Drug Disposition and Nephrotoxicity

项目摘要 急性肾损伤（阿基）是一个日益增长的公共卫生问题，由于广泛使用的肾毒性药物， 用于诊断程序的药物和造影剂。事实上，药物诱导的毒性本身就有助于 大约20%的阿基发作。我们和其他研究人员在接受治疗的患者中观察到多达三分之一的阿基 尽管采取了积极的水化策略，这是令人担忧的，因为顺铂是 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 也是高度致吐的，需要用5-HT 3拮抗剂治疗以控制恶心， 呕吐.我们已经发现使用5-HT 3拮抗剂昂丹司琼与 估计肾小球滤过率（eGFR）降低，eGFR是接受治疗的癌症患者的肾功能指标 与顺铂联合用药，说明有肾毒性顺铂在肾脏的选择性摄取和蓄积 近端小管上皮细胞（PTECs）是肾毒性发病机制的第一步。PTECs 与其他细胞相比，浓缩更大量的顺铂，这在很大程度上是由于 有机阳离子转运蛋白2（OCT 2）。顺铂通过两种转运蛋白排泄到尿液中：多药转运蛋白和 毒素外排转运蛋白1（MATE 1）和多药耐药相关蛋白2（MRP 2）。我们发现5- HT 3拮抗剂是MATE 1活性的抑制剂，我们推测这种反应是增加阿基风险的关键。 本申请的中心假设是5-HT 3抑制MATE 1介导的顺铂分泌 拮抗剂止吐药物导致药物相互作用和对人类肾毒性的易感性增加。 该建议将系统地研究5-HT 3拮抗剂抑制顺铂转运的能力， 加重毒性。预计5-HT 3拮抗剂之间的结构和药代动力学差异 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 和原代人近曲小管细胞沿着与动物实验和前瞻性，随机研究 接受顺铂治疗的癌症患者。我们将评估5-HT 3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， 癌症患者。本多项PI应用中的数据表明， 可以检测癌症患者的亚临床阿基，并提高我们测试止吐药毒性的能力 药物-顺铂相互作用。拟议的研究将提供机制的洞察能力的共同- 给予MATE 1抑制剂以增加顺铂在人体中毒性的风险，并将开发一种新的 用于顺铂-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 实践，使知情的选择和处方的5-HT 3拮抗剂止吐药物， 增加肾脏铂暴露量并导致后续肾毒性的倾向有限。

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.