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Comparison of the Effects of Methadone and Heroin on Humanether-a`-go-go-Related Gene ChannelsBernd J. Zu¨nkler • Maria Wos-MagangaPublished online: 14 May 2010? Springer Science+Business Media, LLC 2010Abstract Torsades de pointes (TdP) is a life-threateningform of ventricular arrhythmia that occurs under conditionsof delayed cardiac repolarization indicated by prolonged QTintervals in ECG recordings. The main mechanism of QTprolongation and TdP is block of the rapid component of thecardiac delayed rectif i er K ? current (I Kr ), which is encodedby hERG (human ether-a`-go-go-related gene). The opioidagonist methadone has previously been demonstrated toinhibit hERG currents, and there are reports of serious car-diac arrhythmias and deaths from TdP and ventricularf i brillation in patients taking methadone. The aim of thepresent study was to compare the effects of the opioid ago-nistsmethadoneandheroin(3,6-diacetylmorphine)onhERGcurrents stably expressed in human embryonic kidney (HEK293) cells using the whole-cell conf i guration of the patch-clamp technique. Both methadone and heroin inhibit hERGcurrents in a concentration-dependent manner. The follow-ing values were calculated for IC 50 (concentration causinghalf-maximal inhibition)and n (theHill coeff i cient):4.8 lMand 0.9 for methadone, 427 lM and 0.7 for heroin. Inconclusion, the potency for block of hERG currents is about100-fold lower for heroin when compared to methadone.Keywords Methadone ? Heroin ? hERG channelIntroductionTorsades de Pointes (TdP) is a life-threatening form ofventricular arrhythmia that occurs under conditions ofdelayed cardiac repolarization indicated by prolonged QTintervals in ECG recordings. The main mechanism of QTinterval prolongation and TdP is block of the rapid com-ponent of the cardiac delayed rectif i er K ? current (I Kr ) [1].hERG (human ether-a`-go-go-related gene) encodes theK v 11.1 protein a-subunit that underlies the I Kr in the heart[2–4].Several non-cardiovascular drugs have the potential toinduce QT interval prolongations or TdP arrhythmias [5].Since most of these torsadogenic drugs block hERG cur-rents, hERG current block is an indicator of potential pro-arrhythmic activity [6]. Therefore, the ICH S7B guideline[7] makes hERG current block studies mandatory in drugdevelopment.In most cases, only a few agents of a therapeutic classshare the ability to inhibit hERG currents [5]. For example,the opioid agonists methadone and L -a-acetyl-methadol(levacetylmethadol, LAAM) have been shown to blockhERG currents at half-maximally inhibitory concentrations(IC 50 values) of 9.8–19 lM [8, 9] and 2.2 lM [8],respectively. In contrast, codeine and morphine are far lesspotent hERG current inhibitors [8].Methadone, a l-opioid receptor agonist, is used formaintenance treatment of opioid-dependent patients and insome countries for treatment of pain. A QTc intervalgreater than 500 ms was observed in 2% of patients whoreceived more than 100 mg/day methadone, and similardoses were found in cases of TdP arrhythmias. However,sudden cardiac death associated with the administration ofmethadone has been described also at lower doses of29 mg/day. This shows that arrhythmias may occur acrossa wide dose range [10]. In 2006, the FDA issued a blackbox warning inserted in the product labeling regardingcardiac arrhythmias and deaths associated with the use ofmethadone. Recently, an expert panel in the USAB. J. Zu¨nkler (&) ? M. Wos-MagangaFederal Institute for Drugs and Medical Devices, Kurt-Georg-Kiesinger-Allee 3, 53175 Bonn, Germanye-mail: Jochen.Zuenkler@bfarm.de; j.zuenkler@bfarm.deCardiovasc Toxicol (2010) 10:161–165DOI 10.1007/s12012-010-9074-y