Evaluation of the CYP2D6 Haplotype Activity Scores Based on Metabolic Ratios of 4,700 Patients Treated With Three Different CYP2D6 Substrates.
Journal
Clinical pharmacology and therapeutics
ISSN: 1532-6535
Titre abrégé: Clin Pharmacol Ther
Pays: United States
ID NLM: 0372741
Informations de publication
Date de publication:
09 2021
09 2021
Historique:
received:
21
10
2020
accepted:
08
02
2021
pubmed:
2
4
2021
medline:
15
9
2021
entrez:
1
4
2021
Statut:
ppublish
Résumé
The metabolic activity of the polymorphic CYP2D6 enzyme is dependent on the CYP2D6 genotype; however, the guidelines for translating the genotype into phenotype, which are of relevance for adequate drug dose personalization, are ambiguous. In the present study, retrospective therapeutic drug monitoring data from 4,700 CYP2D6 genotyped patients treated with risperidone, venlafaxine, and/or aripiprazole were analyzed to quantify the effect of CYP2D6 genotype on the CYP2D6 metabolic activities, as measured by metabolic ratios of these substrates. The patients were categorized into diplotypes based on the presence of normal function (CYP2D6Norm), nonfunctional (CYP2D6Nonf), and decreased function (CYP2D6Decr; i.e., CYP2D6*9, CYP2D6*10, and CYP2D6*41) CYP2D6 haplotypes. Significant correlations between the metabolic ratios were observed in patients (n = 77-103) cotreated with risperidone and venlafaxine, risperidone and aripiprazole, or venlafaxine and aripiprazole (ρ = 0.874, 0.785, and 0.644, respectively; P < 0.001 for all). Relative metabolic CYP2D6 diplotype activity was calculated based on that the metabolic ratios, where median values for CYP2D6Nonf/Nonf and CYP2D6Norm/Norm subgroups were set to 0% and 100%, respectively. The relative CYP2D6 activities were: 7.0% for CYP2D6Nonf/*41, 16.7% for CYP2D6Nonf/*9-10, 13.2% for CYP2D6*41/*41, 24.9% for CYP2D6*41/*9-10, 33.1% for CYP2D6*9-10/*9-10, 41.3% for CYP2D6Nonf/Norm, 55.0% for CYP2D6*41/Norm, 58.9% for CYP2D6*9-10/Norm, and 149.2% for CYP2D6Norm/Normx2. Compared with the CYP2D6Norm alleles, the activity scores of CYP2D6*41 and CYP2D6*9-10 alleles were estimated to be one sixth and one third, respectively. The results of this highly powered study provide a solid basis for the translation of the CYP2D6 genotype into a drug metabolic phenotype.
Substances chimiques
Antipsychotic Agents
0
Venlafaxine Hydrochloride
7D7RX5A8MO
Aripiprazole
82VFR53I78
Cytochrome P-450 CYP2D6
EC 1.14.14.1
Risperidone
L6UH7ZF8HC
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
750-758Subventions
Organisme : Swedish Research Council
ID : 2015-02760
Organisme : European Union's Horizon 2020 research and innovation program
ID : 668353/U-
Organisme : European Union's Horizon 2020 research and innovation program
ID : PGx
Organisme : Swedish Brain Foundation
ID : FO2019-0260
Organisme : South-Eastern Norway Regional Health Authority
ID : 2016-097
Organisme : Science Fund of the Republic of Serbia PROMIS program
ID : 6088600
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2021 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.
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