentanes / Q000633:toxicity; D003915:Dextromethorphan / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008564:Membrane Potentials; D011188:Potassium / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000009:adverse effects*; D013805:Theobromine / Q000633:toxicity; D013997:Time Factors; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000378:metabolism; D014162:Transfection
D000605:Amino Alcohols; D000996:Antitussive Agents; D003517:Cyclopentanes; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D026902:Potassium Channel Blockers; C017135:clobutinol; C018861:carbetapentane; D003915:Dextromethorphan; D013805:Theobromine; D011188:Potassium; D003061:Codeine