Correlation of inter-individual variations of amitriptyline metabolism examined in hairs with CYP2C19 and CYP2D6 polymorphisms.
The metabolite ratio of amitriptyline (AT), nortriptyline (NT) and its 10-hydroxy metabolites (E10-OHAT, Z10-OHAT, E10-OHNT and Z10-OHNT) was examined by liquid chromatography-mass spectrometry in hair samples of 23 white infants after long-term administration of AT. High inter-individual variation of the metabolite ratios were observed (e.g. NT/AT = 0.8-8.1, E10-OHNT/Z10-OHNT = 1.6-10.3). The significance of these variations was proven by confirmation of the temporary stability of these ratios within a hair fibre. Moreover, an association of the metabolic phenotype with genetic disposition was observed. The genotypes of CYP2C19 (alleles *2, *3 and *4) and of CYP2D6 (*3, *4, and *6) were examined by conventional polymerase chain reaction genotyping experiments. The relative amount of demethylation (NT/AT) is clearly affected by the number of functional alleles of CYP2C19. The demethylation capacity of CYP2C19 poor metabolizers (3 individuals, compared to 15 extensive metabolizers) was 4.3 times depleted. Moreover, the selectivity of hydroxylation (e.g. E10-OHNT/Z10-OHNT) is significantly correlated with CYP2C19.
Thieme
Detlef
D
Institute of Forensic Medicine, Nussbaumstrasse 26, 80336 Munich, Germany. det.thieme@web.de
Rolf
Burkhard
B
Sachs
Hans
H
Schmid
Dagmar
D
D000483:Alleles; D000639:Amitriptyline / Q000493:pharmacokinetics*; D000929:Antidepressive Agents, Tricyclic / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002853:Chromatography, Liquid; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D053593:Forensic Toxicology; D005838:Genotype; D006197:Hair / Q000378:metabolism*; D006801:Humans; D013058:Mass Spectrometry; D009661:Nortriptyline / Q000378:metabolism; D011110:Polymorphism, Genetic
D000929:Antidepressive Agents, Tricyclic; D000639:Amitriptyline; D009661:Nortriptyline; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6