The Effects of Chiral Isolates of Methadone on the Cardiac Potassium Channel IKr

Abstract

<i>Objectives:</i> Methadone is a synthetic opioid, an analgesic and an antiaddictive. QT prolongation as well as torsade de pointes ventricular tachycardia and death have been reported with methadone. Methadone’s proarrhythmic toxicity is related to the inhibition of cardiac IKr channel and prolongation of the action potential. We hypothesized that the 2 isomers of methadone may have different effects on the IKr channel. <i>Methods:</i> The effects of the isomers on IKr were evaluated by using an oocytes system with heterogeneously expressed human ether-a-go-go-related gene (HERG) using the 2 electrode voltage clamp technique. <i>r-</i> and <i>s</i>-methadone were obtained by employing chiral high-performance liquid chromatography, separating methadone into 2 isolates, with optical rotations of –141 and +143 degrees. <i>Results:</i> At concentrations of 0.01, 0.03, 0.1, 1 and 3 m<i>M</i>, <i>r/s</i>-methadone produced a dose-dependent inhibition of HERG by 17 ± 5, 23 ± 4, 40 ± 4, 57 ± 3, 69 ± 3 and 80 ± 1%, respectively. The IC<sub>50</sub> of <i>r/s</i>-methadone was 0.21 ± 0.02 m<i>M</i>. At 0.1, 0.3 and 1 m<i>M</i>, <i>s</i>-methadone reduced HERG current by 50 ± 4, 76 ± 5 and 87 ± 5%, respectively, while <i>r</i>-methadone reduced HERG current by 26 ± 4, 53 ± 3 and 77 ± 3%, respectively. <i>Conclusions:</i> There was a significant difference (p < 0.01) in the percentage of current inhibition between <i>r-</i> and <i>s</i>-methadone, at 0.1 and 0.3 m<i>M</i> (52% reduction). Thus, <i>r</i>-methadone may be a safer agent due to less QT effect.