Nitrogen Scavengers: History, Clinical Considerations and Future Prospects

Nitrogen scavengers play a critical role in treating acute and chronic hyperammonemia, especially in urea cycle disorders (UCDs), where impaired ammonia detoxification leads to toxic nitrogen accumulation. These agents complement low-protein diets and urea cycle intermediates. Sodium benzoate and sodium phenylacetate are the main scavengers, conjugating with glycine and glutamine to form hippurate and phenylacetylglutamine, which are excreted in urine. This therapeutic approach, introduced in the 1980s, was based on early findings linking benzoate to reduced urea excretion. Nitrogen scavengers are also used in secondary hyperammonemia from organic acidemias and fatty acid oxidation disorders, though they may become increasingly ineffective in progressing liver failure due to their reliance on hepatocyte function. To improve tolerability, phenylbutyrate was developed as an oral alternative to phenylacetate and is available in sodium-bound and prodrug forms, but issues with taste and side effects persist. While effective, current treatments target nitrogenous waste products rather than ammonia directly, offering an avenue of future drug development for UCDs. This review discusses the chemical properties, clinical use, and limitations of nitrogen scavengers, hereby focusing on phenylacetate and related substances, and highlights the need for improved therapies, including approaches that directly target ammonia removal. For the benefit of readers already experienced in nitrogen scavengers for UCDs, we also include considerations concerning the use of these drugs in animal experiments and a viewpoint on ornithine phenylacetate as a related substance.