Stereoselective block of hERG channel by (S)-methadone and QT interval prolongation in CYP2B6 slow metabolizers.
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 (IC50s (half-maximal inhibitory concentrations) at 37 degrees C: 2 and 7 microM). 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.
Eap
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Unit of Biochemistry and Clinical Psychopharmacology, Centre for Psychiatric Neurosciences, University Department of Psychiatry-CHUV, Hospital of Cery, Prilly-Lausanne, Switzerland. chin.eap@chuv.ch
Crettol
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Rougier
J-S
JS
Schläpfer
J
J
Sintra Grilo
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L
Déglon
J-J
JJ
Besson
J
J
Croquette-Krokar
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M
Carrupt
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PA
Abriel
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D000328:Adult; D000483:Alleles; D000701:Analgesics, Opioid / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D065702:Cytochrome P-450 CYP2B6; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography / Q000187:drug effects; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects*; D005260:Female; D005838:Genotype; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008691:Methadone / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D008875:Middle Aged; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013237:Stereoisomerism
D000701:Analgesics, Opioid; D018076:DNA, Complementary; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D026902:Potassium Channel Blockers; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; D008691:Methadone