EFFECT OF CYTOCHROME P450 2B6 GENETIC POLYMORPHISM

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。Eefavirenz是一种治疗HIV感染的重要药物，但其疗效存在很大的个体差异：一些患者治疗失败，约50%的患者在推荐治疗剂量后出现中枢神经系统(CNS)不良反应。虽然大多数中枢神经系统副作用轻微，反复给药后消退，但仍有约10%的患者因持续严重的中枢神经系统副作用而终止治疗。一些患者治疗失败或中枢神经系统不良反应的风险更大的原因尚不完全清楚。文献中有证据表明，Eefavirenz的血药浓度可预测Eefavirenz的CNS不良反应和抗逆转录病毒疗效。据报道，Eefavirenz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CYP450的不同表达，因为Eefavirenz在肝脏中经历了广泛的氧化。最近，我们在体外发现了基因多态酶CYP2B6，它是参与伊法韦仑代谢的主要异构体。这些数据表明，Eefavirenz药代动力学和反应的实质性差异可能是由于不同的CYP2B6活性造成的。在这里，我们提出了一项临床试验，以检验这一假设，即由于CYP3B6基因功能多态或暴露于药物而导致的CYP2B6可变表达影响Eefavirenz的药代动力学和由此产生的中枢神经系统不良事件。此外，与其他细胞色素P450(如细胞色素P450)类似，细胞色素P450基因B6的遗传变异可能影响对代谢诱导剂的易感性。为此，我们将在用利福平(600 mg/天)或安慰剂药片预处理10天后，在进行了CYP2B6功能性基因变异预基因检测的健康志愿者中，确定单次口服600毫克依法韦仑的药代动力学和中枢神经系统效应。

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.