title: Post-mortem levels and tissue distribution of codeine, codeine-6-glucuronide, norcodeine, morphine and morphine glucuronides in a series of codeine-related deaths.
abstract: This article presents levels and tissue distribution of codeine, codeine-6-glucuronide (C6G), norcodeine, morphine and the morphine metabolites morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) in post-mortem blood (peripheral and heart blood), vitreous fluid, muscle, fat and brain tissue in a series of 23 codeine-related fatalities. CYP2D6 genotype is also determined and taken into account. Quantification of codeine, C6G, norcodeine, morphine, M3G and M6G was performed with a validated solid phase extraction LC-MS method. The series comprise 19 deaths (83%) attributed to mixed drug intoxication, 4 deaths (17%) attributed to other causes of death, and no cases of unambiguous monointoxication with codeine. The typical peripheral blood concentration pattern in individual cases was C6G≫codeine≫norcodeine>morphine, and M3G>M6G>morphine. In matrices other than blood, the concentration pattern was similar, although in a less systematic fashion. Measured concentrations were generally lower in matrices other than blood, especially in brain and fat, and in particular for the glucuronides (C6G, M3G and M6G) and, to some extent, morphine. In brain tissue, the presumed active moieties morphine and M6G were both below the LLOQ (0.0080mg/L and 0.058mg/L, respectively) in a majority of cases. In general, there was a large variability in both measured concentrations and calculated blood/tissue concentration ratios. There was also a large variability in calculated ratios of morphine to codeine, C6G to codeine and norcodeine to codeine in all matrices, and CYP2D6 genotype was not a reliable predictor of these ratios. The different blood/tissue concentration ratios showed no systematic relationship with the post-mortem interval. No coherent degradation or formation patterns for codeine, morphine, M3G and M6G were observed upon reanalysis in peripheral blood after storage.
authors.affiliation: Department of Laboratory Medicine, Children's and Womens's Health, Norwegian University of Science and Technology (NTNU), Trondheim, Norway; Department of Clinical Pharmacology, St. Olav University Hospital, Trondheim, Norway. Electronic address: joachim.frost@stolav.no.
authors.forename: Joachim
authors.initials: J
authors.lastname: Frost
authors.affiliation: Department of Laboratory Medicine, Children's and Womens's Health, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
authors.forename: Trine Nordgård
authors.initials: TN
authors.lastname: Løkken
authors.affiliation: Department of Laboratory Medicine, Children's and Womens's Health, Norwegian University of Science and Technology (NTNU), Trondheim, Norway; Department of Clinical Pharmacology, St. Olav University Hospital, Trondheim, Norway.
authors.forename: Arne
authors.initials: A
authors.lastname: Helland
authors.affiliation: Department of Laboratory Medicine, Children's and Womens's Health, Norwegian University of Science and Technology (NTNU), Trondheim, Norway; Department of Pathology and Medical Genetics, St. Olav University Hospital, Trondheim, Norway.
authors.forename: Ivar Skjåk
authors.initials: IS
authors.lastname: Nordrum
authors.affiliation: Department of Laboratory Medicine, Children's and Womens's Health, Norwegian University of Science and Technology (NTNU), Trondheim, Norway; Department of Clinical Pharmacology, St. Olav University Hospital, Trondheim, Norway.
authors.forename: Lars
authors.initials: L
authors.lastname: Slørdal
mesh_terms: D000273:Adipose Tissue / Q000737:chemistry; D000328:Adult; D000368:Aged; D001923:Brain Chemistry; D002853:Chromatography, Liquid; D003061:Codeine / Q000031:analogs & derivatives / Q000032:analysis* / Q000493:pharmacokinetics*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D005260:Female; D053593:Forensic Toxicology; D005838:Genotype; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D009020:Morphine / Q000032:analysis* / Q000493:pharmacokinetics; D009022:Morphine Derivatives / Q000032:analysis / Q000493:pharmacokinetics; D018482:Muscle, Skeletal / Q000737:chemistry; D009664:Norway / Q000453:epidemiology; D011180:Postmortem Changes; D052616:Solid Phase Extraction; D019966:Substance-Related Disorders / Q000401:mortality; D014018:Tissue Distribution; D014822:Vitreous Body / Q000737:chemistry; D055815:Young Adult
chemical_list: D009022:Morphine Derivatives; C010414:norcodeine; C035349:morphine-6-glucuronide; D009020:Morphine; C061773:codeine-6-glucuronide; D019389:Cytochrome P-450 CYP2D6; C018108:morphine-3-glucuronide; D003061:Codeine
keywords: Codeine; Forensic toxicology; Post-mortem; Tissue distribution; Toxicity