Pharmacokinetic and Pharmacogenomic Determinants of Cisplatin Kidney Injury

描述（由申请人提供）：顺铂是一种无机含金属的化疗药物，用于有效治疗多种实体癌症。不幸的是，三分之一服用顺铂的患者发生急性肾损伤，这可能导致治疗中断或剂量减少，从而影响肿瘤消退、患者生存和慢性肾损害的可能性。目前迫切需要探索癌症患者顺铂肾毒性的新机制。这项资助申请的重点是肾毒性的决定因素，包括药物代谢、运输和直接影响顺铂暴露的肾小管的调节途径。在这项拨款申请中，我们提出了一项转化研究，以调查顺铂肾损伤的药代动力学和药物基因组学决定因素。具体来说，我们打算证明肾脏转运蛋白（OCT2/SLC22A2、MATE1/SLC47A1和MRP2/ABCC2）、谷胱甘肽代谢酶（谷胱甘肽s转移酶，如GSTP1和GSTA1， g-谷氨酰转移酶，如GGT1）和NRF2/NFE2L2转录因子的遗传变异是顺铂暴露和肾毒性的重要决定因素。由于调节这些蛋白的基因主要在肾脏中表达，本资助申请的重点是影响顺铂肾脏暴露的因素。拟议的研究结合了传统的临床肾毒性测量（血清肌酐，血尿素氮）和一种新的生物标志物（尿Kim-1）来检测急性肾损伤的表型。我们研究的中心假设是顺铂相关代谢和转运途径的药代动力学参数和遗传变异是预测使用含顺铂化疗的癌症患者肾毒性的生物标志物。为了验证这些假设，我们将1)测量血浆和尿液中游离和总顺铂浓度，2)评估与顺铂代谢和转运相关的7个基因（SLC22A2、SLC47A1、ABCC2、NFE2L2、GSTA1、GSTP1、GGT1）的遗传变异。这七个基因先前已被证明影响细胞和动物系统的肾毒性。这些结果的预期影响包括通过调整顺铂给药来减少肾脏暴露的重大转化机会，在化疗开始前识别“有风险”的患者，并确保患者接受整个疗程的治疗，以便他们能够获得最大的治愈性治疗机会。这项研究的长期益处是减少了接受顺铂治疗的癌症患者急性和慢性肾毒性的发生率，并提高了化疗治愈率。拟议的研究将通过整合个性化药物方法来预防顺铂肾毒性，作为未来其他药物引起的肾毒性研究的基础，并提供生物标志物的额外应用，从而对当前研究产生重大影响。

DESCRIPTION (provided by applicant): Cisplatin is an inorganic metal-containing chemotherapeutic agent used to effectively treat a myriad of solid cancers. Unfortunately, acute kidney injury occurs in one-third of patients prescribed cisplatin and this can result in therapy discontinuation or dosage reductions that impact tumor regression, patient survival, and likelihood of chronic kidney damage. There is an urgent need to explore novel mechanisms that contribute to cisplatin nephrotoxicity in cancer patients. This grant application focuses on determinants of nephrotoxicity including drug metabolism, transport, and regulatory pathways that directly influence the exposure of kidney tubules to cisplatin. In this grant application, we propose a translational study to investigate pharmacokinetic and pharmacogenomic determinants that govern kidney injury to cisplatin. Specifically, we intend to demonstrate that genetic variants in kidney transporters (OCT2/SLC22A2, MATE1/SLC47A1, and MRP2/ABCC2), glutathione metabolizing enzymes (Glutathione-S-transferases, e.g. GSTP1 and GSTA1, and g-glutamyl transferase1, e.g. GGT1), and the NRF2/NFE2L2 transcription factor are important determinants of cisplatin exposure and nephrotoxicity. Since the genes regulating these proteins are predominantly expressed in kidney, this grant application focuses on factors affecting renal exposure to cisplatin. The proposed studies incorporate traditional measures of clinical nephrotoxicity (serum creatinine, blood urea nitrogen) and a novel biomarker (urinary Kim-1) to detect the phenotype of acute kidney injury. The Central Hypotheses of our research are that pharmacokinetic parameters and genetic variants in cisplatin-relevant metabolic and transport pathways are biomarkers predictive of nephrotoxicity in cancer patients who are prescribed cisplatin-containing chemotherapy. In order to test these hypotheses, we will 1) measure free and total cisplatin concentrations in plasma and urine, and 2) evaluate genetic variants in seven genes (SLC22A2, SLC47A1, ABCC2, NFE2L2, GSTA1, GSTP1, GGT1) relevant to the metabolism and transport of cisplatin. These seven genes have been previously shown to influence nephrotoxicity in cell- and animal-based systems. The anticipated impact of these results include significant translational opportunities to reduce exposure of the kidney by modifying administration of cisplatin, to identify "at risk" patients prir to chemotherapy initiation, and to insure patients receive an entire course of therapy so they can have the greatest chance of curative therapy. The long-term benefits of this research are a reduced incidence of acute and chronic nephrotoxicity in cancer patients receiving cisplatin and enhanced chemotherapy cure rates. The proposed research would have high impact beyond the current study by integrating a personalized medicine approach to prevent cisplatin nephrotoxicity, serving as a basis for future study of other drug-induced nephrotoxicities, and provision of additional applications for biomarkers.