CYP2B6 Genetic Variations and Drug Interactions

描述(由申请人提供)：药物的有益和不良影响的个体差异影响安全和有效的治疗。这项研究的长期目标是了解导致这种差异的机制。在当前的资助期内，我们将重点放在由CYP2B6引起的药物处置和反应的可变性上。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了CYP2B6活性及其相关药物相互作用的广泛个体间差异的影响。我们发现并验证了与临床相关的新底物、抑制剂和遗传标记，这些现在使CYP2B6临床研究成为可能。利用这些工具，我们已经证明了CYP2B6基因变异不仅影响底物代谢，而且深刻影响体外和体内药物相互作用的抑制程度。这种基因和药物相互作用的相互作用在临床上很重要。 因为个体的基因似乎会影响治疗范围较窄的CYP2B6底物所需的剂量调整(例如，Eefavirenz和美沙酮)以避免不良反应。尽管有这些显著的进步，但CYP2B6活性的很大一部分个体间变异 相关的药物相互作用仍未得到解释。在这场竞争性的更新中，我们将利用这些新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可变性的机制。在目标1中，我们将检验这一假设，即CYP2B6中非同源SNPs的作用是底物依赖的，这反过来会影响药物的相互作用。我们将在体外确定CYP2B6*6等位基因对一组底物和抑制剂的代谢动力学和抑制作用的影响。在目标2中，我们将确定CYP2B6基因变异如何影响同时的自我抑制/自我诱导，并共同影响CYP2B6的活性。体内的酶活性将以安非他酮为探针，在基线(对照)、单次口服剂量(抑制)和多次剂量(600 mg/天)(诱导和抑制)后，对携带CYP2B6*6等位基因的健康志愿者进行测定。将开发一个半PBPK模型来预测每个因素的贡献以及这些因素之间的相互作用。在目标3中，我们将检验这一假设，即调节CYP2B6表达和功能的基因的遗传变异预测基础和药物诱导的CYP2B6活性。这种关联性将使用我们建议的(AIM 2)和之前完成的Eefavirenz临床试验的DNA、血浆和尿样进行临床测试。我们的途径引导的方法有望在CYP2B6介导的药物清除和相互作用中识别新的个体间变异的遗传生物标记物，并可能作为研究其他参与药物代谢的基因的范例。总体而言，我们将全面了解导致CYP2B6活性变化的机制及其底物的新陈代谢，这些信息最终可能被用于个性化治疗。

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.