CYP2D6 polymorphism and clinical effect of the antidepressant venlafaxine.

Article Details

Citation

Shams ME, Arneth B, Hiemke C, Dragicevic A, Muller MJ, Kaiser R, Lackner K, Hartter S

CYP2D6 polymorphism and clinical effect of the antidepressant venlafaxine.

J Clin Pharm Ther. 2006 Oct;31(5):493-502.

PubMed ID
16958828 [ View in PubMed
]
Abstract

BACKGROUND: Venlafaxine (V) is a mixed serotonin and noradrenaline reuptake inhibitor used as a first-line treatment of depressive disorders. It is metabolized primarily by the highly polymorphic cytochrome P450 (CYP) enzyme CYP2D6 to yield a pharmacologically active metabolite, O-desmethylvenlafaxine (ODV), and to a lesser extent by CYP3A4, to yield N-desmethylvenlafaxine (NDV). OBJECTIVES: The aim of this study was to assess whether the O-demethylation phenotype of V has an impact on the pharmacokinetics and clinical outcome. METHOD: In 100 patients treated with V, serum concentrations of V, ODV and NDV and the ratios of concentrations ODV/V as a measure of O-demethylation were determined. Individuals exhibiting abnormally high or low metabolic ratios of ODV/V were selected for genotyping. Clinical effects were monitored by the Clinical Global Impressions Scale and side effects by the UKU (Udvalg for Kliniske Undersogelser Side Effect Rating Scale) rating scale. RESULTS: There was wide inter-individual variability in ODV/V ratios. The median ratio ODV/V was 1.8 and the 10th and 90th percentiles 0.3 and 5.2, respectively. Individuals with ODV/V ratios below 0.3 were all identified as poor metabolizers (PM), with the genotypes *6/*4 (n = 1), *5/*4 (n = 2) or *6/*6 (n = 1). Individuals with ratios above 5.2 were all ultra rapid metabolizers (UM, n = 6) due to gene duplications. Five individuals with intermediate metabolic activity (ODV/V, 1.1 +/- 0.8) were heterozygotes with the CYP2D6*4 genotype, and one patient with an intermediate metabolic ratio of 4.8 had the genotype *4/2x*1. Clinical outcome measurements revealed that patients with ODV/V ratios below 0.3 had more side effects (P < 0.005) and reduced serum concentrations of sodium (P < 0.05) in comparison with other patients. Gastrointestinal side effects, notably nausea, vomiting and diarrhoea were the most common. Differences in therapeutic efficacy were not significant between the different phenotypes. CONCLUSION: The O-demethylation phenotype of V depends strongly on the CYP2D6 genotype. A PM phenotype of CYP2D6 increases the risk of side effects.

DrugBank Data that Cites this Article

Pharmaco-genomics
DrugInteracting Gene/EnzymeAllele nameGenotypesDefining change(s)Type(s)DescriptionDetails
VenlafaxineCytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635
CYP2D6*4(A;A)Effect Directly StudiedPatients with this genotype have reduced metabolism of venlafaxine.Details
VenlafaxineCytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635
CYP2D6*6(-;-) / (-;T)Effect Directly StudiedPatients with this genotype have reduced metabolism of venlafaxine.Details
VenlafaxineCytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635
CYP2D6*5Not Available
  • Whole gene deletion, homozygote
Effect Directly StudiedPatients with this genotype have reduced metabolism of venlafaxine.Details