A Novel CYP2C-Haplotype Associated With Ultrarapid Metabolism of Escitalopram.

Autor: Bråten LS; Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway.; Department of Life Sciences and Health, Faculty of Health Sciences, OsloMet - Oslo Metropolitan University, Oslo, Norway., Haslemo T; Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway.; Department of Life Sciences and Health, Faculty of Health Sciences, OsloMet - Oslo Metropolitan University, Oslo, Norway., Jukic MM; Section of Pharmacogenetics, Department of Physiology and Pharmacology, Biomedicum 5B, Karolinska Institutet, Stockholm, Sweden.; Department of Physiology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia., Ivanov M; Copenhagen Plant Science Centre, Department of Plant and Environmental Sciences, University of Copenhagen, Copenhagen, Denmark., Ingelman-Sundberg M; Section of Pharmacogenetics, Department of Physiology and Pharmacology, Biomedicum 5B, Karolinska Institutet, Stockholm, Sweden., Molden E; Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway.; Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway., Kringen MK; Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway.; Department of Life Sciences and Health, Faculty of Health Sciences, OsloMet - Oslo Metropolitan University, Oslo, Norway.
Jazyk: angličtina
Zdroj: Clinical pharmacology and therapeutics [Clin Pharmacol Ther] 2021 Sep; Vol. 110 (3), pp. 786-793. Date of Electronic Publication: 2021 Apr 13.
DOI: 10.1002/cpt.2233
Abstrakt: Escitalopram is one of the most commonly used antidepressant drugs but exhibits a substantial interindividual variation in clinical response. A key factor underlying response differences is the polymorphic nature of the CYP2C19 gene encoding the major enzyme responsible for escitalopram metabolism. Although pre-emptive CYP2C19 genotyping may improve escitalopram treatment outcome by dose individualization, much of the interindividual variability cannot be assigned to the currently known CYP2C19 gene variants. The aim of the present study was to search for novel CYP2C-haplotypes for better genetic prediction of escitalopram metabolism. First, the CYP2C18/CYP2C19 locus was sequenced from gDNA obtained from 24 patients previously genotyped as CYP2C19*1/*1 showing consistently low serum concentrations of escitalopram (< 25 nM/10 mg). Three new haplotypes of the CYP2C locus (CYP2C:TG, CYP2C:TA, and CYP2C:CG) were here identified, and their functional roles were evaluated using gDNA from 875 previously genotyped escitalopram-treated patients. The CYP2C:CG and CYP2C:TA haplotypes had no significant impact on escitalopram concentration. Based on the estimated effects of the novel CYP2C-haplotypes on escitalopram exposure, the predicted serum concentrations of escitalopram in homozygous CYP2C:TG and CYP2C19*17 carriers were 24.8% and 17.3% lower compared with the baseline (CYP2C:CG and CYP2C:TA), respectively. In conclusion, a novel CYP2C-haplotype defined by rs2860840T and rs11188059G associated with ultrarapid metabolism of escitalopram was identified. Further studies should clarify the genetic basis for the enhanced escitalopram metabolism and the impact of the CYP2C:TG haplotype on the metabolism of other CYP2C19 substrates like omeprazole, voriconazole, and clopidogrel.
(© 2021 The Authors. Clinical Pharmacology & Therapeutics © 2021 American Society for Clinical Pharmacology and Therapeutics.)
Databáze: MEDLINE
Externí odkaz: