Postmortem blood concentrations of R- and S-enantiomers of methadone and EDDP in drug users: influence of co-medication and p-glycoprotein genotype.
We investigated toxicological and pharmacogenetic factors that could influence methadone toxicity using postmortem samples. R- and S-methadone were measured in femoral blood from 90 postmortem cases, mainly drug users. The R-enantiomer concentrations significantly exceeded that of the S-enantiomers (Wilcoxon's test, p < 0.001). The samples were divided into four groups according to other drugs detected (methadone only, methadone and strong analgesics, methadone and benzodiazepines, or methadone and other drugs). There was no significant difference in any of the R-methadone/total methadone ratios among the four groups. The median R/S ratio was 1.38, which tends to be higher than that reported for the plasma of living subjects. In addition, we investigated whether small nucleotide polymorphisms in the MDR1 gene that encode the drug transporter P-glycoprotein were associated with the concentrations of R- and S-methadone and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine. No significant association was detected.
Buchard
Anders
A
Section of Forensic Genetics, Department of Forensic Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. anders.buchard@forensic.ku.dk
Linnet
Kristian
K
Johansen
Sys Stybe
SS
Munkholm
Julie
J
Fregerslev
Michael
M
Morling
Niels
N
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000328:Adult; D000700:Analgesics / Q000097:blood; D001569:Benzodiazepines / Q000097:blood; D005260:Female; D053803:Forensic Genetics; D053593:Forensic Toxicology; D005838:Genotype; D006801:Humans; D008297:Male; D008691:Methadone / Q000097:blood* / Q000737:chemistry / Q000506:poisoning; D008875:Middle Aged; D009294:Narcotics / Q000097:blood* / Q000737:chemistry / Q000506:poisoning; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011180:Postmortem Changes; D011759:Pyrrolidines / Q000097:blood* / Q000737:chemistry; D013237:Stereoisomerism; D019966:Substance-Related Disorders / Q000097:blood
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000700:Analgesics; D009294:Narcotics; D011759:Pyrrolidines; D001569:Benzodiazepines; D008691:Methadone; C010724:2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine