Steady state plasma levels of nortriptyline and its 1.0-hydroxy metabolite: Relationship to the CYP2D6 genotype
Steady state plasma levels of nortriptyline and its 1.0-hydroxy metabolite: Relationship to the CYP2D6 genotype
复制标题
DOI：
10.1007/bf02246640
复制
发表时间：
1996-02-01
影响因子：
3.4
通讯作者：
Nordin, C
中科院分区：
文献类型：
--
作者：
Dahl, ML;Bertilsson, L;Nordin, C
研究了21例白种人抑郁症患者CYP2D6基因型与去甲替林（NT）及其主要活性代谢物10-羟基去甲替林（10-OH-NT）稳态血浆水平及NT/10-OH-NT比值的关系。这些患者参加了先前发表的一项研究，该研究调查了NT和10-OH-NT在NT治疗效果中的作用，血浆水平数据来自该研究。在本随访研究中，通过等位基因特异性PCR扩增和EcoRI RFLP对患者CYP2D6多态性进行基因分型。在20个广泛代谢物（EM）中，没有发现基因型（纯合子与杂合子EM）单独解释剂量校正后NT浓度的差异，但当性别也被考虑时，这一差异有显著影响。总的来说，这些因素占了NT水平变异的59%。女性患者血浆NT水平高于男性患者，10-OH-NT水平受基因型影响，NT/10-OH-NT比值受基因型和性别影响。本研究证实了CYP2D6基因型与血浆NT及其活性代谢物水平之间的关系。通过基因分型鉴定PM对预测血浆水平和最佳治疗所需的低于平均剂量的NT具有价值。同样在EM中，基因型对NT和10-OH-NT水平的变化有影响，但单独用于预测最佳剂量的实用价值有限。
The relationship between the CYP2D6 genotype and the steady state plasma levels of nortriptyline (NT), its main active metabolite 10-hydroxynortriptyline (10-OH-NT) and the NT/10-OH-NT ratio were studied in 21 Caucasian depressed patients treated with 100-150 mg NT daily. The patients had participated in a previously published study investigating the role of NT and 10-OH-NT for the therapeutic effect of NT and the plasma level data were from that study. In the present follow-up study, the patients were genotyped with respect to the polymorphic CYP2D6 by allele-specific PCR amplification and EcoRI RFLP. One poor metabolizer (PM) was identified and she had the highest plasma concentration of NT Among the 20 extensive metabolizers (EM), the genotype (homozygous versus heterozygous EM) alone was not found to explain the variance in dose-corrected NT concentrations, but contributed significantly when gender was also taken into account. Together, these factors accounted for 59% of the variability in NT levels. Female patients had higher plasma levels of NT than male patients, 10-OH-NT levels were influenced by genotype, and NT/10-OH-NT ratio by genotype and gender. The present follow-up study confirms a relationship between the CYP2D6 genotype and the plasma levels of NT and its active metabolite. Identification of PM by genotyping should be of value for the prediction of the plasma levels and, consequently, the lower than average dose of NT required for optimal therapy. Also among EM, the genotype contributes to the variability in NT and 10-OH-NT levels but alone is of limited practical value for the prediction of optimal dosage.