Impact of CYP2D6 on serum concentrations of flupentixol, haloperidol, perphenazine and zuclopenthixol.
CYP450
antipsychotics
genetic polymorphism
serum concentrations
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:
05 2021
05 2021
Historique:
revised:
14
09
2020
received:
19
05
2020
accepted:
13
10
2020
pubmed:
30
10
2020
medline:
21
9
2021
entrez:
29
10
2020
Statut:
ppublish
Résumé
To investigate the impact of cytochrome P450 2D6 (CYP2D6) on dose-adjusted serum concentrations of flupentixol, haloperidol, perphenazine and zuclopenthixol in a therapeutic drug monitoring (TDM) cohort of psychiatric patients. We also studied the functional impact of CYP2D6*41 on dose-adjusted serum concentrations in the perphenazine-treated patients. Serum concentrations of flupentixol, haloperidol, perphenazine and zuclopenthixol from CYP-genotyped patients were extracted retrospectively from a routine TDM database in the period March 2005 to May 2019. Samples were divided into three CYP2D6 phenotype subgroups according to genotype; normal metabolizers (NMs), intermediate metabolizers (IMs) and poor metabolizers (PMs). The effect of CYP2D6 phenotype on dose-adjusted serum concentrations of the four antipsychotics was evaluated by multivariable mixed model analyses. Mean dose-adjusted serum concentrations of perphenazine (564 samples) were 3.9-fold and 1.6-fold higher in CYP2D6 PMs and IMs, respectively, compared with NMs (P < .001 and P < .01). For zuclopenthixol (658 samples), mean dose-adjusted serum concentrations were about 1.5-fold and 1.3-fold higher in CYP2D6 PMs and IMs, respectively, compared with NMs (P < .01 and P < .001). CYP2D6 was of minor or no importance to haloperidol (320 samples) and flupentixol (115 samples). In our data material, the genotype CYP2D6 *1/*41 appears to have a similar impact on dose-adjusted serum concentrations of perphenazine as *1/null (null = variant allele encoding no enzyme function). This study shows that CYP2D6 is important for the metabolism of perphenazine and zuclopenthixol, but not for haloperidol and flupentixol. The CYP2D6*41 allele appears to have a reduced function close to nonfunctional variant alleles.
Substances chimiques
Clopenthixol
982-24-1
Cytochrome P-450 CYP2D6
EC 1.14.14.1
Flupenthixol
FA0UYH6QUO
Perphenazine
FTA7XXY4EZ
Haloperidol
J6292F8L3D
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2228-2235Informations de copyright
© 2020 British Pharmacological Society.
Références
Summary of product characteristics: haloperidol. Available at: https://www.ema.europa.eu/en/documents/referral/haldol-article-30-referral-annex-iii_en.pdf. Accessed March 30, 2020.
UpToDate. Haloperidol drug information. Available at: https://www.uptodate.com/contents/haloperidol-drug-information. Accessed March 30, 2020.
UpToDate. Perphenazine drug information. Available at: https://www.uptodate.com/contents/perphenazine-drug-information. Accessed March 30, 2020.
Lundbeck. Zuclopenthixol product monograph. Available at: https://www.lundbeck.com/upload/ca/en/files/pdf/pm/Clopixol.pdf. Accessed March 30, 2020.
UpToDate. Zuclopenthixol drug information. Available at: https://www.uptodate.com/contents/zuclopenthixol-drug-information. Accessed March 30, 2020.
Hiemke C, Bergemann N, Clement HW, et al. Consensus guidelines for therapeutic drug monitoring in Neuropsychopharmacology: update 2017. Pharmacopsychiatry. 2018;51(1-02):9-62.
PharmGKB. Very important pharmacogene: CYP2D6. Available at: https://www.pharmgkb.org/vip/PA166170264. Accessed March 30, 2020.
Caudle KE, Sangkuhl K, Whirl-Carrillo M, et al. Standardizing CYP2D6 genotype to phenotype translation: consensus recommendations from the clinical Pharmacogenetics implementation consortium and Dutch Pharmacogenetics working group. Clin Transl Sci. 2020;13(1):116-124.
Jerling M, Dahl ML, Aberg-Wistedt A, et al. The CYP2D6 genotype predicts the oral clearance of the neuroleptic agents perphenazine and zuclopenthixol. Clin Pharmacol Ther. 1996;59(4):423-428.
Linnet K, Wiborg O. Influence of Cyp2D6 genetic polymorphism on ratios of steady-state serum concentration to dose of the neuroleptic zuclopenthixol. Ther Drug Monit. 1996;18(6):629-634.
Patteet L, Haufroid V, Maudens K, Sabbe B, Morrens M, Neels H. Genotype and co-medication dependent CYP2D6 metabolic activity: effects on serum concentrations of aripiprazole, haloperidol, risperidone, paliperidone and zuclopenthixol. Eur J Clin Pharmacol. 2016;72:175-184.
Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine. 2007. Available at: https://drug-interactions.medicine.iu.edu. Accessed March 30, 2020.
The Norwegian Medicines Agency. Norwegian drug interaction website. Available at: www.legemiddelinteraksjoner.no. Accessed March 30, 2020.
Dahl ML. Cytochrome p450 phenotyping/genotyping in patients receiving antipsychotics: useful aid to prescribing? Clin Pharmacokinet. 2002;41(7):453-470.
Zhou SF. Polymorphism of human cytochrome P450 2D6 and its clinical significance: part II. Clin Pharmacokinet. 2009;48(12):761-804.
Pan L, Vander Stichele R, Rosseel MT, Berlo JA, De Schepper N, Belpaire FM. Effects of smoking, CYP2D6 genotype, and concomitant drug intake on the steady state plasma concentrations of haloperidol and reduced haloperidol in schizophrenic inpatients. Ther Drug Monit. 1999;21(5):489-497.
Brockmöller J, Kirchheiner J, Schmider J, et al. The impact of the CYP2D6 polymorphism on haloperidol pharmacokinetics and on the outcome of haloperidol treatment. Clin Pharmacol Ther. 2002;72(4):438-452.
Shimoda K, Someya T, Morita S, et al. Lower plasma levels of haloperidol in smoking than in nonsmoking schizophrenic patients. Ther Drug Monit. 1999;21(3):293-296.
Jin Y, Pollock BG, Coley K, et al. Population pharmacokinetics of perphenazine in schizophrenia patients from CATIE: impact of race and smoking. J Clin Pharmacol. 2010;50(1):73-80.
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.
Waade RB, Molden E, Refsum H, Hermann M. Serum concentrations of antidepressants in the elderly. Ther Drug Monit. 2012;34(1):25-30.
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.
Molden E, Waade RB, Hoff M, Haslemo T. Impact of ageing on serum concentrations of risperidone and its active metabolite in patients with known CYP2D6 genotype. Basic Clin Pharmacol Toxicol. 2016;119(5):470-475.
Haslemo T, Eliasson E, Jukic MM, Ingelman-Sundberg M, Molden E. 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. Br J Clin Pharmacol. 2019;85(1):194-201.