Sodium phenylbutyrate

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Sodium phenylbutyrate
Sodium phenylbutyrate Structural Formula V1.svg
Clinical data
Trade names Buphenyl, Pheburane, Ammonaps, others
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Pregnancy
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  • AU:B3
Routes of
administration
By mouth
ATC code
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Pharmacokinetic data
Metabolism Liver and kidney to phenylacetic acid
Elimination half-life 0.8 hours (phenylbutyrate), 1.15-1.29 hours (phenylacetate)
Excretion Urine (80-100% as phenylacetylglutamine)
Identifiers
  • Sodium 4-phenylbutanoate
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Chemical and physical data
Formula C10H11NaO2
Molar mass 186.186 g·mol−1
3D model (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 Yes check.svgY
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Sodium phenylbutyrate, sold under the brand name Buphenyl among others, is a salt of an aromatic fatty acid, 4-phenylbutyrate (4-PBA) or 4-phenylbutyric acid. [6] The compound is used to treat urea cycle disorders, because its metabolites offer an alternative pathway to the urea cycle to allow excretion of excess nitrogen. [7] [8]

Contents

Sodium phenylbutyrate is also a histone deacetylase inhibitor and chemical chaperone, leading respectively to research into its use as an anti-cancer agent and in protein misfolding diseases such as cystic fibrosis. [6]

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. [3]

Uses

Medical uses

Sodium phenylbutyrate is taken orally or by nasogastric intubation as a tablet or powder, and tastes very salty and bitter. It treats urea cycle disorders, genetic diseases in which nitrogen waste builds up in the blood plasma as ammonia glutamine (a state called hyperammonemia) due to deficiences in the enzymes carbamoyl phosphate synthetase I, ornithine transcarbamylase, or argininosuccinic acid synthetase. [7] [3] Uncontrolled, this causes intellectual impairment and early death. [3] Sodium phenylbutyrate metabolites allows the kidneys to excrete excess nitrogen in place of urea, and coupled with dialysis, amino acid supplements and a protein-restricted diet, children born with urea cycle disorders can usually survive beyond 12 months. [3] Patients may need treatment for all their life. [3] The treatment was introduced by researchers in the 1990s, and approved by the U.S. Food and Drugs Administration (FDA) in April 1996. [9] [10]

Adverse effects

Nearly 14 of women may experience an adverse effect of amenorrhea or menstrual dysfunction. [3] 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. [3] 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. [7]

Research

Urea cycle disorders

Sodium phenylbutyrate administration was discovered to lead to an alternative nitrogen disposal pathway by Dr. Saul Brusilow, Mark Batshaw and colleagues at the Johns Hopkins School of Medicine in the early 1980s, due to some serendipitous discoveries. They had studied ketoacid therapy for another inborn error of metabolism, citrullinemia, in the late 1970s and they noticed that arginine treatment led to an increase of nitrogen in the urine and a drop in ammonia in the blood. The researchers spoke to Norman Radin about this finding, and he remembered a 1914 article on using sodium benzoate to reduce urea excretion. Another 1919 article had used sodium phenylacetate, and so the researchers treated five patients with hyperammonemia with benzoate and phenylacetate and published a report in Science . [7] [11] In 1982 and 1984, the researchers published on using benzoate and arginine for urea cycle disorders in the NEJM . [7] [12] [13] Use of sodium phenylbutyrate was introduced in the early 1990s, as it lacks the odor of phenylacetate. [7] [14] [15]

Chemical chaperone

In cystic fibrosis, a point mutation in the 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. [16]

Histone deacetylase inhibitor

Deriving from its activity as a histone deacetylase inhibitor, sodium phenylbutyrate is under investigation for use as a potential differentiation-inducing agent in malignant glioma and acute myeloid leukaemia, [6] and also for the treatment of some sickle-cell disorders as an alternative to hydroxycarbamide due to it inducing expression of fetal hemoglobin to replace missing adult hemoglobin. [17] [18] 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. [19]

Other

Phenylbutyrate has been associated with longer lifespans in Drosophila . [20]

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. [21]

Pharmacology

Nitrogen elimination by phenylbutyrate metabolites Nitrogen elimination.jpg
Nitrogen elimination by phenylbutyrate metabolites

Phenylbutyrate is a prodrug. In the human body it is first converted to phenylbutyryl-CoA and then metabolized by mitochondrial beta-oxidation, mainly in the liver and kidneys, to the active form, phenylacetate. [22] 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. [3]

A 5 g tablet or powder of sodium phenylbutyrate taken by mouth can be detected in the blood within 15 minutes, and reaches peak concentration in the bloodstream within an hour. It is metabolized into phenylacetate within half an hour. [3]

Related Research Articles

The urea cycle (also known as the ornithine cycle) is a cycle of biochemical reactions that produces urea (NH2)2CO from ammonia (NH3). Animals that use this cycle, mainly amphibians and mammals, are called ureotelic.

<span class="mw-page-title-main">Cystic fibrosis</span> Medical condition

Cystic fibrosis (CF) is a rare genetic disorder that affects mostly the lungs, but also the pancreas, liver, kidneys, and intestine. The hallmark feature of CF is the accumulation of thick mucus in different organs. Long-term issues include difficulty breathing and coughing up mucus as a result of frequent lung infections. Other signs and symptoms may include sinus infections, poor growth, fatty stool, clubbing of the fingers and toes, and infertility in most males. Different people may have different degrees of symptoms.

<span class="mw-page-title-main">Hyperammonemia</span> Medical condition

Hyperammonemia is a metabolic disturbance characterised by an excess of ammonia in the blood. It is a dangerous condition that may lead to brain injury and death. It may be primary or secondary.

<span class="mw-page-title-main">Sodium benzoate</span> Chemical compound

Sodium benzoate also known as benzoate of soda is the sodium salt of benzoic acid, widely used as a food preservative (with an E number of E211) and a pickling agent. It appears as a white crystalline chemical with the formula C6H5COONa.

<span class="mw-page-title-main">Ornithine transcarbamylase deficiency</span> Medical condition

Ornithine transcarbamylase deficiency also known as OTC deficiency is the most common urea cycle disorder in humans. Ornithine transcarbamylase, the defective enzyme in this disorder, is the final enzyme in the proximal portion of the urea cycle, responsible for converting carbamoyl phosphate and ornithine into citrulline. OTC deficiency is inherited in an X-linked recessive manner, meaning males are more commonly affected than females.

<span class="mw-page-title-main">Amiloride</span> Medication

Amiloride, sold under the trade name Midamor among others, is a medication typically used with other medications to treat high blood pressure or swelling due to heart failure or cirrhosis of the liver. Amiloride is classified as a potassium-sparing diuretic. Amiloride is often used together with another diuretic, such as a thiazide or loop diuretic. It is taken by mouth. Onset of action is about two hours and it lasts for about a day.

<span class="mw-page-title-main">Cystic fibrosis transmembrane conductance regulator</span> Mammalian protein found in humans

Cystic fibrosis transmembrane conductance regulator (CFTR) is a membrane protein and anion channel in vertebrates that is encoded by the CFTR gene.

Protein toxicity is the effect of the buildup of protein metabolic waste compounds, like urea, uric acid, ammonia, and creatinine. Protein toxicity has many causes, including urea cycle disorders, genetic mutations, excessive protein intake, and insufficient kidney function, such as chronic kidney disease and acute kidney injury. Symptoms of protein toxicity include unexplained vomiting and loss of appetite. Untreated protein toxicity can lead to serious complications such as seizures, encephalopathy, further kidney damage, and even death.

<span class="mw-page-title-main">Phenylacetic acid</span> Chemical compound

Phenylacetic acid, also known by various synonyms, is an organic compound containing a phenyl functional group and a carboxylic acid functional group. It is a white solid with a strong honey-like odor. Endogenously, it is a catabolite of phenylalanine. As a commercial chemical, because it can be used in the illicit production of phenylacetone, it is subject to controls in countries including the United States and China.

<span class="mw-page-title-main">N-Acetylglutamate synthase deficiency</span> Medical condition

N-Acetylglutamate synthase deficiency is an autosomal recessive urea cycle disorder.

Carbamoyl phosphate synthetase I deficiency is an autosomal recessive metabolic disorder that causes ammonia to accumulate in the blood due to a lack of the enzyme carbamoyl phosphate synthetase I. Ammonia, which is formed when proteins are broken down in the body, is toxic if the levels become too high. The nervous system is especially sensitive to the effects of excess ammonia.

<span class="mw-page-title-main">Ornithine translocase deficiency</span> Medical condition

Ornithine translocase deficiency, also called hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome, is a rare autosomal recessive urea cycle disorder affecting the enzyme ornithine translocase, which causes ammonia to accumulate in the blood, a condition called hyperammonemia.

<span class="mw-page-title-main">Phenylacetylglutamine</span> Chemical compound

Phenylacetylglutamine is a product formed by the conjugation of phenylacetate and glutamine. It is a common metabolite that occurs naturally in human urine.

<span class="mw-page-title-main">Ivacaftor</span> Cystic fibrosis treatment drug

Ivacaftor is a medication used to treat cystic fibrosis in people with certain mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, who account for 4–5% cases of cystic fibrosis. It is also included in combination medications, lumacaftor/ivacaftor, tezacaftor/ivacaftor, and elexacaftor/tezacaftor/ivacaftor which are used to treat people with cystic fibrosis.

<span class="mw-page-title-main">Argininemia</span> Medical condition

Argininemia is an autosomal recessive urea cycle disorder where a deficiency of the enzyme arginase causes a buildup of arginine and ammonia in the blood. Ammonia, which is formed when proteins are broken down in the body, is toxic if levels become too high; the nervous system is especially sensitive to the effects of excess ammonia.

