CYP2B6 Genetic Variations and Drug Interactions

描述（由申请人提供）：药物的有益和不良作用的个体间差异会影响安全有效的治疗。这项研究的长期目标是了解导致这种变化的机制。在当前的资助期内，我们重点关注了CYP 2B 6引起的药物处置和反应的变异性。这种肝酶代谢许多临床上重要的药物，但这些底物的临床应用受到CYP 2B 6活性及其相关药物相互作用的广泛个体间变异性的影响。我们发现并验证了临床相关的新型底物，抑制剂和遗传标记，使CYP 2B 6临床研究成为可能。使用这些工具，我们已经证明，CYP 2B 6基因变异不仅影响底物代谢，但在体外和体内的抑制药物相互作用的程度产生深远的影响。基因型和药物相互作用之间的这种相互作用在临床上是重要的 因为个体的基因型似乎影响窄治疗范围CYP 2B 6底物所需的剂量调整（例如，依法韦仑和美沙酮），以避免不良反应。尽管有这些显著的进展，但CYP 2B 6活性的大部分个体间变异性 以及相关的药物相互作用仍然无法解释。在这种竞争性的更新中，我们将利用这些新颖的和变革性的临床工具以及令人兴奋的新数据来全面阐明体内这种变异性的机制。在目标1中，我们将检验CYP 2B 6中非同源SNP的作用是底物依赖性的，这反过来又影响药物相互作用的假设。我们将在体外确定CYP 2B 6 *6等位基因对一组底物和抑制剂的代谢动力学和抑制的影响。在目标2中，我们将确定CYP 2B 6遗传变异如何影响同时的自抑制/自诱导，并共同影响CYP 2B 6活性。在CYP 2B 6 *6等位基因基因分型的健康志愿者中，使用安非他酮作为探针，在基线（对照）、单次口服600 mg剂量（抑制）和多次口服（600 mg/天）（诱导和抑制）依法韦仑后测定体内酶活性。将开发一个半PBPK模型来预测这些因素的贡献和相互作用。在目标3中，我们将检验调节CYP 2B 6表达和功能的基因中的遗传变异预测基础和药物诱导的CYP 2B 6活性的假设。将使用我们拟定（目标2）和先前完成的依法韦仑临床试验的DNA、血浆和尿液样本对这种关联进行临床测试。我们的路径引导的方法，预计将确定新的遗传生物标志物的个体间变异的CYP 2B 6介导的药物清除和相互作用，并可能作为一个范例，研究其他基因参与药物代谢。总体而言，我们将全面了解负责可变CYP 2B 6活性及其底物代谢的机制，这些信息最终可用于个性化治疗。

DESCRIPTION (provided by applicant): Interindividual variability in the beneficial and adverse effects of medications compromises safe and effective therapy. The long-term goal of this research is to understand the mechanisms that contribute to this variability. In the current funding period, we have focused on variability in drug disposition and response caused by CYP2B6. This hepatic enzyme metabolizes many clinically important drugs, but the clinical uses of these substrates are compromised by the extensive interindividual variability in CYP2B6 activity and its associated drug interactions. We discovered and validated clinically relevant novel substrate, inhibitors and genetic markers that now make CYP2B6 clinical research possible. Using these tools, we have demonstrated that CYP2B6 genetic variation not only affects substrate metabolism, but profoundly influences the degree of inhibition drug interactions in vitro and in vivo. This interplay between genotype and drug interactions is clinically important because an individual's genotype appears to affect dose adjustment needed for narrow therapeutic range CYP2B6 substrates (e.g., efavirenz and methadone) to avoid adverse effects. Despite these notable advances, the large portion of interindividual variability in CYP2B6 activity and associated drug interactions remains unexplained. In this competing renewal, we will capitalize on these novel and transformative clinical tools as well as exciting new data to comprehensively elucidate the mechanisms responsible for this variability in vivo. In Aim 1, we will test the hypothesis that the effect of nonsynonomous SNPs in CYP2B6 are substrate dependent and this, in turn, affects drug interactions. We will determine the influence of the CYP2B6*6 allele on kinetics of metabolism and inhibition of a panel of substrates and inhibitors in vitro. In Aim 2, we will determine how CYP2B6 genetic variants affect simultaneous auto- inhibition/autoinduction and collectively influence CYP2B6 activity. In vivo enzyme activity will be determined using bupropion as a probe at baseline (control), with a single 600 mg oral dose (inhibition) and after multiple doses (600 mg/day) (induction and inhibition) of efavirenz in healthy volunteers genotyped for CYP2B6*6 allele. A semi-PBPK model will be developed to predict the contribution each and interplay among these factors. In Aim 3, we will the test the hypothesis that genetic variants in genes that regulate CYP2B6 expression and function predict basal and drug-induced CYP2B6 activity. This association will be tested clinically using DNA, plasma and urine samples from our proposed (Aim 2) and previously completed efavirenz clinical trials. Our pathway-guided approach is expected to identify novel genetic biomarkers of interindividual variability in CYP2B6-mediated drug clearance and interactions, and may serve as a paradigm for studying other genes involved in drug metabolism. Overall, we will develop a comprehensive understanding of mechanisms responsible for variable CYP2B6 activity and the metabolism of its substrates, and this information could be eventually used to personalize therapy.