Drug Disposition and Nephrotoxicity

项目摘要 由于肾毒素的广泛使用，急性肾损伤(AKI)日益成为公众关注的问题 用于诊断程序的药物和造影剂。事实上，单是药物引起的毒性就会导致 大约20%的AKI剧集。我们和其他人在接受治疗的患者中观察到了多达三分之一的AKI 使用抗癌药物顺铂，尽管采取了积极的补水策略。这令人担忧，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 也是高度催吐的，需要用5-HT3拮抗剂治疗，以控制恶心和 呕吐。我们发现5-HT3拮抗剂恩丹西酮的使用与 接受治疗的癌症患者估计肾小球滤过率(EGFR)的降低，这是一种衡量肾功能的指标 顺铂，提示有肾毒性。顺铂在肾脏的选择性摄取和蓄积 近端肾小管上皮细胞(PTECs)是肾毒性发病的第一步。PTEC 与其他细胞相比，顺铂的浓度更高，这在很大程度上是由于 有机阳离子转运蛋白2(OCT2)。顺铂通过两种转运体排泄到尿液中：多药和 毒素排出转运体1(MATE1)和多药耐药相关蛋白2(MRP2)。我们发现5- HT3拮抗剂是MATE1活性的抑制剂，我们推测这种反应是增加AKI风险的关键。 这一应用的中心假设是5-HT3抑制MATE1介导的顺铂的分泌 拮抗剂止吐药物会导致药物相互作用，增加人类对肾毒性的易感性。 这项建议将系统地研究5-HT3拮抗剂抑制顺铂转运和 加重毒性。5-HT3拮抗剂之间的结构和药代动力学差异有望 给予不同的可能性来抑制顺铂的转运。我们建议对转基因细胞进行体外研究。 和原代人近端小管细胞，以及动物实验和一项前瞻性随机研究 接受顺铂治疗的癌症患者。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，可能揭示了一种新的肾损伤机制 癌症患者。这一多PI应用中的数据表明，新的和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物毒性的能力 药物与顺铂的相互作用。这项拟议的研究将提供对合作的能力的机械性洞察 使用MATE1抑制剂增加顺铂对人类的毒性风险，并将开发一种新的 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 实现5-HT3拮抗剂止吐药物的知情选择和处方的实践 增加肾脏对铂的暴露并导致随后的肾毒性的倾向有限。

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.