title: 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.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  We studied the relationship between pharmacogenetic variables and methadone metabolites and QT prolongation.
  
  
  METHODS
  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.
  
  
  RESULTS
  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±28.4 ms (mean±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 (∆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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Intermountain Heart Institute, 5121 South Cottonwood Street, Murray, UT, 84107, USA, john.carlquist@ihc.com.
authors.forename: John F
authors.initials: JF
authors.lastname: Carlquist
authors.forename: David E
authors.initials: DE
authors.lastname: Moody
authors.forename: Stacey
authors.initials: S
authors.lastname: Knight
authors.forename: Eric G
authors.initials: EG
authors.lastname: Johnson
authors.forename: Wenfang B
authors.initials: WB
authors.lastname: Fang
authors.forename: John A
authors.initials: JA
authors.lastname: Huntinghouse
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Rollo
authors.forename: Lynn R
authors.initials: LR
authors.lastname: Webster
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Anderson
mesh_terms: D000328:Adult; D000483:Alleles; D001145:Arrhythmias, Cardiac / Q000209:etiology*; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D004562:Electrocardiography; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008691:Methadone / Q000009:adverse effects* / Q000493:pharmacokinetics; D010597:Pharmacogenetics; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide; D011759:Pyrrolidines / Q000009:adverse effects* / Q000493:pharmacokinetics; D013997:Time Factors; D055815:Young Adult
chemical_list: D011759:Pyrrolidines; D065731:Cytochrome P-450 CYP2C19; D008691:Methadone; C010724:2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine