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Methadone and methadone metabolites in postmortem specimens

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Abstract

We have determined drug/metabolite concentrations and ratios of methadone (METH) to two of its metabolites (EDDP, 2-ethylidene-1, 5-dimethyl-3, 3-diphenylpyrrolidine; and EMDP, 2-ethyl-5-methyl-3,3-diphenylpyrroline) in postmortem peripheral blood and liver tissue by liquid chromatography/tandem mass spectrometry. The assays employed deuterated internal standards and multiple reaction monitoring (MRM) techniques. The assay linear range was 0.01–2.0 mg/l for each analyte. METH, EDDP, and EMDP were determined in liver and peripheral blood from 46 methadone-positive cases. METH and EDDP were detected in all specimens, whether blood or liver. EMDP was detected, only in liver, and only 17 cases, at concentrations much lower than those of EDDP. Concentrations of METH and EDDP in blood and liver from EMDP-positive cases were in ranges higher than, but overlapping with, concentrations in blood and liver from EMDP-negative cases. These data suggest that although METH is readily demethylated and cyclized to EDDP, in vivo, conversion to EMDP may be less efficient and its accumulation in postmortem tissues may be highly individual.

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References

  1. Karch SB, Stephens BG. Toxicology and pathology of deaths related to methadone: retrospective review. West J Med. 2000;172:11–4.

    Article  PubMed  CAS  Google Scholar 

  2. Milroy CM, Forrest ARW. Methadone deaths: a toxicological analysis. J Clin Pathol. 2000;53:277–81.

    Article  PubMed  CAS  Google Scholar 

  3. Gagajewski A, Apple FS. Methadone-related deaths in Hennepin County, Minnesota: 1992–2002. J Forensic Sci. 2003;48:668–71.

    PubMed  Google Scholar 

  4. Wolf BC, Lavezzi WA, Sullivan LM, Flannagan LM. Methadone-related deaths in Palm Beach County. J Forensic Sci. 2004;49:375–8.

    Article  PubMed  CAS  Google Scholar 

  5. Beckett AH, Taylor JF, Casy AF, Hasson MA. The biotransformation of methadone in man. Synthesis and identification of a metabolite. J Pharm Pharmacol. 1968;20:754–62.

    PubMed  CAS  Google Scholar 

  6. Pohland A, Boaz HE, Sullivan HR. Synthesis and identification of metabolites resulting from the biotransformation of dl-methadone in man and the rat. J Med Chem. 1971;14:194–7.

    Article  PubMed  CAS  Google Scholar 

  7. Alburges ME, Huang W, Foltz RL, Moody DE. Determination of methadone and its N-demethylation metabolites in biological specimens by GC-PICI-MS. J Anal Toxicol. 1996;20:362–8.

    PubMed  CAS  Google Scholar 

  8. Choo RE, Murphy CM, Jones HE, Huestis MA. Determination of methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine, 2-ethyl-5-methyl-3,3-diphenylpyroline and methadol in meconium by liquid chromatography atmospheric pressure chemical ionization tandem mass spectrometry. J Chromatogr B. 2005;814:369–73.

    Article  CAS  Google Scholar 

  9. Shakleya DM, Jansson LM, Huestis MA. Validation of a LC-APCI-MS-MS method for quantification of methadone, 2-ethylidene-1, 5-dimethyl-3, 3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3, 3-diphenylpyroline (EMDP) in infant plasma following protein precipitation. J Chromatogr B. 2007;856:267–72.

    Article  CAS  Google Scholar 

  10. Sullivan HR, Due SL. Urinary metabolites of d, l-methadone in maintenance subjects. J Med Chem. 1973;16:909–13.

    Article  PubMed  CAS  Google Scholar 

  11. Verebely K, Volavka J, Salvatore M, Resnick R. Methadone in man: pharmacokinetic and excretion studies in acute and chronic treatment. Clin Pharmacol Ther. 1975;18:180–90.

    PubMed  CAS  Google Scholar 

  12. Henderson GL, Wilson BK, Lau DHM. Plasma l-α-acetylmethadol (LAAM) after acute and chronic administration. Clin Pharmacol Ther. 1977;21:16–25.

    PubMed  CAS  Google Scholar 

  13. Kaiko RF, Inturrisi CE. Disposition of acetylmethadol in relation to pharmacological action. Clin Pharmacol Ther. 1975;18:96–103.

    PubMed  CAS  Google Scholar 

  14. Totah RA, Allen KE, Sheffels P, Whittington D, Kharasch ED. Enantiomeric metabolic interactions and stereoselective human methadone metabolism. J Pharmacol Exp Ther. 2007;321:389–99.

    Article  PubMed  CAS  Google Scholar 

  15. Eap CB, Broly F, Mino A, Hammig R, Uelinger C, Meili D, Chevalley AF, Bertschy G, Zullino G, Kosel M, Preisig M, Baumann P. Cytochrome P450 2D6 genotype and methadone steady-state concentrations. J Clin Psychopharmacol. 2001;21:229–34.

    Article  PubMed  CAS  Google Scholar 

  16. Crettol S, Déglon JJ, Besson J, Croquette-Krokkar M, Gothuey I, Hämmig R, Monnat M, Hüttemann H, Baumann P, Eap CB. Methadone enantiomer plasma levels, CYP2B6, CYP2C19, and CYP2C9 genotypes, and response to treatment. Clin Pharmacol Ther. 2005;78:593–604.

    Article  PubMed  CAS  Google Scholar 

  17. Begre S, von Bardeleben U, Ladewig D, Jaquet-Rochat S, Cosendai-Savary L, Golay KP, Kosel M, Baumann P, Eap CB. Paroxetine increases steady-state concentrations of (R)-methadone in CYP2D6 extensive but not poor metabolizers. J Clin Psychopharmacol. 2002;22:211–5.

    Article  PubMed  CAS  Google Scholar 

  18. Uelinger C, Crettol S, Chasson P, Koeb L, Brawand-Amey M, Eap CB. Increased (R)-methadone plasma concentrations by quetiapine in cytochrome P450s and ABCB1 genotyped patients. J Clin Psychopharmacol. 2007;27:273–8.

    Article  Google Scholar 

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Acknowledgements

The authors acknowledge the assistance of Linda Alvarado, Jeffrey Wise and Glenn Schott of the Harris County Medical Examiner’s Office who conducted the LC/MS/MS determinations.

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Correspondence to Ashraf Mozayani.

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Danielson, T.J., Mozayani, A. & Sanchez, L.A. Methadone and methadone metabolites in postmortem specimens. Forensic Sci Med Pathol 4, 170–174 (2008). https://doi.org/10.1007/s12024-008-9039-7

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  • DOI: https://doi.org/10.1007/s12024-008-9039-7

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