Metabolic ratios of psychotropics as indication of cytochrome P450 2D6/2C19 genotype.
The cytochrome P450 enzymes (CYP) 2C19 and 2D6 are involved in the metabolism of many psychotropic drugs. Variability in enzyme activity results in variable metabolic capacities, affecting the metabolism of substrates. The metabolic ratio (MR) of drugs metabolized via these enzymes may therefore reflect the enzyme's activity and/or genotype. To serve as an example for different groups of medications, the selective serotonin reuptake inhibitor venlafaxine, the tricyclic antidepressant amitriptyline, and the antipsychotic risperidone were studied to examine a possible correlation between the MRs of these drugs and the CYP2C19 and/or CYP2D6 genotype. For this purpose data from routine genotyping and serum level analysis were used. The relationships between the observed metabolic ratios and CYP2D6 and/or CYP2C19 genotype were characterized using nonparametric statistical analysis. A clear correlation was observed between the CYP2D6 genotype and the metabolic ratio of venlafaxine. Genotyping of individuals with a log(MR) < -0.6 or a log(MR) > 0.2 would include all patients with an aberrant genotype but would result in a reduction of 52% of genotyping reactions. Slow metabolism of amitriptyline is correlated with a log(MR) > 0.4. Genotyping only those subjects with a log(MR) > 0.4 would result in 88% fewer genotyping reactions. For risperidone, genotyping individuals with a log(MR) > 0.4 would include all CYP2D6 poor metabolizers while reducing the number of genotyping reactions by 93%. According to these data, correlations exist between the log(MR) of venlafaxine, amitriptyline, and risperidone and the genotype of the CYP enzymes involved in their metabolism. From the ranges of log(MR) defined here, a high percentage of aberrant metabolizers can be detected even when patients are not routinely genotyped. Thus, the metabolic ratio may serve as an indication of when genotyping should be considered.
van der Weide
Jan
J
Department of Clinical Chemistry, St Jansdal Hospital, Harderwijk, The Netherlands. j.vander.weide@stjansdal.nl
van Baalen-Benedek
Erica H
EH
Kootstra-Ros
Jenny E
JE
D000483:Alleles; D000639:Amitriptyline / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D003511:Cyclohexanols / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D000069468:Desvenlafaxine Succinate; D004789:Enzyme Activation / Q000187:drug effects; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008657:Metabolic Clearance Rate; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism; D011619:Psychotropic Drugs / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D018967:Risperidone / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D000069470:Venlafaxine Hydrochloride
D003511:Cyclohexanols; D011619:Psychotropic Drugs; D000639:Amitriptyline; D000069470:Venlafaxine Hydrochloride; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D018967:Risperidone; D000069468:Desvenlafaxine Succinate