Drug Metabolizing Enzyme and Transporter Function in Chronic Kidney Disease

描述（由申请方提供）：该提案重点关注维生素D作为慢性肾脏疾病（CKD）患者异生物质清除调节剂的作用。维生素D可以影响负责介导异生物质清除的代谢和运输过程的基因的调节。这是高度相关的，因为维生素D治疗是常见的，因为在高达90%的CKD队列中观察到缺乏症（总25（OH）D水平<30 ng/mL）。主要研究者和其他人先前发表的研究表明，在CKD中，由细胞色素P450（CYP）酶和转运蛋白介导的肾脏和非肾脏异生物质清除途径发生改变。鉴于2400万美国CKD患者平均每天接受10-12种不同药物的处方，CKD中异生物质清除率改变的临床现实（药物相互作用、副作用、疗效改变以及处方和/或监测治疗的临床医生的困惑）并非微不足道。重要的是，越来越多的证据表明，维生素D缺乏是一个重要的非传统心血管风险因素，维生素D对骨骼和肌肉骨骼健康、肾脏保护、癌症预防以及降低自身免疫性疾病和感染性疾病的严重程度或风险都很重要。在这个建议中，我们开发了一个翻译研究，采用在体内和体外研究，以调查维生素D如何改变药物代谢和运输途径的活动在CKD。我们建议在CKD患者和健康对照组中，在维生素D缺乏和补充的相反影响下，表征异生物质代谢和转运途径的体内活性。此外，基于生理学的药代动力学模型将探索维生素D和尿毒症对药物代谢和转运变化的机制，使用来自计划的体内和体外研究的数据。我们的中心假设是维生素D状态独立影响CKD患者的代谢和转运功能。该提案的首要目标是使药物治疗更安全、更有效，以降低CKD患者的显著发病率和死亡率。制定了由体内和体外研究组成的三个独立的特定目的，以解决关键假设：1）异生物质代谢和转运的各个途径的体内功能受到维生素D状态和CKD的影响，2）CKD改变负责维生素D代谢的各个CYP的活性，导致胆钙化醇的药代动力学改变，和3）维生素D治疗和模拟CKD差异性地改变肾和肝细胞中药物代谢酶和转运蛋白的表达和功能。这些研究将是核心，以确定在评估药物相互作用的临床风险，改变疗效和毒性的治疗，并指导适当的维生素D缺乏症和维持方案，在哪里需要更多的审查。这项研究的长期益处是改善药物管理，药物剂量指南以及维生素D治疗患者的靶器官和/或疾病的相应结果。拟议的研究将通过改善为CKD患者提供的护理的公共卫生效益产生很大影响，作为未来研究药物代谢和转运改变的基础，并提供急需的CKD维生素D代谢和药代动力学信息。

DESCRIPTION (provided by applicant): This proposal focuses on the role of vitamin D as a modulator of xenobiotic clearance in patients with chronic kidney disease (CKD). Vitamin D can influence the regulation of genes responsible for metabolism and transport processes that mediate xenobiotic clearance. This is highly relevant since vitamin D treatment is common, as deficiency (total 25(OH)D level <30 ng/mL) is observed in up to 90% of CKD cohorts. Previous published research by the Principal Investigators and others has shown that renal and nonrenal xenobiotic clearance pathways mediated by cytochrome P450 (CYP) enzymes and transporters is altered in CKD. Given the 24 M US citizens with CKD are prescribed an average of 10-12 different medications daily, the clinical realities of altered xenobiotic clearance in CKD (drug interactions, side effects, altered efficacy, and confusion for clinicians prescribing and/or monitoring treatments) are not trivial. Importantly, increasing evidence indicates that vitamin D deficiency is a significant non-traditional cardiovascular risk factor, and vitamin D is important or bone and musculoskeletal health, kidney protection, cancer prevention, and decreased severity or risk of autoimmune and infectious diseases. In this proposal, we developed a translational study employing in vivo and in vitro studies to investigate how vitamin D alters the activity of drug metabolism and transport pathways in CKD. We propose to characterize the in vivo activity of xenobiotic metabolism and transport pathways in CKD patients and healthy controls under the opposing influences of vitamin D deficiency and repletion. Moreover, physiologically-based pharmacokinetic models will explore mechanisms for vitamin D and uremia on variations in drug metabolism and transport using data derived from the planned in vivo and in vitro studies. Our central hypothesis is that vitamin D status independently affects metabolism and transport function in CKD patients. An over-arching goal of this proposal is to make drug therapies safer and more effective to reduce the significant morbidity and mortality in patients with CKD. Three independent Specific Aims comprised of in vivo and in vitro studies were formulated to address the key hypotheses: 1) The in vivo function of individual pathways of xenobiotic metabolism and transport are affected by vitamin D status and by CKD, 2) CKD alters the activity of individual CYPs responsible for vitamin D metabolism, leading to modified pharmacokinetics of cholecalciferol, and 3) Vitamin D treatment and simulated CKD differentially alter the expression and function of drug metabolizing enzymes and transporters in kidney and liver cells. These studies will be central to determine where more scrutiny is warranted in evaluating clinical risks for drug interactions, altered efficacy and toxicity of therapies, and for guidance on appropriate vitamin D deficiency and maintenance regimens. Long term benefits of this research are improvements in medication management, drug dosing guidelines, and corresponding outcomes in targeted organs and/or diseases for vitamin D treated patients. The proposed research would have high impact through the public health benefit of improving care provided to CKD patients, serving as a basis for future study of alterations in drug metabolism and transport, and provision of much needed information on vitamin D metabolism and pharmacokinetics in CKD.