Phenylbutyrate

Health Care Professional Information

Common Name

Sodium phenylbutyrate, 4-phenylbutyric acid, sodium 4-phenylbutyrate

Brand Name

Buphenyl® (Manuf. by Ucyclyd), triButyrate® (Manuf. by Triple Crown America)

Clinical Summary

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).

Purported Uses
  • Cancer treatment
  • Cystic fibrosis
  • Sickle cell disease
  • Thalassemia
  • Urea cycle disorders
Mechanism of Action

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).

Pharmacokinetics

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.
(4)

Warnings

Each 500 mg tablet of sodium phenylbutyrate contains approximately 62 mg sodium. (8)

Adverse Reactions

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)

Literature Summary and Critique

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.

References
  1. Olivieri NF, Rees DC, Ginder GD, et al. Treatment of thalassaemia major with phenylbutyrate and hydroxyurea. Lancet. Aug 16 1997;350(9076):491-492.
  2. Hines P, Dover GJ, Resar LM. Pulsed-dosing with oral sodium phenylbutyrate increases hemoglobin F in a patient with sickle cell anemia. Pediatr Blood Cancer. Feb 2008;50(2):357-359.
  3. Carducci MA, Gilbert J, Bowling MK, et al. A Phase I clinical and pharmacological evaluation of sodium phenylbutyrate on an 120-h infusion schedule. Clin Cancer Res. Oct 2001;7(10):3047-3055.
  4. Gilbert J, Baker SD, Bowling MK, et al. A phase I dose escalation and bioavailability study of oral sodium phenylbutyrate in patients with refractory solid tumor malignancies. Clin Cancer Res. Aug 2001;7(8):2292-2300.
  5. Camacho LH, Olson J, Tong WP, 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.
  6. Hogarth P, Lovrecic L, Krainc D. Sodium phenylbutyrate in Huntington's disease: a dose-finding study. Mov Disord. Oct 15 2007;22(13):1962-1964.
  7. Cudkowicz ME, Andres PL, Macdonald SA, et al. Phase 2 study of sodium phenylbutyrate in ALS. Amyotroph Lateral Scler. Aug 7 2008:1-8.
  8. Package Insert: Buphenyl®, sodium phenylbutyrate. Hunt Valley (MD): Ucyclyd Pharma; 1996.
  9. Odievre MH, Brun M, Krishnamoorthy R, et al. Sodium phenyl butyrate downregulates endothelin-1 expression in cultured human endothelial cells: relevance to sickle-cell disease. Am J Hematol. May 2007;82(5):357-362.
  10. Svechnikova I, Almqvist PM, Ekstrom TJ. HDAC inhibitors effectively induce cell type-specific differentiation in human glioblastoma cell lines of different origin. Int J Oncol. Apr 2008;32(4):821-827.
  11. Witzig TE, Timm M, Stenson M, et al. Induction of apoptosis in malignant B cells by phenylbutyrate or phenylacetate in combination with chemotherapeutic agents. Clin Cancer Res. Feb 2000;6(2):681-692.
  12. Burkitt K, Ljungman M. Phenylbutyrate interferes with the Fanconi anemia and BRCA pathway and sensitizes head and neck cancer cells to cisplatin. Mol Cancer. 2008;7:24.
  13. Pili R, Kruszewski MP, Hager BW, et al. Combination of phenylbutyrate and 12-cis retinoic acid inhibits prostate tumor growth and angiogenesis. Cancer Res. Feb 15 2001;61(4):1477-1485.
  14. DiGiuseppe JA, Weng LJ, Yu KH, et al. Phenylbutyrate-induced G1 arrest and apoptosis in myeloid leukemia cells: structure function analysis. Leukemia. Aug 1999;13(8):1243-1253.
  15. Feinman R, Clarke KO, Harrison LE. Phenylbutyrate-induced apoptosis is associated with inactivation of NF-kB in HT-29 colon cancer cells. Cancer Chemother Pharmacol. Jan 2002;49(1):27-34.
  16. Lin J, Gilbert J, Rudek MA, et al. A phase I dose-finding study of 5-azacytidine in combination with sodium phenylbutyrate in patients with refractory solid tumors. Clin Cancer Res. 2009 Oct 1;15(19):6241-9.
  17. Lo CY, Cheng HL, Hsu JL, et al. The antimicrobial activities of phenylbutyrates against Helicobacter pylori. Chem Pharm Bull (Tokyo). 2013;61(6):604-10.
  18. Yen SH, Wang LW, Lin YH, Jen YM, Chung YL. Phenylbutyrate mouthwash mitigates oral mucositis during radiotherapy or chemoradiotherapy in patients with head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2012 Mar 15;82(4):1463-70.

Consumer Information

How It Works

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.

Purported Uses
  • 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.
Research Evidence

Cancer treatment:
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.

Patient Warnings
Side Effects
  • Fatigue
  • 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.
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