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

Authors :
Iwersen-Bergmann S
Plattner S
Hischke S
Müller A
Andresen-Streichert H
Jungen H
Erb R
Beer-Sandner B
Source :
International journal of legal medicine [Int J Legal Med] 2021 Mar; Vol. 135 (2), pp. 473-482. Date of Electronic Publication: 2021 Jan 17.
Publication Year :
2021

Abstract

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.

Details

Language :
English
ISSN :
1437-1596
Volume :
135
Issue :
2
Database :
MEDLINE
Journal :
International journal of legal medicine
Publication Type :
Academic Journal
Accession number :
33454797
Full Text :
https://doi.org/10.1007/s00414-021-02502-5