An update on the use of benzoate, phenylacetate and phenylbutyrate ammonia scavengers for interrogating and modifying liver nitrogen metabolism and its implications in urea cycle disorders and liver disease.

INTRODUCTION: Ammonia-scavenging drugs, benzoate and phenylacetate (PA)/phenylbutyrate (PB), modulate hepatic nitrogen metabolism mainly by providing alternative pathways for nitrogen disposal. Areas covered: We review the major findings and potential novel applications of ammonia-scavenging drugs, focusing on urea cycle disorders and liver disease. Expert opinion: For over 40 years, ammonia-scavenging drugs have been used in the treatment of urea cycle disorders. Recently, the use of these compounds has been advocated in acute liver failure and cirrhosis for reducing hyperammonemic-induced hepatic encephalopathy. The efficacy and mechanisms underlying the antitumor effects of these ammonia-scavenging drugs in liver cancer are more controversial and are discussed in the review. Overall, as ammonia-scavenging drugs are usually safe and well tolerated among cancer patients, further studies should be instigated to explore the role of these drugs in liver cancer. Considering the relevance of glutamine metabolism to the progression and resolution of liver disease, we propose that ammonia-scavenging drugs might also be used to non-invasively probe liver glutamine metabolism in vivo. Finally, novel derivatives of classical ammonia-scavenging drugs with fewer and less severe adverse effects are currently being developed and used in clinical trials for the treatment of acute liver failure and cirrhosis.