sodium phenylbutyrate/ taurursodiol

Action and Spectrum

Actions and Spectrum: 

sodium phenylbutyrate and taurursodiol are pharmacological agents with distinct actions and effects in the human body. sodium phenylbutyrate, also known as sodium phenylbutyrate, is a butyric acid derivative. It exerts its action by increasing the levels of a compound called phenylacetate in the body. Phenylacetate conjugates with glutamine to form the phenylacetylglutamine, which helps to eliminate excessive ammonia from the body.

sodium phenylbutyrate is primarily used in treating urea cycle disorders, group of the genetic disorders that generally affect the body’s ability to remove ammonia from bloodstream. By reducing ammonia levels, sodium phenylbutyrate helps prevent toxic buildup and associated complications such as hepatic encephalopathy. Additionally, sodium phenylbutyrate has shown promise in treating certain cancers and neurodegenerative diseases, although further research is needed to establish its efficacy in these conditions. 

taurursodiol, or tauroursodeoxycholic acid (TUDCA), is a bile acid derivative with various beneficial effects. It has been extensively studied for its hepatoprotective properties, meaning it protects liver cells from damage and promotes their regeneration. taurursodiol has been shown to mitigate the toxic effects of bile acids on liver cells and has anti-inflammatory and anti-apoptotic properties. It also enhances bile secretion and improves bile flow through the liver and bile ducts.

These properties make taurursodiol a valuable therapeutic agent for treating various liver diseases, including primary biliary cholangitis, non-alcoholic fatty liver disease (NAFLD), and cholestasis. Additionally, taurursodiol has shown promise in protecting against neuronal cell death and may have potential applications in neurodegenerative conditions like Alzheimer’s and Parkinson’s diseases. However, further research is needed to fully elucidate its action mechanisms in these contexts. 

Drug Interaction

Adverse Reaction

Frequency defined 

>10% 

Abdominal pain (21%) 

Nausea (18%) 

Diarrhea (25%) 

Upper respiratory tract infection (18%) 

Salivary hypersecretion (11%) 

Fatigue (12%) 

1-10% 

Dizziness (10%) 

Black Box Warning

Black Box Warning: 

None 

Contraindication / Caution

Contraindication/Caution: 

Contraindication 

sodium Phenylbutyrate: 

• Hypersensitivity: Individuals with known hypersensitivity or allergic reaction to sodium phenylbutyrate or any of its components should avoid its use. 
• Severe liver dysfunction: sodium phenylbutyrate is primarily metabolized by the liver, so individuals with severe liver impairment may have difficulty metabolizing and eliminating the drug properly. Caution should be exercised, and dosage adjustments may be necessary. 
• Pancreatitis: sodium phenylbutyrate has been associated with cases of pancreatitis, and its use should be avoided or carefully monitored in individuals with a history of pancreatitis. 

taurursodiol: 

• Hypersensitivity: Individuals who are hypersensitive or have a known allergy to taurursodiol or bile acid derivatives should not use this medication. 
• Obstruction of the bile ducts: taurursodiol promotes bile flow, and its use is contraindicated in cases of complete obstruction of the bile ducts. 
• Acute cholecystitis: taurursodiol may aggravate symptoms in individuals with acute gallbladder inflammation (cholecystitis), and its use should be avoided in such cases. 
• Pregnancy and breastfeeding: The safety of taurursodiol during pregnancy condition and breastfeeding has not been fully established.  

Caution 

sodium Phenylbutyrate: 

• Renal Impairment: sodium phenylbutyrate is primarily eliminated by the kidneys. Therefore, caution should be exercised, and dosage adjustments may be required in individuals with significant renal impairment. 
• Electrolyte Imbalance: sodium phenylbutyrate contains sodium and can potentially contribute to electrolyte imbalances, especially in individuals with underlying conditions such as hypertension or congestive heart failure. Regular monitoring of electrolyte levels is advisable during treatment. 
• Drug Interactions: sodium phenylbutyrate may interact with other medications, including those metabolized by the same liver enzymes or those affecting ammonia metabolism. It is vital to inform healthcare providers about all medications being taken to avoid potential interactions. 

taurursodiol: 

• Gallbladder Disease: taurursodiol can stimulate the flow of bile, which may worsen symptoms or trigger gallbladder-related issues such as gallstone colic or acute cholecystitis. Close monitoring and caution are necessary for individuals with a history of gallbladder disease. 
• Gastrointestinal Disturbances: taurursodiol may cause gastrointestinal side effects, such as nausea, vomiting, diarrhea, or abdominal discomfort. If these symptoms become severe or persistent, medical attention should be sought. 
• Diabetes: taurursodiol may affect glucose metabolism and insulin sensitivity. Individuals with diabetes should closely monitor their blood glucose levels during treatment and consult their healthcare provider if significant changes occur. 

