Influence of CYP2B6 polymorphism on plasma and intracellular concentrations and toxicity of efavirenz and nevirapine in HIV-infected patients.
Influence of CYP2B6 polymorphism on plasma and intracellular concentrations and toxicity of efavirenz and nevirapine in HIV-infected patients.
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DOI：
10.1097/01213011-200501000-00001
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发表时间：
2005-01-01
影响因子：
2.6
通讯作者：
Telenti, Amalio
中科院分区：
文献类型：
--
作者：
Rotger, Margalida;Colombo, Sara;Telenti, Amalio
背景：依法韦仑（EFV）和奈韦拉平（NVP）经细胞色素P450 2B6（CYP2B6）代谢。等位基因516 G>T（Gln172His）与这种同工酶的活性降低有关，并可能导致药物暴露的差异。方法：我们评估了这个等位基因作为EFV和NVP药代动力学和EFV毒性的药物遗传学标志物，在167名接受EFV和59名接受NVP的瑞士HIV队列研究的遗传学项目中招募。在来自相同样品的血浆和外周血单核细胞（PBMC）中测量药物浓度。神经心理毒性EFV（睡眠障碍，情绪障碍，疲劳）进行了评估，使用标准化的questionnaire.RESULTS AND CONCLUSIONS：CYP2B6 516 TT与更大的血浆和细胞内暴露于EFV，更大的血浆暴露于NVP。细胞内药物浓度和CYP2B6基因型是EFV神经心理毒性的预测因子。CYP2B6基因分型可能有助于补充基于血浆药物测定的个体化策略，以增加EFV的安全性和耐受性。
BACKGROUND: Efavirenz (EFV) and nevirapine (NVP) are metabolized by cytochrome P450 2B6 (CYP2B6). Allele 516 G>T (Gln172His) is associated with diminished activity of this isoenzyme, and may lead to differences in drug exposure.METHODS: We evaluated this allele as a pharmacogenetic marker of EFV and NVP pharmacokinetics and EFV toxicity in 167 participants receiving EFV and 59 receiving NVP recruited within the genetics project of the Swiss HIV Cohort Study. Drug concentrations were measured in plasma and in peripheral blood mononuclear cells (PBMCs) from the same sample. Neuropsychological toxicity of EFV (sleep disorders, mood disorders, fatigue) was assessed using a standardized questionnaire.RESULTS AND CONCLUSIONS: CYP2B6 516TT was associated with greater plasma and intracellular exposure to EFV, and greater plasma exposure to NVP. Intracellular drug concentration, and CYP2B6 genotype were predictors of EFV neuropsychological toxicity. CYP2B6 genotyping may be useful to complement an individualization strategy based on plasma drug determinations to increase the safety and tolerability of EFV.