title: Determination of the unbound fraction of R- and S-methadone in human brain.
abstract: According to the free drug hypothesis, only the unbound fraction (fu) 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 fuvalues 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 fuvalues (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 fuwere found. Small but statistically significant differences in median fufor 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.
authors.affiliation: 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.holm@sund.ku.dk.
authors.forename: Karen M D
authors.initials: KM
authors.lastname: Holm
authors.affiliation: 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.
authors.forename: Kristian
authors.initials: K
authors.lastname: Linnet
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D053593:Forensic Toxicology; D066128:Gray Matter / Q000737:chemistry*; D006801:Humans; D008297:Male; D008691:Methadone / Q000032:analysis* / Q000493:pharmacokinetics; D008875:Middle Aged; D009294:Narcotics / Q000032:analysis* / Q000493:pharmacokinetics; D013237:Stereoisomerism; D055815:Young Adult
chemical_list: D009294:Narcotics; D008691:Methadone
keywords: Brain concentration; Equilibrium dialysis; Forensic toxicology; Methadone; R/S-enantiomers; Unbound fraction