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.
Highlights
Methadone is a μ-opioid receptor agonist and the primary drug used in maintenance treatment of heroin-dependentS
The aim of this study was to investigate if brain/blood ratios of methadone correlate with these common ABCB1 polymorphisms, which might reveal new insights into the toxicity of methadone
In 19 cases (17.7%), death was attributable to methadone toxicity alone, whereas for the remaining 82.3% of cases, death was attributed to a combination of methadone and blood alcohol levels > 0.3% (19.2%), benzodiazepines (31.0%), opiates/heroin (17.2%), or cocaine (13.9%)
Summary
Methadone is a μ-opioid receptor agonist and the primary drug used in maintenance treatment of heroin-dependentS. (R)-methadone, better known as levomethadone, is available for therapy. It is the active enantiomer at the μ-opioid receptor [3] and about twice as potent as the racemate. Methadone is metabolized mainly in the liver by cytochrome P450 (CYP) enzymes. CYP2B6 and CYP3A4 are the main CYP enzymes with CYP2D6 and CYP2C19 making minor contributions [4, 5]. Polymorphisms in the genes that encode the CYP enzymes result in poor, extensive, or rapid metabolizers. A given dose of methadone can show broad inter-individual variations in methadone blood concentrations in living individuals. Eap and coworkers [4] reported a 17-fold inter-individual variation of blood concentrations for the same dose of
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