Combined effect of CYP2C19 and CYP2D6 genotypes on escitalopram serum concentration and its metabolic ratio in a European patient population.
CYP2C19
CYP2D6
escitalopram
pharmacogenetics
therapeutic drug monitoring
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:
26 Jun 2024
26 Jun 2024
Historique:
revised:
30
05
2024
received:
09
01
2024
accepted:
09
06
2024
medline:
27
6
2024
pubmed:
27
6
2024
entrez:
26
6
2024
Statut:
aheadofprint
Résumé
The aim of the present study was to investigate the impact of CYP2D6 genotype on exposure and metabolism of escitalopram in patients stratified by CYP2C19 genotype in a large real-world population. Patients were included from a therapeutic drug monitoring service if they had measured serum concentration of escitalopram and the metabolite, N-desmethyl escitalopram, and performed CYP2C19 and CYP2D6 genotyping. Patients were divided into 16 combined genotype-predicted phenotype subgroups (poor [PM], intermediate [IM], normal [NM] and ultrarapid metabolizers [UM]) of CYP2C19/CYP2D6. The concentration-to-dose (CD) ratio and metabolite-to-parent ratio (metabolic ratio) of escitalopram were compared across subgroups using the Kruskal-Wallis test followed by Dunn's test with CYP2D6 NMs as the reference group. A total of 5067 patients were included in the study. A stepwise increase in escitalopram CD ratio by decreasing CYP2D6 activity was observed in all CYP2C19 subgroups, except for in CYP2C19 UMs. The percentage differences in escitalopram CD ratio between CYP2D6 PMs and NMs were 24% in CYP2C19 NMs (P < .001), 28% in CYP2C19 IMs (P < .001) and 31% in CYP2C19 PMs (P = .04). As for the CD ratio, CYP2D6 genotype effect on metabolic ratio increased stepwise by decreasing CYP2C19 metabolism. CYP2D6 genotype is of significant importance for the individual variation in escitalopram pharmacokinetics. The most relevant increase in escitalopram concentration is seen in individuals with decreased and/or absent CYP2C19 activity. By combining CYP2C19 and CYP2D6 genotypes, the optimal dose for patients may be predicted with greater precision than for CYP2C19 genotype alone.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : ERA PerMed
ID : ERAPERMED2021-357
Informations de copyright
© 2024 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
Références
Norwegian Institute of Public Health. Norwegian prescription database. Accessed December 8, 2023. https://www.reseptregisteret.no/
Kobayashi K, Chiba K, Yagi T, et al. Identification of cytochrome P450 isoforms involved in citalopram N‐demethylation by human liver microsomes. J Pharmacol Exp Ther. 1997;280(2):927‐933.
Rochat B, Amey M, Gillet M, Meyer UA, Baumann P. Identification of three cytochrome P450 isozymes involved in N‐demethylation of citalopram enantiomers in human liver microsomes. Pharmacogenetics. 1997;7(1):1‐10. doi:10.1097/00008571‐199702000‐00001
Sindrup SH, Brøsen K, Hansen MGJ, Aaes‐Jørgensen T, Overø KF, Gram LF. Pharmacokinetics of citalopram in relation to the sparteine and the mephenytoin oxidation polymorphisms. Ther Drug Monit. 1993;15(1):11‐17. doi:10.1097/00007691‐199302000‐00002
Von Moltke LL, Greenblatt DJ, Giancarlo GM, Granda BW, Harmatz JS, Shader RI. Escitalopram (S‐citalopram) and its metabolites in vitro: cytochromes mediating biotransformation, inhibitory effects, and comparison to R‐citalopram. Drug Metab Dispos. 2001;29:1102‐1109.
Bousman CA, Stevenson JM, Ramsey LB, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A genotypes and serotonin reuptake inhibitor antidepressants. Clin Pharmacol Ther. 2023;114(1):51‐68. doi:10.1002/cpt.2903
Pharmacogene Variation Consortium (PharmVar). Accessed December 8, 2023. https://www.pharmvar.org/
Jukić MM, Haslemo T, Molden E, Ingelman‐Sundberg M. Impact of CYP2C19 genotype on escitalopram exposure and therapeutic failure: a retrospective study based on 2,087 patients. Am J Psychiatry. 2018;175(5):463‐470. doi:10.1176/appi.ajp.2017.17050550
Hu X‐x, Yuan L‐j, Fang P, et al. Effect of CYP2D6 genetic polymorphism on the metabolism of citalopram in vitro. Drug Metab Pharmacokinet. 2016;31(2):133‐138. doi:10.1016/j.dmpk.2016.01.001
Herrlin K, Yasui‐Furukori N, Tybring G, Widén J, Gustafsson LL, Bertilsson L. Metabolism of citalopram enantiomers in CYP2C19/CYP2D6 phenotyped panels of healthy Swedes. Br J Clin Pharmacol. 2003;56(4):415‐421. doi:10.1046/j.1365‐2125.2003.01874.x
Faraj P, Hermansen A, Molden E, Hole K. Identification of escitalopram metabolic ratios as potential biomarkers for predicting CYP2C19 poor metabolizers. Ther Drug Monit. 2022;44(6):720‐728. doi:10.1097/FTD.0000000000000991
Bråten LS, Haslemo T, Jukic MM, et al. A novel CYP2C‐haplotype associated with ultrarapid metabolism of escitalopram. Clin Pharmacol Ther. 2021;110(3):786‐793. doi:10.1002/cpt.2233
Waade RB, Hermann M, Moe HL, Molden E. Impact of age on serum concentrations of venlafaxine and escitalopram in different CYP2D6 and CYP2C19 genotype subgroups. Eur J Clin Pharmacol. 2014;70(8):933‐940. doi:10.1007/s00228‐014‐1696‐8
Rudberg I, Mohebi B, Hermann M, Refsum H, Molden E. Impact of the ultrarapid CYP2C1917 allele on serum concentration of escitalopram in psychiatric patients. Clin Pharmacol Ther. 2008;83(2):322‐327. doi:10.1038/sj.clpt.6100291
Brouwer JMJL, Nijenhuis M, Soree B, et al. Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene–drug interaction between CYP2C19 and CYP2D6 and SSRIs. Eur J Hum Genet. 2022;30(10):1114‐1120. doi:10.1038/s41431‐021‐01004‐7
Alexander SPH, Fabbro D, Kelly E, et al. The concise guide to PHARMACOLOGY 2023/24: enzymes. Br J Pharmacol. 2023;180(Suppl 2):S289‐S373. doi:10.1111/bph.16181
Tsuchimine S, Ochi S, Tajiri M, et al. Effects of cytochrome P450 (CYP) 2C19 genotypes on steady‐state plasma concentrations of escitalopram and its desmethyl metabolite in Japanese patients with depression. Ther Drug Monit. 2018;40(3):356‐361. doi:10.1097/FTD.0000000000000506
Fudio S, Borobia AM, Piñana E, et al. Evaluation of the influence of sex and CYP2C19 and CYP2D6 polymorphisms in the disposition of citalopram. Eur J Pharmacol. 2010;626(2‐3):200‐204. doi:10.1016/j.ejphar.2009.10.007
Scherf‐Clavel M, Frantz A, Eckert A, et al. Effect of CYP2D6 pharmacogenetic phenotype and phenoconversion on serum concentrations of antidepressants and antipsychotics: a retrospective cohort study. Int. J Clin Pharm Ther. 2023;45(5):1107‐1117. doi:10.1007/s11096‐023‐01588‐8
Shelton RC, Parikh SV, Law RA, et al. Combinatorial pharmacogenomic algorithm is predictive of citalopram and escitalopram metabolism in patients with major depressive disorder. Psychiatry Res. 2020;290:113017. doi:10.1016/j.psychres.2020.113017
Olesen OV, Linnet K. Studies on the stereoselective metabolism of citalopram by human liver microsomes and cDNA‐expressed cytochrome P450 enzymes. Pharmacology. 1999;59(6):298‐309. doi:10.1159/000028333
Rohrbacher J, Bex P, Gallacher DJ. Citalopram metabolites inhibit IKs and IKr differentially: is this a possible explanation for the sudden deaths in dogs? J Pharmacol Toxicol Methods. 2012;66(2):170. doi:10.1016/j.vascn.2012.08.040
Jin Y, Pollock BG, Frank E, et al. Effect of age, weight, and CYP2C19 genotype on escitalopram exposure. J Clin Pharmacol. 2010;50(1):62‐72. doi:10.1177/0091270009337946
Reis M, Aamo T, Spigset O, Ahlner J. Serum concentrations of antidepressant drugs in a naturalistic setting: compilation based on a large therapeutic drug monitoring database. Ther Drug Monit. 2009;31(1):42‐56. doi:10.1097/FTD.0b013e31819114ea
Birkeland Waade R, Molden E, Refsum H, Hermann M. Serum concentrations of antidepressants in the elderly. Ther Drug Monit. 2012;34(1):25‐30. doi:10.1097/FTD.0b013e318241dce0
Lundbeck Limited. Cipralex 5 mg film‐coated tablets Summary of Product Characteristics (SmPC). Accessed January 8, 2024. https://www.medicines.org.uk/emc/product/7718/smpc#about-medicine