EFFECT OF CYTOCHROME P450 2B6 GENETIC POLYMORPHISM

细胞色素 P450 2B6 基因多态性的影响

• 批准号: 7379091
• 负责人: Zeruesenay Desta
• 金额: $ 5.85万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7379091
• 关键词: EFFECT; CYTOCHROME; P450; 2B6; GENETIC

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Efavirenz is an important drug in the therapy of HIV infection, but there is wide interindividual variability in its response: some patients fail therapy and approximately 50% of patients experience central nervous system (CNS) adverse effects after recommended therapeutic doses of efavirenz. Although most CNS side effects are mild and subside after repeated administration, about 10% of patients terminate therapy with efavirenz because of persistent and severe CNS adverse effects. The reason why some patients are at greater risk for failure of treatment or CNS adverse effects is not fully known. There is evidence in the literature that plasma concentrations of efavirenz predict CNS adverse effects and antiretroviral efficacy of efavirenz. Efavirenz pharmacokinetics has been reported to exhibit extensive intersubject variability. This is probably a reflection of variable expression of the CYP450s involved in its metabolism, as efavirenz undergoes extensive oxidation in the liver. Recently, we identified the genetically polymorphic enzyme CYP2B6 as the main isoform involved in efavirenz metabolism in vitro. These data suggest that the substantial difference in efavirenz pharmacokinetics and response may be due to variable CYP2B6 activity. Here, we propose a clinical trial to test the hypothesis that variable expression of CYP2B6 that result from functional polymorphisms in the CYP3B6 gene or exposure to drugs influence efavirenz pharmacokinetics and the resulting CNS adverse events. In addition, similar to other CYPs (e.g. CYP2C19), genetic variations of CYP2B6 may influence the susceptibility to metabolic inducers. To this end, we will determine the pharmacokinetics and CNS effects of a single 600 mg oral dose of efavirenz administered after pretreatment with rifampin (600 mg/day) or placebo pills for 10 days in healthy volunteers pregenotyped for functional CYP2B6 genetic variants.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。依法韦仑是治疗HIV感染的重要药物，但其反应存在广泛的个体间差异：一些患者治疗失败，约50%的患者在推荐治疗剂量的依法韦仑后出现中枢神经系统（CNS）不良反应。虽然大多数CNS副作用是轻微的，并在重复给药后消退，但约10%的患者因持续和严重的CNS副作用而终止依法韦仑治疗。一些患者治疗失败或CNS不良反应风险更高的原因尚不完全清楚。文献中有证据表明，依法韦仑的血浆浓度可预测依法韦仑的CNS不良反应和抗逆转录病毒疗效。据报道，依法韦仑的药代动力学表现出广泛的受试者间变异性。这可能反映了参与其代谢的CYP 450的可变表达，因为依法韦仑在肝脏中发生广泛氧化。最近，我们确定了基因多态性酶CYP 2B 6作为参与依法韦仑体外代谢的主要亚型。这些数据表明，依非韦伦药代动力学和反应的显著差异可能是由于CYP 2B 6活性不同所致。在这里，我们提出了一项临床试验，以测试的假设，即CYP 2B 6的可变表达，导致在CYP 3B 6基因的功能多态性或暴露于药物影响依法韦仑的药代动力学和由此产生的CNS不良事件。此外，与其他CYP（如CYP 2C 19）相似，CYP 2B 6的遗传变异可能影响对代谢诱导剂的敏感性。为此，我们将在预先进行CYP 2B 6功能性遗传变异基因分型的健康志愿者中，确定利福平（600 mg/天）或安慰剂片剂预处理10天后单次口服600 mg依法韦仑的药代动力学和CNS效应。