CYP2D6 and CYP2C19 genotypes and amitriptyline metabolite ratios in a series of medicolegal autopsies.
In a series of 202 postmortem toxicology cases, the CYP2D6 and CYP2C19 genes were genotyped, and the concentrations of amitriptyline (AT) and six metabolites were analyzed. The polymorphic CYP2D6 and CYP2C19 genes encode enzymes participating in the metabolism of several potentially toxic drugs, and mutations in these genes may lead to adverse drug reactions, possibly even intoxications. AT was chosen as the substrate of interest because it is mainly metabolized by these enzymes, is considered relatively toxic, and ranks among the major causes of fatal drug poisoning in Finland. Our objective was to evaluate genetically determined interindividual variation in conjunction with metabolite ratios of drugs found in toxicological analysis in a series of medicolegal autopsies. Positive correlations were found between the proportion of trans-hydroxylated metabolites and the number of functional copies of CYP2D6 and between the proportion of demethylated metabolites and the number of functional copies of CYP2C19. None of the accidental or undetermined AT poisonings coincided with the CYP2D6 or CYP2C19 genotype which predicts a poor metabolizer phenotype. However, an unusually high femoral blood concentration of AT, 60mg/l, was found in one suicide case with no functional CYP2D6 genes. Our study shows a concordance of AT metabolite patterns with CYP2D6 and CYP2C19 genotypes in the presence of confounding factors typical for postmortem material. This result demonstrates the feasibility of postmortem pharmacogenetic analysis and supports the dominant role of genes in drug metabolism.
Koski
Anna
A
Laboratory of Toxicology, Department of Forensic Medicine, P.O. Box 40, FI-00014 University of Helsinki, Finland. anna.koski@iki.fi
Sistonen
Johanna
J
Ojanperä
Ilkka
I
Gergov
Merja
M
Vuori
Erkki
E
Sajantila
Antti
A
D000639:Amitriptyline / Q000031:analogs & derivatives / Q000378:metabolism* / Q000506:poisoning; D000929:Antidepressive Agents, Tricyclic / Q000378:metabolism* / Q000506:poisoning; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D002853:Chromatography, Liquid; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005554:Forensic Medicine; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D006899:Mixed Function Oxygenases / Q000235:genetics*; D009661:Nortriptyline / Q000378:metabolism
D000929:Antidepressive Agents, Tricyclic; D000639:Amitriptyline; D009661:Nortriptyline; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; C033738:10-hydroxyamitriptyline