A Possible Mechanistic Link Between the CYP2C19 Genotype, the Methadone Metabolite Ethylidene-1,5-Dimethyl-3,3-Diphenylpyrrolidene (EDDP), and Methadone-Induced Corrected QT Interval Prolongation in a Pilot Study

Methadone use and methadone-associated sudden cardiac death have increased dramatically. Prolongation of the QT interval of the cardiac cycle predisposes to arrhythmia and is common among methadone users. We studied the relationship between pharmacogenetic variables and methadone metabolites and QT prolongation. Blood was obtained on days 1, 7, and 21 from consenting individuals initiating methadone treatment. Plasma methadone and ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidene (EDDP) were measured using liquid chromatographic-electrospray ionization-tandem mass spectrometry. The corrected QT interval (QTc) from 12-lead electrocardiograms (ECGs) was obtained at baseline and at 21 days. Total plasma EDDP, (S)-EDDP, and (R)-EDDP concentrations were significantly higher for individuals carrying the CYP2C19*2 variant (n = 8) than in 17 subjects carrying the CYP2C19 wild-type allele (p < 0.004). Seventeen (68 %) of 25 subjects experienced a QTc (Bazett) of 39.9 +/- A 28.4 ms (mean +/- A standard deviation). The methadone dose and the plasma EDDP concentration corrected for dose were both significantly associated with QTc at study termination and with change in QTc interval from baseline (a dagger QTc) (p < 0.03 to p < 0.0003). Based on a QTc increase, five subjects had a potentially increased arrhythmia risk. Compared with other participants, the mean dose for those individuals was higher (50.8 vs. 42.5 mg/day; p < 0.04) as was the total plasma EDDP (36.8 vs. 21.0 ng/mL; p < 0.002) and dose-corrected EDDP (0.27 vs. 0.16 ng/mL/mg; p < 0.003). These results suggest that a notable change in the QTc interval was associated with both oral dose and increased methadone metabolism, as indicated by the higher plasma concentration of the principal methadone metabolite. The oral dose and plasma EDDP concentration may be useful in identifying individuals at risk for methadone-related arrhythmia.