The effects of chiral isolates of methadone on the cardiac potassium channel IKr.
OBJECTIVE
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.


METHODS
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. r- and s-methadone were obtained by employing chiral high-performance liquid chromatography, separating methadone into 2 isolates, with optical rotations of -141 and +143 degrees.


RESULTS
At concentrations of 0.01, 0.03, 0.1, 1 and 3 mM, r/s-methadone produced a dose-dependent inhibition of HERG by 17 +/- 5, 23 +/- 4, 40 +/- 4, 57 +/- 3, 69 +/- 3 and 80 +/- 1%, respectively. The IC50 of r/s-methadone was 0.21 +/- 0.02 mM. At 0.1, 0.3 and 1 mM, s-methadone reduced HERG current by 50 +/- 4, 76 +/- 5 and 87 +/- 5%, respectively, while r-methadone reduced HERG current by 26 +/- 4, 53 +/- 3 and 77 +/- 3%, respectively.


CONCLUSIONS
There was a significant difference (p < 0.01) in the percentage of current inhibition between r- and s-methadone, at 0.1 and 0.3 mM (52% reduction). Thus, r-methadone may be a safer agent due to less QT effect.
Lin
Congrong
C
Rush University, Chicago, Ill., USA.
Somberg
Trudie
T
Molnar
Janos
J
Somberg
John
J
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects*; D005260:Female; D006801:Humans; D008691:Methadone / Q000494:pharmacology*; D009206:Myocardium / Q000378:metabolism; D009865:Oocytes; D020033:Protein Isoforms / Q000187:drug effects; D013237:Stereoisomerism; D014982:Xenopus laevis
D000701:Analgesics, Opioid; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D020033:Protein Isoforms; D008691:Methadone