sodium phenylbutyrate and taurursodiol

Action and Spectrum

Actions and spectrum: 

sodium phenylbutyrate: 

• Action: sodium phenylbutyrate is a prodrug that gets metabolized into phenylacetate in the body. Phenylacetate conjugates with glutamine and forms phenylacetylglutamine, which is excreted in the urine. This mechanism helps to remove excess nitrogen from the body, reducing ammonia levels. 
• Spectrum: sodium phenylbutyrate is primarily used for the treatment of urea cycle disorders, including deficiencies of various enzymes in the urea cycle. UCDs are a group of inherited metabolic disorders characterized by the impaired ability to convert ammonia into urea, leading to the accumulation of ammonia in the body. 

taurursodiol: 

• Action: taurursodiol, also known as ursodeoxycholic acid (UDCA), is a naturally occurring bile acid that has cytoprotective and anti-inflammatory properties. It helps to promote the bile flow and reduces the concentration of toxic bile acids in the liver. 
• Spectrum: taurursodiol is used in the treatment of various liver diseases, including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). It helps in improving liver function and reduce liver damage in these conditions. In combination with sodium phenylbutyrate, taurursodiol may be used for the treatment of UCDs to enhance the nitrogen removal process and improve metabolic balance. 

Drug Interaction

Adverse Reaction

Frequency defined 

1-10% 

Dizziness (10%)  

>10% 

Abdominal pain (21%) 

URTI (18%) 

Salivary hypersecretion (11%) 

Diarrhea (25%) 

Nausea (18%) 

Fatigue (12%) 

Black Box Warning

Black Box Warning: 

There is no specific black box warning associated with the combination of sodium phenylbutyrate and taurursodiol. 

Contraindication / Caution

Contraindication/Caution: 

Contraindication: 

• Hypersensitivity: sodium phenylbutyrate/ taurursodiol is contraindicated in individuals with a known hypersensitivity to the medication or any of its components. 
• Obstruction of the bile ducts: taurursodiol is contraindicated in cases of complete obstruction of the bile ducts. 
• Acute inflammation of gallbladder or biliary tract: taurursodiol should not be used in individuals with acute inflammation of gallbladder or biliary tract. 
• Calcified gallstones: taurursodiol is contraindicated in individuals with calcified gallstones.

Caution: 

• Gallbladder Disease: taurursodiol is a bile acid and may affect the function of the gallbladder. Caution is advised in patients with gallbladder disease or a history of gallstones. Regular monitoring may be necessary to assess gallbladder function. 
• Gastrointestinal Disorders: Both medications can cause gastrointestinal side effects such as nausea, vomiting, abdominal discomfort, and diarrhea. Caution is recommended in patients with a history of gastrointestinal disorders or those prone to gastrointestinal symptoms. 
• Bleeding Disorders: sodium phenylbutyrate and taurursodiol may have an impact on blood clotting. Caution is recommended in patients with bleeding disorders or those taking anticoagulant medications. Close monitoring of bleeding parameters may be necessary. 
• Drug Interactions: Both medications can interact with other drugs, including antacids, bile acid sequestrants, and certain medications that affect liver enzymes. It is important to review the patient’s medication profile and consider potential drug interactions before initiating sodium phenylbutyrate and taurursodiol therapy.

Comorbidities: 

• Urea Cycle Disorders (UCDs): sodium phenylbutyrate and taurursodiol are commonly used in the treatment of UCDs, which are genetic disorders that affect the body’s ability to break down nitrogen waste. Comorbidities that can be associated with UCDs include liver dysfunction, neurological abnormalities, and metabolic disturbances. 
• Primary Biliary Cholangitis (PBC): taurursodiol, also known as ursodeoxycholic acid, is used in the treatment of PBC, a chronic liver disease characterized by the progressive destruction of the bile ducts in liver. Comorbidities that may be associated with PBC include fatigue, pruritus (itching), osteoporosis, and autoimmune conditions. 
• Primary Sclerosing Cholangitis (PSC): taurursodiol may also be used in the treatment of PSC. Comorbidities that can be associated with PSC include inflammatory bowel disease (such as ulcerative colitis), gallbladder disease, and liver cirrhosis. 
• Hepatic Impairment: Patients with liver disease or hepatic impairment may require the use of sodium phenylbutyrate or taurursodiol. Comorbidities such as hepatitis, cirrhosis, or other liver disorders may be present in these individuals. 
• Renal Impairment: sodium phenylbutyrate and taurursodiol are eliminated from the body through the kidneys. Patients with renal impairment requires dose adjustments or close monitoring when using these medications. 

Pregnancy / Lactation

Pregnancy consideration: US FDA pregnancy category: Not assigned 

Lactation: Excreted into human milk: Data not available  

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: 

• Mechanism of Action: sodium phenylbutyrate is a prodrug that is metabolized in the body into phenylacetate. Phenylacetate conjugates with glutamine to form phenylacetylglutamine. This process helps to eliminate excess nitrogen from the body by providing an alternative pathway for nitrogen disposal, reducing ammonia levels. 

taurursodiol (Ursodeoxycholic Acid): 

• Mechanism of Action: taurursodiol is a bile acid derivative that exhibits cytoprotective and anti-inflammatory properties. It acts by reducing the concentration of toxic bile acids in the liver, promoting the flow of bile, and protecting hepatocytes from damage. 

