Sodium Phenylbutyrate Works

Phenylbutyrate Works

Sodium phenylbutyrate is metabolized safely and naturally, helping the kidneys eliminate wastes and controlling the expression of certain genes that may cause cancer and other diseases.

How Sodium Phenylbutyrate Benefits the Human Body

Sodium phenylbutyrate is an approved treatment for people who have urea cycle disorders that allow nitrogen waste to build up in the blood plasma as ammonia glutamine, which is a condition known as hyperammonemia. When hyperammonemia persists in the body, it leads to mental disability, physical limitations, and early death.

Sodium phenylbutyrate encourages histone deacetylase (HDAC) enzymes to remove an acetyl group from histones, allowing them to bind DNA and inhibit gene transcription. HDAC is a family of 11 enzymes that may act as master regulators of many diseases by controlling gene expression.

The targets of HDAC enzymes are the acetyl (CH3CO) groups of histones. Histones are proteins that form a scaffold structure, around which a cell’s DNA is wrapped. Modification of these histone proteins by acetylation – the addition of acetyl groups – controls the tightness of the DNA around the histone proteins, thereby controlling the expression of the genes. 

In cancer, for instance, increased HDAC expression results in deacetylation of histone proteins through the removal of acetyl groups. Deacetylation causes the DNA to be wrapped too tightly around the histones, thereby inhibiting gene expression. If the genes affected are tumor suppressor genes, cancer can result.

Today, the two main functions of sodium phenylbutyrate that are responsible for its effectiveness are glutamine depletion and cell differentiation.

Glutamine Depletion

Glutamine is a non-essential amino acid and serves as the major nitrogen source for nucleic acid and protein synthesis. It is also an important energy substrate in rapidly-dividing cells. Tumor cells are significantly more sensitive to glutamine depletion than normal cells because they function on limiting levels of glutamine availability due to their increased utilization and accelerated catabolism.

Sodium phenylbutyrate depletes the cells of glutamine without affecting the glutamine-utilizing enzymes. In its metabolized form, it is capable of conjugating glutamine to yield phenyl acetyl glutamine (PAG), which is then excreted in the urine. This means the tumor cells will not have enough fuel to continue growing and multiplying. 

Normal cells are not affected by the recommended dosages of sodium phenylbutyrate. It has been shown that sodium phenylbutyrate arrests tumor growth and induces differentiation of premalignant and malignant cells through its non-toxic mechanism.

Cell Differentiation

Phenylbutyrate has been shown to be a non-toxic differentiation inducer, promoting maturation of various types of malignant cells. This is a good thing for the human body because maturation makes the cells less aggressive, causing them to cease dividing and eventually die.

Differentiation therapy also holds therapeutic potential for other diseases such as inherited anemias. Some exceptional results have been shown in the use of phenylbutyrate in sickle cell anemia/thalassemia, where it works by raising the HbF levels. 

In-vitro studies of cystic fibrosis have shown encouraging results where phenylbutyrate restored missing cellular protein.

Sodium Phenylbutyrate’s Mechanisms of Action in the Body

Sodium phenylbutyrate is an aromatic fatty acid that inhibits histone deacetylase by binding non-competitively to the enzyme and preventing it from binding to its substrate. It is metabolized to phenylacetate, with which it shares HDAC inhibitory activity and high levels of brain bioavailability. 

Phenylacetate is rapidly metabolized to phenylacetylglutamine, a reaction that scavenges glutamines and underlies its efficacy in improving nitrogen clearance. Because an additional action of sodium phenylbutyrate is peroxisome proliferation with improved fatty acid oxidation rates, it is also being examined in peroxisome biogenesis disorders such as adrenoleukodystrophy. In homozygous beta thalassemia, sodium phenylbutyrate is used to increase gamma-globulin and hemoglobin transcription, presumably through its activity as an HDAC inhibitor.


In terms of the pharmacokinetics, plasma bioavailability of sodium phenylbutyrate was comparable when given orally or intravenously. In urea cycle disorders, the recommended adult oral doses of sodium phenylbutyrate are 9.9 to 13 g/m2/day. Peak serum levels occur approximately one hour after oral doses. The elimination half-life is 48 minutes and is independent of the dose. 

Sodium phenylbutyrate exhibits nonlinear elimination kinetics and is eliminated primarily in urine as phenylacetylglutamine. It crosses the blood-brain barrier and intravenous dosing in non-human primates showed excellent cerebrospinal fluid (CSF) penetration with a median half-life of 132 minutes.

Safety and Clinical Use in Humans

Sodium phenylbutyrate is approved by the FDA for use in hyperammonemia due to urea cycle disorders. The drug has also been used in the long-term treatment of patients with ornithine transcarbamylase deficiency at the median dose of 352 mg/kg per day for an average of 26 months. Long-term use in this population is well tolerated. 

The most common adverse effects of sodium phenylbutyrate are menstrual irregularities in female patients, reduced appetite, body odor, and a bad taste in the mouth. Other effects include liver function test abnormalities, weight gain, edema, abdominal pain, nausea, vomiting, headache, and skin rash. Irregular menses occurred in 23% of patients. Approximately 4% of patients discontinued due to taste disturbance and/or loss of appetite. 

Sodium phenylbutyrate is under development as an anti-cancer agent because of its activity as an HDAC inhibitor causing tumor differentiation, growth arrest, and apoptosis. Aplastic anemia has been associated with phenylbutyrate therapy in one patient with urea cycle disorders, although a causal relationship is unproven. 

Similarly, occasional instances of anemia, leukopenia, leukocytosis, and thrombocytopenia and rare cases of thrombocytosis have been observed during therapy, but have not been directly associated with the drug. Arrhythmias and syncope have occurred rarely in patients treated with sodium phenylbutyrate, but a direct drug effect has not been shown.

 In a dose-escalation study in patients with refractory solid tumor malignancies, doses of up to 45 g/day were administered. Due to dose-limiting toxicities, the study concluded that 27 g/day was the maximally tolerated dose. Nausea, vomiting, hypocalcemia, and fatigue occurred at the 36g/day and 45g/day doses. Gastrointestinal upset including nausea, dyspepsia, and vomiting occurred at the lowest dose of 9g/day and was seen within 30 minutes of drug ingestion. However, 82% of patients completed the study despite these side effects. 

Other frequently reported side effects include a sweat-like odor, usually noticeable only to the caregiver. Mild neurotoxicity, including confusion and lethargy, has been noted at higher doses of close to 30g/day but resolved with dose reduction. 

A dose-escalation study of intravenous sodium phenylbutyrate in patients with myelodysplastic syndromes and acute myelogenous leukemia found a maximally-tolerated dose at 375 mg/kg/day (26.3 g/day for a 70 kg individual) with no serious toxicities detected in patients receiving doses between 125 and 375 mg/kg/day (8.8 and 26.3 g/day for a 70 kg individual). Dose-limiting toxicities like lethargy, confusion, and slurred speech were detected at 440 and 500 mg/kg/day sodium phenylbutyrate (30.8 and 35 g/day respectively, for a 70 kg individual). 

Reports of edema have been blamed on the high sodium load associated with the drug. Phase I/I I studies in subjects with sickle cell anemia, beta thalassemia, and adrenoleukodystrophy report similar side effects. Another phase I study in patients with refractory solid tumors tested intravenous sodium phenylbutyrate doses between 150 to 515 mg/kg/day (10 to 36 g/day for a 70 kg individual) with dose-limiting toxicities like excessive somnolence, confusion, and electrolyte abnormalities resulting at a dose of 515 mg/kg/day (36.0 g/day for a 70 kg individual). 

The maximally tolerated dose of sodium phenylbutyrate was determined to be 410 mg/kg/day (28.7 g/day for a 70 kg individual) as there were no dose-limiting toxicities at this dose and no patients required dose-reductions or escalations. Although there have been normal pregnancies on sodium phenylbutyrate, there remains a concern about possible teratogenic effects.


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