sodium phenylbutyrate

Action and Spectrum

Actions and Spectrum: 

sodium phenylbutyrate (SPB) exhibits a dual action encompassing its nitrogen-scavenging properties and histone deacetylase (HDAC) inhibition. Firstly, SPB is utilized to treat urea cycle disorders (UCDs), genetic disorders impairing the body’s ability to eliminate ammonia. SPB is converted to phenylacetate in the body, conjuring with glutamine to form phenylacetylglutamine. This conjugate is then excreted via urine, removing excess ammonia and reducing its toxicity.

By providing an alternate pathway for nitrogen waste elimination, SPB helps manage UCDs and prevents the accumulation of ammonia, which can lead to serious neurological complications. In addition to its nitrogen-scavenging action, SPB acts as an HDAC inhibitor. HDACs are enzymes involved in gene regulation through histone deacetylation. By inhibiting HDACs, SPB alters the acetylation status of histone proteins, modulating gene expression.

This broadens the spectrum of SPB’s potential therapeutic effects beyond UCDs. It may exhibit anti-inflammatory properties by influencing the expression of inflammatory genes. Moreover, SPB’s HDAC inhibition has been investigated in the context of neurodegenerative diseases and cancer. SPB’s ability to modify gene expression may have neuroprotective effects in neurodegenerative diseases like Huntington’s disease and ALS. In cancer, HDAC inhibitors, including SPB, have shown promise in inhibiting tumor growth, promoting differentiation, and inducing cell death. 

Drug Interaction

Adverse Reaction

Frequency defined 

>10% 

Hypoalbuminemia (11%) 

Amenorrhea/dysmenorrhea (23%) 

Metabolic acidosis (14%) 

1-10% 

Hypokalemia (1%) 

Hypernatremia (1%) 

Hyperuricemia (2%) 

Hypophosphatemia (2%) 

Thrombocytopenia (3%) 

Strong body odor (3%) 

Anorexia (4%) 

Leukopenia (4%) 

Anemia (9%) 

Black Box Warning

Black Box Warning: 

None 

Contraindication / Caution

Contraindication/Caution: 

Contraindication 

• Hypersensitivity: SPB should not be used in individuals with known hypersensitivity or allergy to sodium phenylbutyrate or its components. Allergic reactions may range from mild skin rashes to severe systemic reactions and require immediate medical attention. 
• Severe Hepatic Dysfunction: Individuals with severe liver impairment or hepatic failure may have an increased risk of adverse effects when using sodium phenylbutyrate. SPB is primarily metabolized in the liver, and impaired liver function can affect its clearance, leading to potential toxicity. Close monitoring of liver function may be necessary in individuals with mild to moderate hepatic dysfunction. 
• Pancreatic Insufficiency: sodium phenylbutyrate can potentially worsen pancreatic insufficiency, a condition characterized by inadequate production or secretion of digestive enzymes by the pancreas. It is crucial to consider the risk-benefit ratio and closely monitor individuals with pancreatic insufficiency if using SPB. 
• Pregnancy and Breastfeeding: Using sodium phenylbutyrate during pregnancy or breastfeeding is generally not recommended due to limited safety data. It is key to consult with a healthcare professional to weigh the potential risks and also benefits in such situations. 
• Interaction with Valproic Acid: Co-administration of sodium phenylbutyrate and valproic acid, a medication commonly used for epilepsy and mood disorders, may increase the risk of hyperammonemia (elevated ammonia levels). This combination should be avoided unless specifically recommended and closely monitored by a healthcare professional. 
• Other Medications: sodium phenylbutyrate may interact with certain medications, including anticoagulants, antiplatelet agents, and drugs metabolized by specific liver enzymes.  

