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Published in: Forensic Science, Medicine and Pathology 3/2008

01-09-2008 | Original Paper

Methadone and methadone metabolites in postmortem specimens

Authors: Terry J. Danielson, Ashraf Mozayani, Luis A. Sanchez

Published in: Forensic Science, Medicine and Pathology | Issue 3/2008

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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.
Literature
1.
go back to reference Karch SB, Stephens BG. Toxicology and pathology of deaths related to methadone: retrospective review. West J Med. 2000;172:11–4.PubMedCrossRef Karch SB, Stephens BG. Toxicology and pathology of deaths related to methadone: retrospective review. West J Med. 2000;172:11–4.PubMedCrossRef
2.
go back to reference Milroy CM, Forrest ARW. Methadone deaths: a toxicological analysis. J Clin Pathol. 2000;53:277–81.PubMedCrossRef Milroy CM, Forrest ARW. Methadone deaths: a toxicological analysis. J Clin Pathol. 2000;53:277–81.PubMedCrossRef
3.
go back to reference Gagajewski A, Apple FS. Methadone-related deaths in Hennepin County, Minnesota: 1992–2002. J Forensic Sci. 2003;48:668–71.PubMed Gagajewski A, Apple FS. Methadone-related deaths in Hennepin County, Minnesota: 1992–2002. J Forensic Sci. 2003;48:668–71.PubMed
4.
go back to reference Wolf BC, Lavezzi WA, Sullivan LM, Flannagan LM. Methadone-related deaths in Palm Beach County. J Forensic Sci. 2004;49:375–8.PubMedCrossRef Wolf BC, Lavezzi WA, Sullivan LM, Flannagan LM. Methadone-related deaths in Palm Beach County. J Forensic Sci. 2004;49:375–8.PubMedCrossRef
5.
go back to reference 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 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
6.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
7.
go back to reference 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 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
8.
go back to reference 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.CrossRef 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.CrossRef
9.
go back to reference 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.CrossRef 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.CrossRef
10.
go back to reference Sullivan HR, Due SL. Urinary metabolites of d, l-methadone in maintenance subjects. J Med Chem. 1973;16:909–13.PubMedCrossRef Sullivan HR, Due SL. Urinary metabolites of d, l-methadone in maintenance subjects. J Med Chem. 1973;16:909–13.PubMedCrossRef
11.
go back to reference 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 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
12.
go back to reference Henderson GL, Wilson BK, Lau DHM. Plasma l-α-acetylmethadol (LAAM) after acute and chronic administration. Clin Pharmacol Ther. 1977;21:16–25.PubMed Henderson GL, Wilson BK, Lau DHM. Plasma l-α-acetylmethadol (LAAM) after acute and chronic administration. Clin Pharmacol Ther. 1977;21:16–25.PubMed
13.
go back to reference Kaiko RF, Inturrisi CE. Disposition of acetylmethadol in relation to pharmacological action. Clin Pharmacol Ther. 1975;18:96–103.PubMed Kaiko RF, Inturrisi CE. Disposition of acetylmethadol in relation to pharmacological action. Clin Pharmacol Ther. 1975;18:96–103.PubMed
14.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
15.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
16.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
17.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
18.
go back to reference 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.CrossRef 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.CrossRef
Metadata
Title
Methadone and methadone metabolites in postmortem specimens
Authors
Terry J. Danielson
Ashraf Mozayani
Luis A. Sanchez
Publication date
01-09-2008
Publisher
Humana Press Inc
Published in
Forensic Science, Medicine and Pathology / Issue 3/2008
Print ISSN: 1547-769X
Electronic ISSN: 1556-2891
DOI
https://doi.org/10.1007/s12024-008-9039-7

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