Pregnancy / Lactation

Pregnancy consideration:  

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 acts as a prodrug that undergoes rapid metabolism to phenylacetate. Phenylacetate combines with glutamine to form phenylacetylglutamine, which helps remove excess ammonia from the body. sodium phenylbutyrate also modulates gene expression and protein function, potentially contributing to its effects in certain cancers and neurodegenerative diseases. taurursodiol, on the other hand, is a bile acid derivative that exhibits hepatoprotective properties.

It reduces hepatocellular apoptosis, mitigates the toxic effects of bile acids, and enhances bile flow, improving liver function. taurursodiol may also exert neuroprotective effects by reducing oxidative stress, inhibiting apoptosis, and modulating mitochondrial function. Both sodium phenylbutyrate and taurursodiol have unique pharmacological actions that make them valuable in treating specific conditions. 

Pharmacodynamics: 

Mechanism of action: The action of sodium phenylbutyrate and taurursodiol can be described as follows: 

sodium phenylbutyrate: 

• Urea Cycle Disorders (UCD): sodium phenylbutyrate is primarily used to treat UCDs. It works by increasing the levels of phenylacetate in the body. Phenylacetate conjugates with glutamine in the mitochondria to form phenylacetylglutamine. Phenylacetylglutamine is a non-toxic compound that facilitates the excretion of excess nitrogen, mainly in the form of phenylacetylglutamine, thereby reducing ammonia levels. By promoting the removal of ammonia, sodium phenylbutyrate helps prevent ammonia toxicity and associated neurological complications. 
• Epigenetic Regulation: sodium phenylbutyrate has been found to have epigenetic effects, meaning it can modify gene expression without altering the underlying DNA sequence. It acts as histone deacetylase inhibitor, which leads to increased histone acetylation. This modification can result in changes in gene expression patterns and can potentially impact various cellular processes, including those involved in cancer progression and neurodegenerative diseases. The precise mechanisms and specific genes affected by sodium phenylbutyrate’s epigenetic actions are still under investigation. 

taurursodiol: 

• Hepatoprotective Effects: taurursodiol exerts hepatoprotective effects by multiple mechanisms. It helps protect liver cells from injury and apoptosis (cell death) caused by various insults, including toxic bile acids, oxidative stress, and inflammation. taurursodiol stabilizes the mitochondrial membrane, inhibits mitochondrial permeability transition, and reduces mitochondrial oxidative stress. It also promotes the secretion and flow of bile, enhancing the elimination of toxic bile acids and maintaining the bile acid pool in a more non-toxic form. 
• Anti-Apoptotic and Anti-Inflammatory Effects: taurursodiol has been shown to modulate apoptotic pathways and suppress inflammation in liver cells. It inhibits the release of pro-apoptotic factors and reduces the activation of inflammatory signaling pathways, thereby protecting hepatocytes from injury and inflammation. 
• Neuroprotective Effects: taurursodiol has also demonstrated neuroprotective properties in preclinical studies. It can attenuate neuronal cell death by reducing oxidative stress, inhibiting apoptosis, and modulating mitochondrial function. taurursodiol’s ability to preserve mitochondrial integrity and regulate cellular energy metabolism contributes to its neuroprotective effects. 

Pharmacokinetics: 

Absorption 

sodium Phenylbutyrate: After oral administration, sodium phenylbutyrate is readily absorbed from the gastrointestinal tract. The absorption occurs mainly in the small intestine. 

taurursodiol: It is also well absorbed after oral administration. It is absorbed in the small intestine, similar to sodium phenylbutyrate. 

