EFFECT OF CYTOCHROME P450 2B6 GENETIC POLYMORPHISM

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。依非韦伦是治疗HIV感染的重要药物，但其反应存在广泛的个体差异：一些患者治疗失败，约50%的患者在推荐治疗剂量的依非韦伦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的副作用是轻微的，并在反复给药后消退，但约有10%的患者因持续和严重的中枢神经系统不良反应而终止使用依非韦伦。有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，依非韦伦的血浆浓度可预测中枢神经系统不良反应和依非韦伦的抗逆转录病毒疗效。据报道，依非韦伦的药代动力学表现出广泛的主体间变异性。这可能反映了参与其代谢的cyp450的可变表达，因为依非韦伦在肝脏中经历了广泛的氧化。最近，我们发现基因多态性酶CYP2B6是参与依非韦伦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疗效的实质性差异可能是由于CYP2B6活性的变化。在这里，我们提出了一项临床试验来验证CYP3B6基因的功能多态性或药物暴露导致的CYP2B6的可变表达会影响依非韦伦的药代动力学和由此产生的中枢神经系统不良事件的假设。此外，与其他CYPs（如CYP2C19）类似，CYP2B6的遗传变异可能影响对代谢诱导剂的易感性。为此，我们将在对CYP2B6基因变异进行预基因分型的健康志愿者中，确定在利福平（600 mg/天）或安慰剂丸预处理后，单次口服600 mg依非韦伦10天的药代动力学和中枢神经系统影响。

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.