The reduction in the hepatic capacity to detoxify ammonia in Urea Cycle Disorders (UCD) patients results in hyperammonemia that causes irritability, lethargy, cerebral edema, seizures and coma that can lead to death. Current clinical practice for the metabolic management of the disorders depends on dietary protein restriction and the administration of sodium benzoate or sodium phenylbutyrate, drugs that elicit alternative pathways for nitrogen disposal. There has been no direct comparison of the ability of these two drugs to conjugate amino acids, excrete nitrogen and reduce plasma ammonia. Despite the lack of data regarding the comparative efficacy of these drugs, sodium phenylbutyrate is usually the preferred option despite the fact that its cost is ~350 fold greater than that of sodium benzoate. This grant application combines clinical, preclinical and tracer kinetics studies to investigate an compare sodium benzoate and sodium phenylbutyrate in their abilities to conjugate nitrogenous compounds and control plasma ammonia after a meal. The utilization of 13C labeled drug analogues will allow for the determination of classical pharmacokinetics and conjugation efficiency of these drugs in UCD subjects undergoing chronic drug therapy. In addition, 15N labeled dietary protein will allow us to establish the source of the nitrogen (endogenous or dietary) conjugated and excreted by these two drugs. The data generated will, for the first time, allow a direct comparison between the two drugs. Due to differences in the cost of these drugs (benzoate ~$250, phenylbutyrate $90,000 for a 70 kg patient/year) and the increased survival and longer life expectancy of these patients, the knowledge gained will be crucial to devise cost effective metabolic management of patients with UCD. If no large differences between the two drugs are found, the partial or total replacement of sodium phenylbutyrate with sodium benzoate has the potential to reduce the cost of metabolic management without compromising the quality of care.
The goals of this proposal are to determine and compare the ability of sodium benzoate and sodium phenylacetate, drugs currently used for the metabolic management of Urea Cycle Disorders, to control plasma ammonia and to conjugate and excrete nitrogenous compounds. Due to the 350 fold difference in the cost of these two drugs, a direct comparison in the ability of these two drugs to dispose of nitrogen and maintain low plasma ammonia levels is crucial for the cost-effective management of these disorders.