<span class="mw-page-title-main">Glycerol phenylbutyrate</span> Chemical compound

Glycerol phenylbutyrate, sold under the brand name Ravicti, is a medication used in the treatment of certain inborn urea cycle disorders. The medication works by preventing the harmful buildup of ammonia in the body. It is an FDA-approved prescription drug in the US. It was developed by Hyperion Therapeutics based on the existing medication sodium phenylbutyrate, and received approval in February 2013.

<span class="mw-page-title-main">Citrullinemia type I</span> Medical condition

Citrullinemia type I (CTLN1), also known as arginosuccinate synthetase deficiency, is a rare disease caused by a deficiency in argininosuccinate synthetase, an enzyme involved in excreting excess nitrogen from the body. There are mild and severe forms of the disease, which is one of the urea cycle disorders.

<span class="mw-page-title-main">Mark Batshaw</span> American geneticist

Mark Levitt Batshaw is a Canadian-born physician, medical researcher and academic administrator. He was a professor in the department of pediatrics and an associate dean at the George Washington University School of Medicine & Health Sciences and was the physician-in-chief and chief academic officer at Children’s National Hospital in Washington, D.C. He is known for his research into urea cycle disorders and gene therapy, and is the author of the classic textbook "Children with Disabilities".

Marshall Summar American geneticist

Marshall L. Summar is an American physician, clinical geneticist and academic specializing in the field of genetics and rare disease. He is board-certified in pediatrics, biochemical genetics and clinical genetics. He is best known for his work in caring for children with rare genetic diseases.

Elexacaftor/tezacaftor/ivacaftor, sold under the brand names Trikafta and Kaftrio, is a fixed-dose combination medication used to treat cystic fibrosis. Elexacaftor/tezacaftor/ivacaftor is composed of a combination of ivacaftor, a chloride channel opener, and elexacaftor and tezacaftor, CFTR modulators.

References

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  2. "Prescription medicines and biologicals: TGA annual summary 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 31 March 2024.
  3. 1 2 3 4 5 6 7 8 9 10 "Buphenyl- sodium phenylbutyrate tablet Buphenyl- sodium phenylbutyrate powder". DailyMed. 11 March 2020. Retrieved 19 October 2020.
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  5. "Ammonaps EPAR". European Medicines Agency. 17 September 2018. Retrieved 3 January 2023.
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  8. Walker V (September 2009). "Ammonia toxicity and its prevention in inherited defects of the urea cycle". Diabetes, Obesity & Metabolism. 11 (9): 823–835. doi:10.1111/j.1463-1326.2009.01054.x. PMID   19531057. S2CID   25998574.
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  10. Buphenyl FDA approval package (PDF). U.S. Food and Drugs Administration (FDA) (Report).
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  14. Brusilow SW (February 1991). "Phenylacetylglutamine may replace urea as a vehicle for waste nitrogen excretion". Pediatric Research. 29 (2): 147–150. doi: 10.1203/00006450-199102000-00009 . PMID   2014149.
  15. Tuchman M, Knopman DS, Shih VE (October 1990). "Episodic hyperammonemia in adult siblings with hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome". Archives of Neurology. 47 (10): 1134–1137. doi:10.1001/archneur.1990.00530100104022. PMID   2222247.
  16. Chanoux RA, Rubenstein RC (17 July 2012). "Molecular Chaperones as Targets to Circumvent the CFTR Defect in Cystic Fibrosis". Frontiers in Pharmacology. 3 (137): 137. doi: 10.3389/fphar.2012.00137 . PMC   3398409 . PMID   22822398.
  17. Dover GJ, Brusilow S, Charache S (July 1994). "Induction of fetal hemoglobin production in subjects with sickle cell anemia by oral sodium phenylbutyrate". Blood. 84 (1): 339–343. doi: 10.1182/blood.V84.1.339.339 . PMID   7517215.
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  19. Moumné L, Betuing S, Caboche J (October 2013). "Multiple Aspects of Gene Dysregulation in Huntington's Disease". Frontiers in Neurology. 4: 127. doi: 10.3389/fneur.2013.00127 . PMC   3806340 . PMID   24167500.
  20. Kang HL, Benzer S, Min KT (January 2002). "Life extension in Drosophila by feeding a drug". Proceedings of the National Academy of Sciences of the United States of America. 99 (2): 838–843. Bibcode:2002PNAS...99..838K. doi: 10.1073/pnas.022631999 . PMC   117392 . PMID   11792861.
  21. Iannitti T, Palmieri B (September 2011). "Clinical and experimental applications of sodium phenylbutyrate". Drugs in R&D. 11 (3): 227–249. doi:10.2165/11591280-000000000-00000. PMC   3586072 . 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]
  22. Kormanik K, Kang H, Cuebas D, Vockley J, Mohsen AW (December 2012). "Evidence for involvement of medium chain acyl-CoA dehydrogenase in the metabolism of phenylbutyrate". Molecular Genetics and Metabolism. 107 (4): 684–689. doi:10.1016/j.ymgme.2012.10.009. PMC   3504130 . PMID   23141465.