Inhibition of Intestinal Na/Phosphate Cotransporter in Renal Failure and Hyperten
DESCRIPTION (provided by applicant): With 500,000 Americans in the final stage of chronic kidney disease (CKD) and another 40 million at risk for developing CKD due to obesity, diabetes and hypertension renal disease is a modem epidemic. Serum phosphorus (Pi) levels are thought to be the crux of the problem In CKD contributing to the rate of disease progression and poor patient outcomes. In the later stages When residual kidney function cannot keep pace with serum Pi, hyperphosphatemia becomes overt. Current treatments are ineffective at reducing serum Pi for 70% of pat tents in the later stages of CKD and cannot prevent the continued loss of renal function. New CKD treatments designed around preventing abnormal Pi handling are needed. Decreasing dietary phosphorus absorption by inhibiting the intestinal protein responsible for 50% to 70% of Pi absorption is the focus of this proposal. The Inhibitor, 2'-fluorophosphophloretin (2FP) is a small natural product derivative with no known intestinal side effects orcardiovascular toxicities. The long term goal is to bring a pill form of 2FP to the CKD population. The goal of this proposal is to examine the toxicity and pharmacokinetics of 2FP in rats and guinea pigs. The specific aims are: 1. Determine genetic,mammalian cell, cardiac, and liver toxicity of 2FP 2. Determine the no observed adverse effect level (NOAEL) of 2FP in rats and guinea pigs. 3 Examine blood and urine metabolites of 2FP and determine organ distributions of 2FP and its metabolites. Completion of specific aim 1 will accelerate drug development by completing preliminary toxicity studies required for the IND. First in human studies require NOAEL studies in a animal species to establish initial doses in humans. Specific aim 3 will confirm 2FP metabolism and organ distribution. These studies are expected to verify ab silica results indicating that 2FP has limited intestinal permeability, that 2FP is metabolized o phloretin, and that 2FP has a blood short half-life. In addition 10 verifying the safety of 2FP these studies will provide guidance for further animal studies required for the complete IND packet. PUBLIC HEALTH RELEVANCE: Chronic kidney disease (CKD) is a major healthcare burden accounting for nearly 8% of Medicare spending.An effective therapy will slow disease progression, reduce Medicare Spending, and Will reverse the loss of renal function for the 70% of CKD patients unaffected by current therapies.
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