Drug Disposition and Nephrotoxicity

药物处置和肾毒性

基本信息

批准号：
10247491
负责人：
Lauren M Aleksunes
金额：
$ 47.17万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10247491
关键词：
ABCB1 gene Acute Renal Failure with Renal Papillary Necrosis Affect Animal Experiments Animals Antiemetics Antineoplastic Agents Apical Biochemical Biological Markers Blood Cancer Patient Cells Cisplatin Clinical Clinical Research Contrast Media Data Diagnostic Procedure Drug Interactions Drug Kinetics Drug usage Epithelial Cells Excretory function Exposure to FDA approved Glomerular Filtration Rate Goals Granisetron Human Hydration status In Vitro Injury to Kidney Kidney Malignant Neoplasms Measures Mediating Mus Nausea and Vomiting Ondansetron Organic Cation Transporter Parents Pathogenesis Patients Pharmaceutical Preparations Physiological Platinum Predisposition Prospective Studies Proximal Kidney Tubules Public Health Randomized Regimen Renal function Research Risk Scientist Structure Testing Toxic effect Toxicity Tests Toxin Tubular formation Urine Vomiting World Health Organization base bioaccumulation chemotherapy clinical practice clinical risk clinically relevant copper transporter 1 drug disposition in silico in vivo inhibitor/antagonist insight multi drug transporter multidrug resistance-associated protein 2 nephrotoxicity novel novel marker overexpression pharmacokinetic model pre-clinical prevent prospective renal damage response simulation uptake urinary

项目摘要

PROJECT ABSTRACT Acute kidney injury (AKI) is a growing public health concern due to the widespread use of nephrotoxic medications and contrast agents for diagnostic procedures. In fact, drug-induced toxicity alone contributes to approximately 20% of all AKI episodes. We and others have observed AKI in up to one-third of patients treated with the cancer drug cisplatin despite aggressive hydration strategies. This is concerning given that cisplatin is a widely used drug and is considered one of the World Health Organization’s Essential Medications. Cisplatin is also highly emetogenic and requires treatment with 5-HT3 antagonists in order to control nausea and vomiting. We have discovered an association between use of the 5-HT3 antagonist ondansetron and a decrease in estimated glomerular filtration rate (eGFR), a measure of kidney function in cancer patients treated with cisplatin, suggesting nephrotoxicity. The selective uptake and accumulation of cisplatin into kidney proximal tubule epithelial cells (PTECs) is the first step in the pathogenesis of nephrotoxicity. PTECs concentrate greater amounts of cisplatin compared to other cells in large part due to the presence of the organic cation transporter 2 (OCT2). Cisplatin’s excretion into urine occurs by two transporters: multidrug and toxin extrusion transporter 1 (MATE1) and multidrug resistance-associated protein 2 (MRP2). We found that 5- HT3 antagonists are inhibitors of MATE1 activity, a response that we speculate is key to increasing AKI risk. The central hypothesis of this application is that inhibition of MATE1-mediated secretion of cisplatin by 5-HT3 antagonist antiemetic drugs leads to drug interactions and increased susceptibility to nephrotoxicity in humans. This proposal will systematically investigate the ability of 5-HT3 antagonists to inhibit cisplatin transport and exacerbate toxicity. Structural and pharmacokinetic differences between the 5-HT3 antagonists are expected to impart different likelihoods for inhibiting cisplatin transport. We propose in vitro studies with transfected cells and primary human proximal tubule cells along with animal experiments and a prospective, randomized study of cancer patients receiving cisplatin. We will assess the ability of 5-HT3 antagonists to alter cisplatin excretion, pharmacokinetics, intra-renal exposures and toxicity, likely revealing a novel mechanism for kidney injury in cancer patients. Data in this multiple PI application demonstrate that novel and sensitive urinary biomarkers can detect subclinical AKI in cancer patients and advance our ability to test for toxicity resulting from antiemetic drug-cisplatin interactions. The proposed research will provide mechanistic insight into the ability of co- administered MATE1 inhibitors to increase the risk of cisplatin toxicity in humans and will develop a novel PBPK model for cisplatin-drug interaction simulation. The long-term goal of this research is to influence clinical practice by enabling the informed selection and prescription of 5-HT3 antagonist antiemetic drugs that have limited propensity to increase kidney exposures to platinum and contribute to subsequent nephrotoxicity.

项目摘要由于肾毒性的广泛使用，急性肾损伤 (AKI) 已成为日益严重的公共卫生问题事实上，仅药物引起的毒性就会导致诊断过程中的药物和造影剂。我们和其他人在多达三分之一的接受治疗的患者中观察到 AKI 事件，约占所有 AKI 事件的 20%。尽管采取了积极的水合策略，但仍使用抗癌药物顺铂，这是令人担忧的。一种广泛使用的药物，被认为是世界卫生组织的基本药物之一。也具有高度致吐性，需要使用 5-HT3 拮抗剂治疗以控制恶心和我们发现使用 5-HT3 拮抗剂昂丹司琼与呕吐之间存在关联。估计肾小球滤过率 (eGFR) 降低，eGFR 是治疗癌症患者的肾功能指标与顺铂，表明顺铂选择性摄取并积聚到肾脏中。近端肾小管上皮细胞（PTEC）是肾毒性发病机制的第一步。与其他细胞相比，在很大程度上由于存在顺铂有机阳离子转运蛋白 2 (OCT2) 通过两种转运蛋白排泄到尿液中：多药和我们发现，毒素挤压转运蛋白 1 (MATE1) 和多药耐药相关蛋白 2 (MRP2)。 HT3 拮抗剂是 MATE1 活性的抑制剂，我们推测这种反应是增加 AKI 风险的关键。本申请的中心假设是 5-HT3 抑制 MATE1 介导的顺铂分泌拮抗剂止吐药会导致药物相互作用并增加人类对肾毒性的易感性。该提案将系统地研究5-HT3拮抗剂抑制顺铂转运的能力和 5-HT3 拮抗剂之间的结构和药代动力学差异预计会恶化。赋予抑制顺铂转运的不同可能性。我们建议用转染细胞进行体外研究。和原代人近端小管细胞以及动物实验和前瞻性随机研究我们将评估 5-HT3 拮抗剂改变顺铂排泄的能力，药代动力学、肾内暴露和毒性，可能揭示了肾损伤的新机制该多项 PI 应用中的数据表明，新型且敏感的尿液生物标志物。可以检测癌症患者的亚临床 AKI，并提高我们测试止吐药引起的毒性的能力拟议的研究将为了解药物-顺铂相互作用的能力提供机制见解。施用 MATE1 抑制剂以增加人类顺铂毒性风险，并将开发一种新的用于模拟顺铂药物相互作用的 PBPK 模型这项研究的长期目标是对临床产生影响。通过明智地选择和处方 5-HT3 拮抗剂止吐药物来进行实践增加肾脏对铂的暴露并导致随后的肾毒性的倾向有限。