Stereoselective block of hERG channel by (S)-methadone and QT interval prolongation in CYP2B6 slow metabolizers.

Détails

ID Serval
serval:BIB_DBDA92B48C27
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Stereoselective block of hERG channel by (S)-methadone and QT interval prolongation in CYP2B6 slow metabolizers.
Périodique
Clinical Pharmacology and Therapeutics
Auteur(s)
Eap C.B., Crettol S., Rougier J.S., Schläpfer J., Sintra Grilo L., Déglon J.J., Besson J., Croquette-Krokar M., Carrupt P.A., Abriel H.
ISSN
0009-9236
Statut éditorial
Publié
Date de publication
2007
Peer-reviewed
Oui
Volume
81
Numéro
5
Pages
719-728
Langue
anglais
Résumé
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.
Mots-clé
Adult, Alleles, Analgesics, Opioid, Aryl Hydrocarbon Hydroxylases, DNA, Complementary, Electrocardiography, Ether-A-Go-Go Potassium Channels, Female, Genotype, Heart Rate, Humans, Kinetics, Long QT Syndrome, Male, Methadone, Middle Aged, Oxidoreductases, N-Demethylating, Patch-Clamp Techniques, Potassium Channel Blockers, Reverse Transcriptase Polymerase Chain Reaction, Stereoisomerism
Pubmed
Web of science
Création de la notice
05/02/2008 13:40
Dernière modification de la notice
20/08/2019 16:00
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