Distribution 

sodium Phenylbutyrate: sodium phenylbutyrate distributes widely throughout the body. It has a large volume of distribution, indicating extensive tissue distribution. 

taurursodiol is known to distribute throughout various tissues, including the liver and other organs. It has a moderate volume of distribution. 

Metabolism 

sodium Phenylbutyrate: sodium phenylbutyrate undergoes rapid metabolism in the body. It is converted to phenylacetate through β-oxidation in the liver. Phenylacetate is further conjugated with glutamine to form phenylacetylglutamine, which is excreted in the urine. 

taurursodiol: It undergoes metabolism in the liver, conjugating with glycine to form glycocholic acid. It is then further metabolized in the intestine by gut bacteria. 

Elimination and Excretion 

sodium Phenylbutyrate: The main route of excretion for sodium phenylbutyrate and its metabolites is through the kidneys. Phenylacetylglutamine is primarily excreted in the urine. 

taurursodiol and its metabolites are excreted in the bile. The bile is then eliminated from the body through feces. 

Adminstartion

Administration: 

Oral administration 

sodium Phenylbutyrate: 

• Dosage: The dosage of sodium phenylbutyrate is determined based on the patient’s age, weight, and the specific condition being treated. A healthcare professional typically prescribes it and may require periodic adjustments. 
• Oral Administration: sodium phenylbutyrate is usually taken orally as tablets or powder. It can be taken with or without food, but taking it with a meal is generally recommended to minimize gastrointestinal side effects. 
• Mixing with Food or Liquids: If the medication is in powder form, it can be mixed with a small amount of food or liquids to facilitate administration. However, following the specific instructions the healthcare professional provides or the medication’s packaging is crucial. 
• Compliance: Taking sodium phenylbutyrate consistently and as prescribed is crucial. Missing doses or discontinuing treatment without medical advice may affect the effectiveness of the medication. 

taurursodiol: 

• Dosage: The dosage of taurursodiol is determined based on the patient’s condition, severity, and response to treatment. A healthcare professional prescribes it and may require periodic adjustments. 
• Oral Administration: taurursodiol is typically administered orally through tablets or capsules. It is generally recommended to take it with water or without food, following the specific instructions provided by the healthcare professional or the medication’s packaging. 
• Compliance: It is crucial to take taurursodiol consistently and as prescribed. Missing doses or discontinuing treatment without medical advice may impact the desired therapeutic effects. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: sodium phenylbutyrate/ taurursodiol 

Pronounced: [ SOW-dee-um-fen-il-BYOO-ti-rate-and-taur-UR-so-DYE-ol ] 

Why do we use sodium phenylbutyrate/ taurursodiol? 

Uses of sodium Phenylbutyrate: 

• Urea Cycle Disorders (UCD): sodium phenylbutyrate is primarily used to treat UCDs, group of genetic disorders that generally affect the body’s ability to process and eliminate ammonia. It helps reduce ammonia levels by increasing the formation of phenylacetylglutamine, which aids in excretion from the body. By managing ammonia levels, sodium phenylbutyrate helps prevent complications associated with UCDs, such as hepatic encephalopathy. 
• Investigational Uses: sodium phenylbutyrate is also being investigated for potential therapeutic applications in other conditions. It has shown promise in preclinical and early-stage clinical trials for treating certain cancers, including solid tumors and hematological malignancies. Additionally, research suggests a potential role in neurodegenerative diseases, such as Huntington’s disease and Parkinson’s disease, by modulating gene expression and protein function. However, further studies are needed to establish its efficacy in these areas. 

Uses of taurursodiol: 

• Liver Diseases: taurursodiol is commonly used to treat various liver diseases. It has been studied extensively for its hepatoprotective properties, including primary biliary cholangitis (PBC), non-alcoholic fatty liver disease (NAFLD), and cholestasis. taurursodiol helps protect liver cells from damage, reduces inflammation, and improves bile flow, thus promoting liver health and function. 
• Neurodegenerative Diseases: taurursodiol has also shown potential benefits in neurodegenerative conditions. It has been studied in animal models and early clinical trials for its neuroprotective properties in diseases such as Alzheimer’s and Parkinson’s. taurursodiol’s mechanism of action may involve reducing oxidative stress, inhibiting apoptosis (cell death), and modulating mitochondrial function. However, further research is needed to establish its efficacy and safety in human populations.