Caution 

• Renal Impairment: SPB is primarily eliminated through the kidneys. Therefore, caution should be exercised when administering sodium phenylbutyrate to individuals with significant renal impairment or those requiring dialysis. Close monitoring of renal function and appropriate dosage adjustments may be necessary. 
• Gastrointestinal Issues: sodium phenylbutyrate can cause gastrointestinal side effects such as nausea, vomiting, diarrhea, and abdominal discomfort. Individuals with pre-existing gastrointestinal conditions or a history of chronic diarrhea should be closely monitored when using SPB. Adjustments to the dosage or administration method may be necessary to manage these symptoms. 
• Electrolyte Imbalance: sodium phenylbutyrate contains sodium, and excessive sodium intake may lead to electrolyte imbalances, especially in individuals on sodium-restricted diets or with conditions such as congestive heart failure or hypertension. Careful monitoring of sodium levels and electrolyte balance is advised in such cases. 
• Bleeding Disorders: sodium phenylbutyrate may affect platelet function and prolong bleeding time. Individuals with bleeding disorders or taking anticoagulant medications should be cautious when using SPB and closely monitored for signs of increased bleeding or bruising. 
• Central Nervous System Effects: Some individuals may experience central nervous system (CNS) side effects such as dizziness, somnolence (excessive sleepiness), and confusion while taking sodium phenylbutyrate. Caution should be exercised when driving, operating machinery, or engaging in activities that require alertness until the individual’s response to the medication is known. 
• Pediatric and Geriatric Populations: The safety and efficacy of sodium phenylbutyrate in pediatric and geriatric populations have not been extensively studied. Caution should be exercised when using SPB in these age groups, and appropriate dosage adjustments may be required. 
• Mental Health Considerations: sodium phenylbutyrate’s use in individuals with underlying psychiatric conditions should be closely monitored, as it may potentially exacerbate specific mental health symptoms. Regular evaluation by a healthcare professional is recommended in such cases. 

Pregnancy / Lactation

Pregnancy consideration:  

AU TGA pregnancy category: B3
US FDA pregnancy category: Not assigned. 

Lactation:   

Excreted into human milk: Not known. 

Pregnancy category: 

• Category A: well-controlled and Satisfactory studies show no risk to the fetus in the first or later trimester. 
• Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women. 
• Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.    
• Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.    
• Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.    
• Category N: There is no data available for the drug under this category 

Pharmacology

Pharmacology: 

sodium phenylbutyrate (SPB) is a prodrug rapidly absorbed and converted into phenylacetate in the body. Phenylacetate is then conjugated with glutamine to form phenylacetylglutamine, which is excreted through urine. SPB acts as a nitrogen-scavenging agent, providing an alternate pathway for eliminating nitrogen waste products.

This mechanism helps reduce ammonia levels in urea cycle disorders and hyperammonemia. Additionally, SPB exhibits histone deacetylase (HDAC) inhibitory activity, modulating gene expression and potentially impacting various processes such as inflammation, cell differentiation, and apoptosis. 

Pharmacodynamics: 

Mechanism of action: The action of sodium phenylbutyrate (SPB) involves several key aspects: 

• Urea Cycle Disorders (UCDs): SPB is primarily used to treat UCDs, a group of genetic disorders that impair the body’s ability to remove ammonia, a toxic substance, from the blood. SPB provides an alternate pathway for the elimination of nitrogen waste products. It is converted to phenylacetate in the body, conjuring with glutamine to form phenylacetylglutamine. This compound is then excreted through urine, effectively removing excess ammonia and reducing its toxic effects. 
• Histone Deacetylase (HDAC) Inhibition: sodium phenylbutyrate acts as an HDAC inhibitor. HDACs are enzymes involved in the regulation of gene expression. By inhibiting HDACs, SPB modulates the acetylation status of histone proteins. Histones are involved in packaging DNA, and their acetylation status plays a crucial role in gene transcription and expression. By inhibiting HDACs, SPB promotes the acetylation of histones, leading to changes in gene expression patterns. This modulation of gene expression can have various effects, including anti-inflammatory, anti-cancer, and neuroprotective properties. 
• Other Cellular Effects: sodium phenylbutyrate has been shown to have various effects on cellular processes. It can induce differentiation of specific cell types, promote apoptosis (programmed cell death), inhibit cell proliferation, and regulate cellular signaling pathways. These effects are thought to be mediated, at least in part, by the modulation of gene expression through HDAC inhibition. 

Pharmacokinetics: 

Absorption 

sodium phenylbutyrate (SPB) is orally administered and rapidly absorbed from the gastrointestinal tract. The exact bioavailability of SPB can vary depending on the formulation and individual factors. It is primarily absorbed in the small intestine. 

Distribution 

After absorption, SPB is distributed throughout the body. It readily crosses cell membranes and distributes into various tissues and fluids. 

Metabolism 

Once absorbed, sodium phenylbutyrate undergoes extensive metabolism in the body. It is rapidly converted to phenylacetate through β-oxidation. Phenylacetate is further conjugated with glutamine in the liver to form phenylacetylglutamine, a water-soluble compound that can be excreted in the urine. 

Elimination and Excretion 

The primary route of excretion for SPB and its metabolites is through the kidneys. Phenylacetylglutamine is excreted in the urine, contributing to the elimination of nitrogen waste products, including ammonia. The elimination half-life of SPB and its metabolites can vary based on individual factors, but it is generally within a few hours. 

Adminstartion

Patient Information Leaflet