Information about Phenylbutyrate
Phenylbutyrate and sodium benzoate are orphan drugs approved for the treatment of hyperammonemia in patients with urea cycle disorders, a series of at least 8 rare genetic enzyme deficiencies. The urea cycle is the major pathway of elimination of excess nitrogen including ammonia, and absence of one of the urea cycle enzymes often causes elevations in serum ammonia which can be severe, life-threatening and result in permanent neurologic damage and cognitive deficiencies. Both phenylbutyrate and sodium benzoate act by promoting an alternative pathway of nitrogen elimination.
Liver safety of Phenylbutyrate
Neither phenylbutyrate nor sodium benzoate have been linked to cases of liver injury either in the form of serum enzyme elevations during therapy or clinically apparent acute liver injury.
Phenylbutyrate (fen" il beu' ti rate) is a prodrug that is metabolized to phenylacetate, which is the active molecule that combines with glutamine (an amino acid with two nitrogen molecules) to form phenylacetylglutamine which is rapidly excreted by the kidneys and does not require metabolism via the urea cycle. Phenylbutyrate thus provides an “ammonia sink”, an alternative pathway for excretion of excess nitrogen and ammonia. The active metabolite phenylacetate is also effective therapeutically, but has a disagreeable odor and taste that affect compliance and acceptability.
Mechanism of action of Phenylbutyrate
Phenylbutyrate is odorless but does have a bitter, salty taste and is better tolerated than phenylacetate, but still not well accepted, particularly because it must be given in high doses, often as 3 to 12 tablets three times daily. Nevertheless, phenylbutyrate has been found to be effective in lowering ammonia levels in newborns, children and adults with acute hyperammonemic crises as well as to maintain normal or near normal levels of ammonia in patients between episodes (sometimes brought on by infection or excess dietary protein).
FDA approval information for Phenylbutyrate
Sodium phenylbutyrate received orphan drug approval for this indication in 1996.
Dosage and administration for Phenylbutyrate
It is available in tablets of 500 mg and as a powder for oral solution under the brand name Buphenyl. The typical dose varies by body weight or surface area, but is in general in the range of 5 to 20 grams daily given in three equally divided doses with meals. Phenylbutyrate is administered in conjunction with a low protein diet, often combined with sodium benzoate (another ammonia “sink”) and essential amino acids (such as citrulline or arginine). However, the regimen used must be individualized based upon the type of urea cycle disorder and specific clinical features. Phenylbutyrate should be administered only by physicians with expertise in managing urea cycle disorders and with proper diagnostic evaluation and monitoring.
Side effects of Phenylbutyrate
Common effects of sodium phenylbutyrate are bitter taste, loss of appetite, nausea, vomiting, diarrhea and edema. Rare side effects include fever and rash. Because of the need to calculate dosages, overdosing can easily occur. Accidental use of higher than appropriate doses of phenylbutyrate can result in severe metabolic side effects and death.
The poor acceptance of standard, sodium phenylbutyrate because of its bitter taste, high sodium content and pill burden (as many as 40 tablets daily) was a major impetus to the development of the glycerol-tri-phenylbutyrate, a formulation that is both tasteless and odorless, has a low sodium content and can be given orally as a liquid in a small volume. Glycerol phenylbutyrate was approved for treatment of hyperammonemia due to urea cycle disorders in 2013 and is available as an oral solution (1.1 g/mL) under the brand name Ravicti. The typical dose is 5 to 12 g/m2 daily (~5-10 mL) in three divided doses with meals. The common side effects of sodium phenylbutyrate such as bitter taste, anorexia, nausea and vomiting are less with glycerol phenylbutyrate and the high sodium intake of the standard formulation can be avoided. Nevertheless, care in calculation of the dose is critical, and monitoring of ammonia and drug levels during treatment is recommended.
genetic disorder agents
- gaucher disease agents
glucosylceramide synthase inhibitors (substrate restriction therapy)
lysosomal acid lipase deficiency agents
- agalsidase beta, alglucosidase alfa, alpha1-proteinase inhibitor, elosulfase alfa, galsulfase, idursulfase, laronidase, pegademase
Huntington disease agents
Urea Cycle Disorder Agents