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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

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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.

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Acknowledgments

MEMORIES (ClinicalTrials.gov identifier NCT01191242) was funded in part by Grants from the Intermountain Healthcare Research and Medical Foundation and the Del Loy Hansen Heart Foundation. The authors would like to acknowledge Mark Morgan and Dawn Neimann and Discovery House Addiction Treatment Center for their invaluable contributions to the conduct of this study.

Conflict of interest

There are no financial relationships on the part of any author that could potentially bias the findings reported in the manuscript.

Author contributions

John F. Carlquist: Obtained funding, study design and analysis, manuscript preparation (guarantor of content). David E. Moody: Study design, metabolite analysis, manuscript preparation. Stacey Knight: Study design, statistical design, manuscript preparation. Eric G. Johnson: Study design and coordination. Wenfang B. Fang: Methadone and methadone metabolite analyses, manuscript preparation. John A. Huntinghouse: Designed and validated single nucleotide polymorphism (SNP) assays, manuscript preparation. Jeffrey S. Rollo: Designed and validated SNP assays, manuscript preparation. Lynn R. Webster: Study design, methadone maintenance treatment consultant, manuscript preparation. Jeffrey L. Anderson: Study design, ECG interpretation, manuscript preparation.

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Authors and Affiliations

  1. Intermountain Heart Institute, Intermountain Healthcare, Murray, UT, USA

    Stacey Knight, Eric G. Johnson, John A. Huntinghouse, Jeffrey S. Rollo & Jeffrey L. Anderson

  2. Cardiology Division, Department of Medicine, University of Utah, Salt Lake City, UT, USA

    John F. Carlquist & Jeffrey L. Anderson

  3. Center for Human Toxicology, University of Utah, Salt Lake City, UT, USA

    David E. Moody & Wenfang B. Fang

  4. Lifetree Clinical Research, Salt Lake City, UT, USA

    Lynn R. Webster

  5. Intermountain Heart Institute, 5121 South Cottonwood Street, Murray, UT, 84107, USA

    John F. Carlquist

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  1. John F. Carlquist
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Correspondence to John F. Carlquist.

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Carlquist, J.F., Moody, D.E., Knight, S. et al. 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. Mol Diagn Ther 19, 131–138 (2015). https://doi.org/10.1007/s40291-015-0137-4

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  • DOI: https://doi.org/10.1007/s40291-015-0137-4

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