Significantly lower CYP2D6 metabolism measured as the O/N-desmethylvenlafaxine metabolic ratio in carriers of CYP2D6*41 versus CYP2D6*9 or CYP2D6*10: a study on therapeutic drug monitoring data from 1003 genotyped Scandinavian patients.
Aged
Alleles
Antidepressive Agents, Second-Generation
/ administration & dosage
Cyclohexanols
/ administration & dosage
Cytochrome P-450 CYP2D6
/ genetics
Desvenlafaxine Succinate
/ administration & dosage
Drug Monitoring
/ statistics & numerical data
Female
Genotype
Humans
Male
Middle Aged
Norway
Retrospective Studies
Venlafaxine Hydrochloride
/ administration & dosage
CYP2D6
CYP2D6*10
CYP2D6*41
CYP2D6*9
genotype
phenotype
Journal
British journal of clinical pharmacology
ISSN: 1365-2125
Titre abrégé: Br J Clin Pharmacol
Pays: England
ID NLM: 7503323
Informations de publication
Date de publication:
01 2019
01 2019
Historique:
received:
29
05
2018
revised:
26
09
2018
accepted:
30
09
2018
pubmed:
13
10
2018
medline:
31
12
2019
entrez:
13
10
2018
Statut:
ppublish
Résumé
CYP2D6*9, CYP2D6*10 and CYP2D6*41 are the most frequent reduced-function CYP2D6 alleles in Caucasians. Despite lacking in vivo evidence, they are collectively classified with an enzyme activity score of 0.5. Thus, the aim of this study was to compare the functional impact of CYP2D6*9, CYP2D6*10 and CYP2D6*41 on CYP2D6 metabolism in a large patient population. A total of 1003 patients (mainly Caucasians) with data on CYP2D6 genotype and serum concentrations of venlafaxine and metabolites were included from a therapeutic drug monitoring service in Oslo, Norway. The O-desmethyl-to-N-desmethyl-venlafaxine metabolic ratio (MR) was applied as CYP2D6 biomarker and compared (Mann-Whitney) between carriers of CYP2D6*9-10 (merged) and CYP2D6*41, either combined with CYP2D6*1 or non-coding (null) alleles. MR subgroup estimates were obtained by multiple linear regression for calculations of CYP2D6*9-10 and CYP2D6*41 activity scores. MR was significantly lower in carriers of CYP2D6*41 than CYP2D6*9-10 (P < 0.002). The majority of CYP2D6*41/null carriers (86.7%) had MR in the observed range of CYP2D6null/null carriers compared with the minority of CYP2D6*9-10/null carriers (17.4%). CYP2D6 genotype explained 60.7% of MR variability in the multivariate analysis providing subgroup estimates of 9.54 (95% CI; 7.45-12.20), 3.55 (2.06-6.10), 1.33 (0.87-2.05) and 0.47 (0.35-0.61) in carriers of CYP2D6*1/null (n = 269), CYP2D6*9-10/null (n = 17), CYP2D6*41/null (n = 30) and CYP2D6null/null (n = 95), respectively. Based on these estimates, the calculated activity score of CYP2D6*41 was 0.095 compared to 0.34 for CYP2D6*9-10. CYP2D6 metabolism measured as the O/N-desmethylvenlafaxine ratio is significantly lower in Scandinavian carriers of CYP2D6*41 vs. CYP2D6*9-10. Thus, these alleles should be differentiated when classifying CYP2D6 phenotype from genotype.
Identifiants
pubmed: 30312494
doi: 10.1111/bcp.13788
pmc: PMC6303206
doi:
Substances chimiques
Antidepressive Agents, Second-Generation
0
Cyclohexanols
0
N-desmethylvenlafaxine
19V5EX4E8B
Venlafaxine Hydrochloride
7D7RX5A8MO
Cytochrome P-450 CYP2D6
EC 1.14.14.1
Desvenlafaxine Succinate
ZB22ENF0XR
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
194-201Informations de copyright
© 2018 The British Pharmacological Society.
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