glycerol phenylbutyrate

Action and Spectrum

Mechanism of action 

It is a medication used to decrease elevated plasma ammonia levels, which can be caused by certain medical conditions such as urea cycle disorders. It is metabolized in the body to form phenylbutyrate (PBA), which is then further metabolized to phenylacetate (PAA). PAA is then conjugated with glutamine to form phenylacetylglutamine (PAGN), a nitrogen waste product excreted by the kidneys. By providing an alternate mechanism for nitrogen excretion, sodium phenylbutyrate can help reduce ammonia levels in the blood. 

Spectrum 

The spectrum of GPB is used as a treatment for the same conditions as Sodium Phenylbutyrate, mainly in Urea Cycle disorders (UCDs), which are a group of genetic disorders that affect the ability of the body to process waste nitrogen. GPB is also used for off-label uses as it has been studied in several conditions, such as chronic kidney disease, liver disease, and cancer. It also has been used for the management of hyperammonemia and hyperammonemia-associated encephalopathy. 

Drug Interaction

Adverse Reaction

Frequency defined:  

>10% 

Flatulence 

Headache 

Diarrhea 

Children 

Vomiting 

Diarrhea 

Hypophagia 

Rhinorrhea 

Papule 

Increased hepatic enzymes 

Anemia 

Dehydration 

Thrombocytosis 

Lymphocytosis 

Lethargy 

Neutropenia 

Constipation 

Pyrexia 

Cough 

Rash 

Gastroesophageal reflux 

Feeding disorder 

Cough 

Metabolic acidosis 

1-10% 

Vomiting 

Dyspepsia 

Fatigue 

Abdominal pain 

Decreased appetite 

Increased ammonia 

Nausea 

Post marketing reports 

Gagging 

Neutropenia 

Hypophagia 

Nasal congestion 

Rash and papule 

Dysgeusia 

Pyrexia 

Cough 

Rhinorrhea 

Black Box Warning

Contraindication / Caution

Contraindications 

Hypersensitivity reactions are a possible side effect of phenylbutyrate, the active metabolite of medications like sodium phenylbutyrate and glycerol phenylbutyrate. These reactions can occur when the body has an abnormal response to the medication, ranging from mild to severe. 

The most common symptoms of hypersensitivity reactions to phenylbutyrate include wheezing, shortness of breath, coughing, low blood pressure, flushing, nausea, and rash. These symptoms may occur immediately or within a few hours after taking the medication. If you experience these symptoms, you must stop taking the medication and seek medical attention immediately. 

Caution 

• Patients with known hypersensitivity to phenylbutyrate, its excipients, or any formulation component should not take GPB. 
• GPB should be used with caution in patients with renal or hepatic impairment, as these patients may be more susceptible to developing hyperammonemia. It is recommended to monitor the blood ammonia levels closely in these patients and adjust the dosage accordingly. 
• Patients taking GPB should be advised to increase their fluid intake, as GPB is usually given with oral sodium phenylacetate, which may lead to dehydration. 
• It is also important to note that GPB can cause drowsiness, and patients should avoid driving or operating heavy machinery until the effects of the medication are known. 
• GPB should be used with caution in pregnant or breastfeeding women, as there is a lack of safety data on the use of GPB during these periods. 

Pregnancy / Lactation

Pregnancy consideration: Insufficient data available 

Lactation: Excretion of the drug in human breast milk is unknown 

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 available 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 

GPB is a prodrug of phenylbutyrate, which is an active metabolite. GPB is rapidly hydrolyzed in the gut to glycerol and phenylbutyrate. Phenylbutyrate is a small molecule taken up by the liver, where it is rapidly conjugated with glutamine to form phenylacetylglutamine (PAGN). PAGN is then excreted in the urine, providing an alternate mechanism for nitrogen excretion. 

GPB is used primarily in treating urea cycle disorders (UCDs), a group of inherited metabolic disorders in which the body cannot metabolize nitrogen waste products properly. Hyperammonemia, caused by the accumulation of ammonia in the blood, is a common symptom of UCDs, and GPB help to reduce it by providing an alternate mechanism for nitrogen excretion. 

Additionally, GPB has been studied in several conditions, such as chronic kidney disease, liver disease, and cancer. It has also been used for the management of hyperammonemia and hyperammonemia-associated encephalopathy. 

Pharmacodynamics 

The primary mechanism of action of GPB is to provide an alternate mechanism for nitrogen excretion in patients with urea cycle disorders (UCDs). GPB is metabolized in the liver to phenylbutyrate, which is then conjugated with glutamine to form phenylacetylglutamine (PAGN), a nitrogen waste product excreted by the kidneys. This helps to reduce the levels of ammonia in the blood, which is a common symptom of UCDs. 

GPB has been shown to have anti-inflammatory and anti-cancer properties as well. It has been shown to reduce pro-inflammatory cytokines and increase anti-inflammatory cytokines, indicating a potential beneficial effect in inflammatory disorders. It has also been shown that GPB may have a role in cancer treatment, as it can inhibit cancer cell growth and induce apoptosis. 

Pharmacokinetics 

Absorption: GPB is rapidly and completely absorbed after oral administration. It is rapidly hydrolyzed to glycerol and phenylbutyrate after oral administration. The maximum plasma concentrations of phenylbutyrate are reached within 1 to 2 hours after oral administration.  

Distribution: GPB is widely distributed in the body. The volume of distribution of phenylbutyrate is high, indicating that it distributes extensively into the body’s tissues.  

Metabolism: GPB is metabolized primarily in the liver by beta-oxidation to phenylacetate and phenylacetylglutamine. Phenylacetate is then conjugated with glutamine to form phenylacetylglutamine (PAGN), excreted in the urine.  

Excretion: Most GPB is excreted in the urine, primarily as PAGN. The elimination half-life of GPB is approximately 4 to 6 hours. 

Adminstartion

Administration 

glycerol phenylbutyrate (GPB) is administered orally as a liquid or granule formulation. The recommended dosage and frequency of administration will vary depending on the patient’s age, weight, and medical condition. It is essential to follow the dosing instructions provided by a healthcare professional and stay within the recommended dosage. 

It is usually administered twice a day, with food, and it is usually taken with oral sodium phenylacetate, which may cause dehydration, and that’s why it is essential to increase fluid intake when taking GPB. 

It is important to note that GPB can cause drowsiness, so patients should avoid driving or operating heavy machinery until the effects of the medication are known. 

It is also essential to monitor blood ammonia levels, as GPB can cause hyperammonemia, especially in patients with renal or hepatic impairment. Dosage adjustments may be needed to manage this. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: glycerol phenylbutyrate 

Pronounced: [ GLIS-er-ol-FEN-il-BUE-ti-rate] 

Why do we use glycerol phenylbutyrate? 

glycerol phenylbutyrate (GPB) is a nitrogen-binding agent used to manage patients with urea cycle disorders (UCDs).