Medication Summary
Long-term treatment of arginase deficiency is based on a low-protein diet and, possibly, administration of oral sodium benzoate or sodium phenylbutyrate.
Urea Cycle Disorder Treatment Agents
Class Summary
The use of benzoate and phenylacetate is based on the need to provide alternate routes for disposition of waste nitrogen. Benzoate is transaminated to form hippuric acid, which is rapidly cleared by the kidney. Phenylacetate is converted to phenylacetyl coenzyme A (CoA) and then conjugated with glutamine to form phenylacetylglutamine. These 2 pathways result in disposition of 1 and 2 molecules of ammonia, respectively. Phenylbutyrate is more acceptable as a form of oral therapy because of a diminished odor but is not available for intravenous use.
Sodium benzoate and sodium phenylacetate (Ucephan, Ammonul)
Sodium benzoate combines with glycine to form hippurate, which is excreted in urine. One mol of benzoate removes 1 mol nitrogen. Sodium phenylacetate converted to phenylacetylglutamine, thereby taking up 1 mol per mol of free ammonia. The PO (Ucephan) and IV (Ammonul) products contain a combination of sodium benzoate 10 g/100 mL and sodium phenylacetate 10 g/100 mL (100 mg of each/mL).
Sodium phenylbutyrate (Buphenyl)
Prodrug rapidly converted PO to phenylacetylglutamine, which serves as substitute for urea and is excreted in the urine carrying 2 mol of nitrogen per mol of phenylacetylglutamine, assisting in clearance of nitrogenous waste.
Glycerol phenylbutyrate (Ravicti)
Glycerol phenylbutyrate is a nitrogen-binding agent for long-term management of adult and pediatric patients (including newborns) with urea cycle disorders who cannot be managed with dietary protein restriction and/or amino acid supplementation alone. It is a pre-prodrug that is metabolized by ester hydrolysis and pancreatic lipases to phenylbutyrate and then by beta oxidation to phenylacetate. Glutamine is conjugated with phenylacetate to form phenylacetylglutamine, a nitrogen waste product that is excreted in the urine. It is not indicated for the treatment of hyperammonemia.
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Compounds that comprise the urea cycle are sequentially numbered, beginning with carbamyl phosphate (1). At this step, the first waste nitrogen is incorporated into the cycle; N-acetylglutamate exerts its regulatory control on the mediating enzyme, carbamoyl phosphate synthetase (CPS), in this step. Compound 2 is citrulline, the product of condensation between carbamyl phosphate (1) and ornithine (8); the mediating enzyme is ornithine transcarbamylase. Compound 3 is aspartic acid, which is combined with citrulline to form argininosuccinic acid (ASA) (4); the reaction is mediated by ASA synthetase. Compound 5 is fumaric acid generated in the reaction that converts ASA to arginine (6), which is mediated by ASA lyase.
