Sodium phenylbutyrate

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Not to be confused with Sodium butyrate.

Sodium phenylbutyrate
Clinical data
Trade namesBuphenyl, Pheburane, Ammonaps, others
AHFS/Drugs.comMicromedex Detailed Consumer Information
License data
Pregnancy
category
  • AU: B3
By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
MetabolismLiver and kidney to phenylacetic acid
Elimination half-life0.8 hours (phenylbutyrate), 1.15-1.29 hours (phenylacetate)
ExcretionUrine (80-100% as phenylacetylglutamine)
Identifiers
  • Sodium 4-phenylbutanoate
JSmol)
  • [Na+].[O-]C(=O)CCCC1=CC=CC=C1
  • InChI=1S/C10H12O2.Na/c11-10(12)8-4-7-9-5-2-1-3-6-9;/h1-3,5-6H,4,7-8H2,(H,11,12);/q;+1/p-1 checkY
  • Key:VPZRWNZGLKXFOE-UHFFFAOYSA-M checkY
 ☒NcheckY (what is this?)  (verify)

Sodium phenylbutyrate, sold under the brand name Buphenyl among others, is a salt of an aromatic fatty acid,

urea cycle disorders, because its metabolites offer an alternative pathway to the urea cycle to allow excretion of excess nitrogen.[8][9]

Sodium phenylbutyrate is also a

protein misfolding diseases such as cystic fibrosis.[7]

Structure and properties

Sodium phenylbutyrate is a sodium salt of an aromatic fatty acid, made up of an

aromatic ring and butyric acid. The chemical name for sodium phenylbutyrate is 4-phenylbutyric acid, sodium salt. It forms water-soluble off-white crystals.[4]

Uses

Medical uses

Sodium phenylbutyrate is taken orally or by

Food and Drugs Administration (FDA) in April 1996.[10][11]

Adverse effects

Nearly 1⁄4 of women may experience an adverse effect of amenorrhea or menstrual dysfunction.[4] Appetite loss is seen in 4% of patients. Body odor due to metabolization of phenylbutyrate affects 3% of patients, and 3% experience unpleasant tastes. Gastrointestinal symptoms and mostly mild indications of neurotoxicity are also seen in less than 2% of patients, among several other reported adverse effects.[4] Administration during pregnancy is not recommended because sodium phenylbutyrate treatment could mimic maternal phenylketonuria due to the production of phenylalanine, potentially causing fetal brain damage.[8]

Research

Urea cycle disorders

Sodium phenylbutyrate administration was discovered to lead to an alternative nitrogen disposal pathway by Dr.

NEJM.[8][13][14] Use of sodium phenylbutyrate was introduced in the early 1990s, as it lacks the odor of phenylacetate.[8][15][16]

Chemical chaperone

In

Cystic Fibrosis Transmembrane Conductance Regulator protein, ΔF508-CFTR, causes it to be unstable and misfold, hence trapped in the endoplasmic reticulum and unable to reach the cell membrane. This lack of CFTR in the cell membrane leads to disrupted chloride transport and the symptoms of cystic fibrosis. Sodium phenylbutyrate can act as a chemical chaperone, stabilising the mutant CFTR in the endoplasmic reticulum and allowing it to reach the cell surface.[17]

Histone deacetylase inhibitor

Deriving from its activity as a

sickle-cell disorders as an alternative to hydroxycarbamide due to it inducing expression of fetal hemoglobin to replace missing adult hemoglobin.[18][19] While small-scale investigation is proceeding, there is to date no published data to support the use of the compound in the clinical treatment of cancer, and it remains under limited investigation. Sodium phenylbutyrate is also being studied as a therapeutic option for the treatment of Huntington's disease.[20]

Other

Phenylbutyrate has been associated with longer lifespans in Drosophila.[21]

University of Colorado researchers Curt Freed and Wenbo Zhou demonstrated that phenylbutyrate stops the progression of Parkinson's disease in mice by turning on a gene called DJ-1 that can protect dopaminergic neurons in the midbrain from dying. As of July 2011 they plan on testing phenylbutyrate for the treatment of Parkinson's disease in humans.[22]

Pharmacology

Nitrogen elimination by phenylbutyrate metabolites

Phenylbutyrate is a

beta-oxidation, mainly in the liver and kidneys, to the active form, phenylacetate.[23] Phenylacetate conjugates with glutamine to phenylacetylglutamine, which is eliminated with the urine. It contains the same amount of nitrogen as urea, which makes it an alternative to urea for excreting nitrogen.[4]

Sodium phenylbutyrate taken by mouth can be detected in the blood within fifteen minutes, and reaches peak concentration in the bloodstream within an hour. It is metabolized into phenylacetate within half an hour.[4]

References

  1. ^ "Prescription medicines: registration of new chemical entities in Australia, 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 9 April 2023.
  2. ^ "Prescription medicines and biologicals: TGA annual summary 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 31 March 2024.
  3. ^ "Health Canada New Drug Authorizations: 2015 Highlights". Health Canada. 4 May 2016. Retrieved 7 April 2024.
  4. ^ a b c d e f g h i j "Buphenyl- sodium phenylbutyrate tablet Buphenyl- sodium phenylbutyrate powder". DailyMed. 11 March 2020. Retrieved 19 October 2020.
  5. ^ "Olpruva - sodium phenylbutyrate kit". DailyMed. 22 December 2022. Retrieved 21 January 2023.
  6. ^ "Ammonaps EPAR". European Medicines Agency. 17 September 2018. Retrieved 3 January 2023.
  7. ^
    PMID 21902286
    .
  8. ^
    PMID 11148549
    .
  9. S2CID 25998574
    .
  10. Food and Drugs Administration
    (FDA). Retrieved 26 October 2013.
  11. Food and Drugs Administration
    (FDA) (Report).
  12. PMID 6243418
    .
  13. PMID 7078580
    .
  14. PMID 6427608
    .
  15. PMID 2014149
    .
  16. PMID 2222247
    .
  17. PMID 22822398
    .
  18. PMID 7517215
    .
  19. S2CID 23928373
    .
  20. PMID 24167500
    .
  21. PMID 11792861
    .
  22. PMID 21902286
    . The same authors investigated the effects of phenylbutyrate on the accumulation of Parkin-associated endothelin receptor-like receptor (Pael-R), pathologically relevant to the loss of dopaminergic neurons in autosomal recessive juvenile parkinsonism, showing that (i) phenylbutyrate restores the normal expression of Pael-R protein and suppresses ER stress induced by the overexpression of Pael-R; (ii) phenylbutyrate attenuates the activation of ER stress-induced signal transduction pathways and subsequent neuronal cell death; and (iii) phenylbutyrate restores the viability of yeasts that fail to induce an ER stress response under ER stress conditions. These findings lead the author to conclude that phenylbutyrate suppresses ER stress by directly reducing the amount of misfolded protein, including Pael-R accumulated in the ER.[175]
  23. PMID 23141465
    .
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