Drug Disposition and Nephrotoxicity

药物处置和肾毒性

• 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
• 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

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 急性肾脏损伤（AKI）由于使用肾毒性而越来越多的公共卫生问题 用于诊断程序的药物和对比剂。实际上，仅药物引起的毒性就会有助于 所有AKI发作中约有20％。我们和其他人在多达三分之一的患者中观察到AKI 伴有癌症药物顺铂欲望积极的水合策略。这担心顺铂是 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。顺铂 还具有高度的突出作用，需要用5-HT3拮抗剂进行治疗，以控制恶心和 呕吐。我们发现使用5-HT3拮抗剂Ondansetron和A之间存在关联 估计的肾小球滤过率（EGFR）的降低，这是治疗癌症患者肾功能的度量 与顺铂有关，提示肾毒性。顺铂的选择性吸收和积累到肾脏 近端细胞上皮细胞（PTEC）是肾毒性发病机理的第一步。 ptecs 与其他细胞相比，大量的顺铂浓缩，这在很大程度上是由于存在 有机阳离子转运蛋白2（OCT2）。顺铂的排泄成尿液是由两个转运蛋白出现的：多药和 毒素推广转运蛋白1（MATE1）和多药相关蛋白2（MRP2）。我们发现5- HT3拮抗剂是MATE1活性的抑制剂，我们推测的反应是增加AKI风险的关键。 该应用的中心假设是5-HT3对MATE1介导的顺铂分泌的抑制 拮抗剂抗毒药会导致药物相互作用，并增加对人类肾毒性的敏感性。 该提案将系统地研究5-HT3拮抗剂抑制顺铂转运和 恶化的毒性。预计5-HT3拮抗剂之间的结构和药代动力学差异将 抑制顺铂转运的不同可能性。我们提出了对翻译细胞的体外研究 和原代人近端小管细胞以及动物实验和前瞻性，随机研究 接受顺铂的癌症患者。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，可能揭示了一种新型的肾脏损伤机制 癌症患者。此多个PI应用中的数据证明了新颖和敏感的尿生物标志物 可以在癌症患者中检测亚临床AKI，并提高我们测试抗体导致毒性的能力 药物 - 铂相互作用。拟议的研究将提供有关共同能力的机械洞察力 施用MATE1抑制剂，以增加人类毒性毒性的风险，并会发展出一种新型 顺铂 - 药物相互作用模拟的PBPK模型。这项研究的长期目标是影响临床 通过启用5-HT3拮抗剂抗过敏药物的知情选择和处方练习 有限的承诺增加了肾脏暴露于铂，并导致随后的肾毒性。