ArticleMolecular diagnosis & therapy2015
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.
Article in Molecular diagnosis & therapy, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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12 citing papers in PubMed, 29 citations in OpenAlex.
- Exploring the Role of Metabolites in Torsadogenic Risk Assessment: A Text-Mining Approach.Turkish journal of pharmaceutical sciences · 2026Article
- Methadone administration and QT interval prolongation: protocol for a systematic review and meta-analysis.BMJ open · 2026Article
- Pharmacogenetic exploration of buprenorphine and related metabolites in umbilical cord blood.Toxicology reports · 2025Article
- The Relevance of Pharmacokinetic Biomarkers in Response to Methadone Treatment: A Systematic Review.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Genetic Associations of Persistent Opioid Use After Surgery Point to OPRM1 but Not Other Opioid-Related Loci as the Main Driver of Opioid Use Disorder.Genetic epidemiology · 2025Article
- Methadone pharmacogenetics in vitro and in vivo: Metabolism by CYP2B6 polymorphic variants and genetic variability in paediatric disposition.British journal of clinical pharmacology · 2022Article
- Stereoselective methadone disposition after administration of racemic methadone to anesthetized Shetland ponies assessed by capillary electrophoresis.Electrophoresis · 2021Article
- Pharmacogenomics of methadone: a narrative review of the literature.Pharmacogenomics · 2020Review
- Integrating in vitro data and physiologically based kinetic modeling-facilitated reverse dosimetry to predict human cardiotoxicity of methadone.Archives of toxicology · 2020Article
- Effects of cytochrome P450 single nucleotide polymorphisms on methadone metabolism and pharmacodynamics.Biochemical pharmacology · 2018Review
- Pharmacogenetics of Opioid Use Disorder Treatment.CNS drugs · 2018Review
- Pharmacogenetics of Methadone Response.Molecular diagnosis & therapy · 2018Review
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundMethadone 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.
objectiveWe studied the relationship between pharmacogenetic variables and methadone metabolites and QT prolongation.
methodsBlood 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.
resultsTotal 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).
conclusionsThese 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.
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