Drug Disposition and Nephrotoxicity

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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.