Brain/blood ratios of methadone and ABCB1 polymorphisms in methadone-related deaths

Autor: S. Hischke, Stefanie Iwersen-Bergmann, R. Erb, Hilke Jungen, B. Beer-Sandner, Alexander Müller, Hilke Andresen-Streichert, S. Plattner
Rok vydání: 2020
Předmět:
Adult
Male
medicine.medical_specialty
Spectrometry
Mass
Electrospray Ionization
ATP Binding Cassette Transporter
Subfamily B
Genotype
Single-nucleotide polymorphism
rs1045642
P-glycoprotein
030226 pharmacology & pharmacy
Polymorphism
Single Nucleotide
Gas Chromatography-Mass Spectrometry
Pathology and Forensic Medicine
03 medical and health sciences
Forensic Toxicology
0302 clinical medicine
Internal medicine
Cerebellum
Medicine
Humans
030216 legal & forensic medicine
Chromatography
High Pressure Liquid
Methadone-related death
Medulla Oblongata
biology
business.industry
Venous blood
Femoral Vein
Middle Aged
Brain/blood-ratio
ABCB1 polymorphism
Endocrinology
Opioid
Blood-Brain Barrier
Toxicity
biology.protein
Female
Original Article
business
Site of action
Blood Chemical Analysis
Methadone
medicine.drug
Zdroj: International Journal of Legal Medicine
ISSN: 1437-1596
Popis: Methadone is an opioid that often leads to fatalities. Interpretation of toxicological findings can be challenging if no further information about the case history is available. The aims of this study were (1) to determine whether brain/blood ratios can assist in the interpretation of methadone findings in fatalities; (2) to examine whether polymorphisms in the gene encoding the P-glycoprotein (also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1)), which functions as a multispecific efflux pump in the blood–brain barrier, affect brain/blood ratios of methadone. Femoral venous blood and brain tissue (medulla oblongata and cerebellum) from 107 methadone-related deaths were analysed for methadone by gas chromatography-mass spectrometry. In addition, all the samples were genotyped for three common ABCB1 single nucleotide polymorphisms (SNPs rs1045642, rs1128503, and rs2032582) using ion-pair reversed-phase high-performance liquid chromatography-electrospray ionization mass spectrometry (ICEMS). In nearly all cases, methadone concentrations were higher in the brain than in the blood. Inter-individual brain/blood ratios varied (0.6–11.6); the mean ratio was 2.85 (standard deviation 1.83, median 2.35). Moreover, significant differences in mean brain/blood ratios were detected among the synonymous genotypes of rs1045642 in ABCB1 (p = 0.001). Cases with the T/T genotype had significantly higher brain/blood ratios than cases with the other genotypes (T/T vs. T/C difference (d) = 1.54, 95% CI [1.14, 2.05], p = 0.002; T/T vs. C/C d = 1.60, 95% CI [1.13, 2.29], p = 0.004). Our results suggest that the rs1045642 polymorphisms in ABCB1 may affect methadone concentrations in the brain and its site of action and may be an additional factor influencing methadone toxicity.
Databáze: OpenAIRE
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