Shams M E E, Arneth B, Hiemke C, Dragicevic A, Müller M J, Kaiser R, Lackner K, Härtter S
Department of Psychiatry, University of Mainz, Mainz, Germany.
J Clin Pharm Ther. 2006 Oct;31(5):493-502. doi: 10.1111/j.1365-2710.2006.00763.x.
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).
The aim of this study was to assess whether the O-demethylation phenotype of V has an impact on the pharmacokinetics and clinical outcome.
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.
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 CYP2D64 genotype, and one patient with an intermediate metabolic ratio of 4.8 had the genotype 4/2x1. 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.
The O-demethylation phenotype of V depends strongly on the CYP2D6 genotype. A PM phenotype of CYP2D6 increases the risk of side effects.
文拉法辛（V）是一种5-羟色胺和去甲肾上腺素再摄取抑制剂，用作抑郁症的一线治疗药物。它主要通过具有高度多态性的细胞色素P450（CYP）酶CYP2D6代谢，生成具有药理活性的代谢产物O-去甲基文拉法辛（ODV），在较小程度上通过CYP3A4代谢，生成N-去甲基文拉法辛（NDV）。
本研究旨在评估V的O-去甲基化表型是否对药代动力学和临床结果有影响。
在100例接受V治疗的患者中，测定V、ODV和NDV的血清浓度以及ODV/V浓度比作为O-去甲基化的指标。选择ODV/V代谢比异常高或低的个体进行基因分型。通过临床总体印象量表监测临床效果，通过UKU（临床研究副作用评定量表）评定量表监测副作用。
ODV/V比值存在较大的个体间差异。ODV/V比值的中位数为1.8，第10和第90百分位数分别为0.3和5.2。ODV/V比值低于0.3的个体均被鉴定为慢代谢者（PM），基因型为*6/4（n = 1）、5/4（n = 2）或6/6（n = 1）。比值高于5.2的个体均为基因重复导致的超快代谢者（UM，n = 6）。5例代谢活性中等（ODV/V，1.1±0.8）的个体为CYP2D64基因型杂合子，1例代谢比为4.8的患者基因型为4/2x1。临床结果测量显示，与其他患者相比，ODV/V比值低于0.3的患者有更多副作用（P < 0.005）且血清钠浓度降低（P < 0.05）。胃肠道副作用，尤其是恶心、呕吐和腹泻最为常见。不同表型之间的治疗效果差异不显著。
V的O-去甲基化表型强烈依赖于CYP2D6基因型。CYP2D6的PM表型会增加副作用风险。
