Drug metabolic enzyme genotype-phenotype discrepancy: High phenoconversion rate in patients treated with antidepressants

Y. Gloor, C. Lloret-Linares, M. Bosilkovska, N. Perroud, H. Richard-Lepouriel, J. M. Aubry, Y. Daali, J. A. Desmeules, M. Besson

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18 Citations (Scopus)

Résumé

Cytochromes from the P450 family (CYP) play a central role in the primary metabolism of frequently prescribed antidepressants, potentially affecting their efficacy and tolerance. There are however important differences in the drug metabolic capacities of each individual resulting from a combination of intrinsic and environmental factors. This variability can present an important risk for patients and increases the difficulty of drug prescription in clinical practice. Pharmacogenetic studies have uncovered a number of alleles defining the intrinsic metabolizer status, however, additional factors affecting cytochrome activity can modify this activity and result in a phenoconversion. The present study investigates the discrepancy between the genetically predicted and actually measured activities for the six most important liver cytochromes (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) in a cohort of patients under antidepressant treatment, previously shown to have a high proportion of patients with low metabolizing activities. We now performed the genetic characterization of this cohort to determine the extent of the genetic versus environmental contribution in these decreased activities. For all enzyme tested, we observed an important rate of phenoconversion, affecting between 33 % and 65 % of the patients, as well as a significant (p < 1E-06) global reduction in the effective but not predicted activities of CYP2D6, CYP2C9 and CYP2C19 compared to the general population. Our results highlight the advantages of phenotyping versus genotyping as well as the increased risk of treatment failure or adverse effect occurrence in a polymedicated population.

Langue d'origineEnglish
Numéro d'article113202
JournalBiomedicine and Pharmacotherapy
Volume152
DOI
Statut de publicationPublished - août 2022
Publié à l'externeOui

Note bibliographique

Funding Information:
This work was supported by the APSI (Anesthesiology, Pharmacology and Intensive Care) department of the Geneva University Hospitals (HUG).

Publisher Copyright:
© 2022 The Authors

ASJC Scopus Subject Areas

  • Pharmacology

PubMed: MeSH publication types

  • Journal Article

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