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Determination of the unbound fraction of R- and S-methadone in human brain

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Abstract

According to the free drug hypothesis, only the unbound fraction (f u ) of a given drug is biologically available in terms of its pharmacologic activity. Methadone shows large interpersonal variation in toxicity. The goal of the work presented here was to examine whether isolating the unbound fraction of the active R-methadone enantiomer from brain matter could be of value as a forensic tool. A method applying equilibrium dialysis to postmortem brain samples was validated and showed good reproducibility for the previously published f u values for eight common drugs (alprazolam, citalopram, codeine, methadone, morphine, diazepam, oxycodone, tramadol), as well as methadone enantiomers. This method was then applied to approximately 50 authentic case samples with R-methadone and S-methadone concentrations ranging from 0.03 to 13 and 0.6 to 6.8 mg/kg, respectively; median f u values (R-and S-methadone) were 3.9 % (range 3.0–5.3 %) and 3.7 % (range 2.9–4.9 %). No overall correlation between the active R-methadone concentration and f u were found. Small but statistically significant differences in median f u for the R-methadone enantiomer were identified between case-categories (i.e., poisoning with multiple drugs, methadone poisoning, and deaths unrelated to methadone), but these are thought to be too low to be of any forensic value.

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Acknowledgments

Thank you to Bente Jensen at H. Lundbeck A/S, Copenhagen, for giving a hands-on introduction to the applied dialysis principle.

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  1. Section of Forensic Chemistry, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Frederik Femte Vej 11, DK-2100, Copenhagen, Denmark

    Karen M. D. Holm & Kristian Linnet

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  1. Karen M. D. Holm
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  2. Kristian Linnet
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Correspondence to Karen M. D. Holm.

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Holm, K.M.D., Linnet, K. Determination of the unbound fraction of R- and S-methadone in human brain. Int J Legal Med 130, 1519–1526 (2016). https://doi.org/10.1007/s00414-016-1365-9

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  • DOI: https://doi.org/10.1007/s00414-016-1365-9

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