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Stereoselective Block of hERG Channel by ( S )‐Methadone and QT Interval Prolongation in CYP2B6 Slow Metabolizers
Author(s) -
Eap C B,
Crettol S,
Rougier JS,
Schläpfer J,
Sintra Grilo L,
Déglon JJ,
Besson J,
CroquetteKrokar M,
Carrupt PA,
Abriel H
Publication year - 2007
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/sj.clpt.6100120
Subject(s) - herg , methadone , cyp2b6 , qt interval , pharmacology , medicine , long qt syndrome , anesthesia , confidence interval , potassium channel , cytochrome p450 , cyp3a4 , metabolism
Methadone inhibits the cardiac potassium channel hERG and can cause a prolonged QT interval. Methadone is chiral but its therapeutic activity is mainly due to ( R )‐methadone. Whole‐cell patch‐clamp experiments using cells expressing hERG showed that ( S )‐methadone blocked the hERG current 3.5‐fold more potently than ( R )‐methadone (IC 50 s (half‐maximal inhibitory concentrations) at 37°C: 2 and 7 μ M ). As CYP2B6 slow metabolizer (SM) status results in a reduced ability to metabolize ( S )‐methadone, electrocardiograms, CYP2B6 genotypes, and ( R )‐ and ( S )‐methadone plasma concentrations were obtained for 179 patients receiving ( R , S )‐methadone. The mean heart‐rate‐corrected QT (QTc) was higher in CYP2B6 SMs ( *6/*6 genotype; 439±25 ms; n =11) than in extensive metabolizers (non *6/*6 ; 421±25 ms; n =168; P =0.017). CYP2B6 SM status was associated with an increased risk of prolonged QTc (odds ratio=4.5, 95% confidence interval=1.2–17.7; P =0.03). This study reports the first genetic factor implicated in methadone metabolism that may increase the risk of cardiac arrhythmias and sudden death. This risk could be reduced by the administration of ( R )‐methadone. Clinical Pharmacology & Therapeutics (2007) 81 , 719–728. doi: 10.1038/sj.clpt.6100120 ; published online 28 February 2007