- Sodium phenylbutyrate
- 4-phenylbutyric acid
- Sodium 4-phenylbutyrate
For Patients & Caregivers
Phenylbutyrate is effective in treating certain urea cycle disorders. There is some evidence of its anticancer activity. More studies are needed.
Phenylbutyrate helps remove nitrogen from the body. It is therefore approved for use in urea cycle disorders, in which the body has an impaired capacity to excrete nitrogen and ammonium build up in the blood. Phenylbutyrate has also been shown to increase fetal hemoglobin production in patients with thalassemia, a genetic disease resulting in anemia, and sickle cell disease.
In laboratory experiments, phenylbutyrate causes various types of cancer cells to stop growing, appear more “normal”, and/or undergo cell death when directly applied to these cells. In an animal model, phenylbutyrate plus retinoic acid, a form of vitamin A, stopped the growth of blood vessels around a prostate tumor and caused cell death in prostate cancer cells. These effects have not been shown in humans.
- To treat cancer
Although phenylbutyrate stops the growth of certain cancer cells when it is directly applied to them in the laboratory, most of the time such results do not translate into effects in the human body. Four small clinical trials do not support this use.
- To treat cystic fibrosis
One clinical trial weakly supports this use. More studies are needed.
- To treat hemoglobin disorders such as sickle cell anemia and thalassemia (a genetic disease resulting in anemia)
Laboratory studies and clinical data from small case studies support this use; however, larger studies with placebo control groups are needed.
- To treat urea cycle disorders
Phenylbutyrate is approved by the FDA as a drug to treat urea cycle disorders.
- Stomach upset
- Nausea and vomiting
- Body odor
- Anorexia (loss of appetite)
- Menstrual cycle irregularities, including amenorrhea (lack of menstruation)
- Less frequent side effects include low blood calcium, edema, and skin rash
- A few cases of liver toxicity and renal tubular acidosis have been reported.
For Healthcare Professionals
Phenylbutyrate is a prodrug of phenylacetate, an aromatic fatty acid. Patients are prescribed phenylbutyrate off-label to treat cancer. Sodium phenylbutyrate is classified by the FDA as an orphan drug for the treatment of urea cycle disorders.
Phenylbutyrate and its metabolites have been shown to increase fetal hemoglobin production in patients with thalassemia (1) and sickle cell disease (2). Data also indicate that they enhance cytotoxicity of chemo agents such as doxorubicin and cisplatin (11), and exert antibacterial effects against Helicobacter pylori in vitro (17).
Several phase I trials are underway to evaluate phenylbutyrate for leukemias, lymphomas, and refractory solid tumors. Published phase I studies indicate low toxicity and possible activity in these cancers. A number of patients experienced disease stabilization in these trials, although disease regression was not observed (3) (4) (5) (16).
A small study showed that a phenylbutyrate mouthwash decreased the impact of oral mucositis in patients with head and neck cancer (18).
Multiple dose escalation trials have been performed in patients with solid tumors (3) (4) (5), Huntington’s disease (6), and Amyotrophic lateral sclerosis (7); however, the optimal dose has yet to be defined. Oral doses up to 36 grams per day have been used with minimal toxicity (4).
In urea cycle disorders, phenylacetate reduces or normalizes serum ammonium and glutamate levels (8). Phenylbutyrate and its metabolites have been shown to increase fetal hemoglobin production in patients with thalassemia (1) and sickle cell disease (2); it also influences the expression of endothelial adhesion molecules such as endothelin-1, possibly reducing erythrocyte attachment to vascular walls (9).
In vitro studies suggest that phenylbutyrate causes cancer cell cytostasis, differentiation (10), and apoptosis (11). Phenylbutyrate also increases the sensitivity of head and neck cancer cells to cisplatin (12). Animal studies indicate that phenylbutyrate, when combined with 13-cis retinoic acid, inhibits angiogenesis and causes apoptosis of prostate cancer cells (13). Other studies show that phenylbutyrate and its metabolites up-regulate numerous lipid-metabolizing genes via human peroxisome transcription factors, inhibit p21ras prenylation, resulting in G1 arrest and apoptosis in myeloid cells (14), and down-regulate Bcl-2 in MCF7ras breast cancer cells. In vitro studies with HT-29 colon cancer cells indicate that phenylbutyrate inactivates NF-kB, resulting in apoptosis (15).
Common: Fatigue, dyspepsia, nausea, vomiting (4), body odor, anorexia, menstrual cycle irregularities, and amenorrhea (8)
Reported: Hypocalcemia, edema (possibly related to sodium content), skin rash (4)
Rare: Liver toxicity (elevations in AST, ALT, bilirubin, and alk phos), renal tubular acidosis (8)