Pharmacodynamics: 

sodium phenylbutyrate: 

• Urea Cycle Disorders (UCDs): sodium phenylbutyrate provides an alternative pathway for the disposal of excess nitrogen in the body. It is converted to phenylacetate, which conjugates with glutamine to form phenylacetylglutamine. This process helps in the excretion of nitrogen as phenylacetylglutamine in the urine, reducing ammonia levels. By reducing ammonia toxicity, sodium phenylbutyrate helps to manage UCDs. 

taurursodiol (Ursodeoxycholic Acid): 

• Bile Acid Metabolism: taurursodiol exerts its pharmacodynamic effects by influencing bile acid metabolism. It reduces the concentration of toxic bile acids in the liver, such as chenodeoxycholic acid and lithocholic acid, while increasing the proportion of hydrophilic bile acids, like ursodeoxycholic acid (UDCA) and tauroursodeoxycholic acid (TUDCA). This shift in the bile acid profile helps protect hepatocytes and prevents cholestasis and hepatotoxicity. 
• Hepatoprotective Effects: taurursodiol has cytoprotective properties and helps maintain the integrity and function of hepatocytes. It reduces hepatocyte apoptosis, inhibits pro-inflammatory cytokines, and promotes anti-inflammatory pathways. These effects contribute to the overall hepatoprotective actions of taurursodiol. 
• Immunomodulatory Effects: taurursodiol may also modulate the immune response, suppressing inflammatory processes and reducing immune-mediated liver damage. It has been shown to affect immune cells, including macrophages and lymphocytes, and regulate cytokine production. 

Pharmacokinetics: 

sodium phenylbutyrate: 

• Absorption: sodium phenylbutyrate is orally administered and undergoes rapid absorption in the gastrointestinal tract. It is absorbed primarily in the small intestine. 
• Distribution: After absorption, sodium phenylbutyrate is distributed throughout the body. It has a moderate volume of distribution and is distributed into various tissues. 
• Metabolism: sodium phenylbutyrate is metabolized in the liver through β-oxidation to form phenylacetate. Phenylacetate is further conjugated with glutamine to form phenylacetylglutamine, which is excreted in the urine. 
• Excretion: The main route of excretion for sodium phenylbutyrate and its metabolites is via the urine, primarily as phenylacetylglutamine. 

taurursodiol (Ursodeoxycholic Acid): 

• Absorption: taurursodiol is orally administered and undergoes absorption primarily in the small intestine. It is absorbed into bloodstream and transported to the liver. 
• Distribution: taurursodiol is distributed throughout the body, including the liver, where it exerts its pharmacological effects. 
• Metabolism: taurursodiol undergoes metabolism in the liver, where it is conjugated with the amino acid taurine to form tauroursodeoxycholic acid (TUDCA). 
• Excretion: taurursodiol and its metabolites, including TUDCA, are excreted in bile. A small fraction may undergo enterohepatic circulation. 

Adminstartion

Administration: 

sodium phenylbutyrate: 

• Route of Administration: sodium phenylbutyrate is available in oral formulations, including tablets and powder for oral suspension. It is taken by mouth. 
• Administration Instructions: sodium phenylbutyrate should be taken with food to enhance its absorption. The exact dosing instructions, including the frequency and duration of treatment, should be determined by a healthcare professional based on the specific condition being treated and individual patient factors. It’s important to follow the prescribed dosage and administration instructions provided by the healthcare provider. 

taurursodiol (Ursodeoxycholic Acid): 

• Route of Administration: taurursodiol is available in oral formulations, such as capsules and tablets. It is taken by mouth. 
• Administration Instructions: taurursodiol is usually taken with food to improve its absorption. The exact dosage and administration instructions may vary based on the specific condition treated and individual patient factors. It’s important to follow the instructions provided by the healthcare professional or as indicated on the product label. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: sodium phenylbutyrate and taurursodiol 

Pronounced: (soh-dee-uhm fen-il-byoo-tuh-rayt-and- taw-roor-soh-dye-ol)  

Why do we use sodium phenylbutyrate and taurursodiol ? 

sodium phenylbutyrate: sodium phenylbutyrate is used for the treatment of certain urea cycle disorders (UCDs), which are genetic disorders characterized by the inability to properly metabolize ammonia in the body. It is indicated for the chronic management of patients with UCDs who cannot be managed with dietary protein restriction and/or amino acid supplementation alone. sodium phenylbutyrate helps in the excretion of excess nitrogen as phenylacetylglutamine in the urine, reducing ammonia levels and preventing ammonia toxicity. 

• Primary Biliary Cholangitis (PBC): taurursodiol is approved for the treatment of primary biliary cholangitis by the destruction of small bile ducts in liver. It helps to improve liver function, reduce liver inflammation, and slows down the disease progression. 
• Primary Sclerosing Cholangitis (PSC): taurursodiol may be used off-label for primary sclerosing cholangitis, a chronic inflammatory disease affecting the bile ducts. It helps in improving liver function and reduce symptoms in some patients. 
• Gallstone Dissolution: taurursodiol may be used to dissolve cholesterol gallstones in patients who are not candidates for surgery. It helps to modify the composition of bile and promote the dissolution of gallstones.