- Sodium phenylbutyrate
- 4-phenylbutyric acid
- Sodium 4-phenylbutyrate
For Patients & Caregivers
Bottom Line: 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, differentiate (appear more “normal”), and/or undergo cell death (apoptosis) when it is 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.
To date, clinical trials of phenylbutyrate as a cancer treatment have been small, evaluating the safety of different doses of phenylbutyrate:
A treatment schedule for intravenous phenylbutyrate was studied in 21 patients with advanced, solid tumors. The patients received different doses of phenylbutyrate (60-360 mg/kg/d). One course of treatment consisted of two infusions each day for 2 consecutive weeks (M-F); this course was repeated every month. Some patients complained of short-term memory loss, sedation, confusion, nausea, and vomiting. While tumor shrinkage was not detected in any patient, disease stability (no increased tumor growth) was detected in 3 patients for 4-7 months. In this study, the maximum dose that was tolerated by the patients was 300 mg/kg/d. The researchers concluded that this treatment schedule may allow for longer treatments with phenylbutyrate; 1 patient tolerated 8 courses of treatment.
- 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).
Following oral administration, phenylbutyrate tablets are roughly 80% bioavailable. Phenylbutyrate has an approximate distribution of 0.3 L/kg. Cmax increases linearly following oral doses of 18, 27, and 36 grams, with blood concentrations of approximately 1670, 2327, and 3508 mM/L, respectively. Following oral or parenteral administration, phenylbutyrate is metabolized rapidly by beta-oxidation in the kidneys and liver to phenylacetate and phenylacetylglutamine. The biologic half-life is around 1 hour for the parent compound and approximately 1.8 and 2.8 hours for phenylacetate and phenylacetylglutamine, respectively. Metabolites are eliminated primarily via the kidneys.
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)
Available literature consist only of phase I studies, which suggest relative safety of both parenterally and orally administered sodium phenylbutyrate in cancer patients.
Camacho LH, et al. Phase I dose escalation clinical trial of phenylbutyrate sodium administered twice daily to patients with advanced solid tumors. Invest New Drugs. Apr 2007;25(2):131-138.
In this phase I dose escalation trial that included 21 patients with advanced, solid tumors, participants were administered various doses of phenylbutyrate infusions (60-360 mg/kg/d). One course of treatment consisted of twice daily infusions for 2 consecutive weeks (M-F); this course was repeated monthly. Dose limiting toxicities included short-term memory loss, sedation, confusion, nausea, and vomiting. Disease stability was detected in 3 patients for 4-7 months. In this study, the maximum tolerated dose was 300 mg/kg/d; 1 patient tolerated 8 courses of treatment at this dose.