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.[4] 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.[5][6]
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.[1]
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 enzymescarbamoyl phosphate synthetase I, ornithine transcarbamylase, or argininosuccinic acid synthetase.[5][1] Uncontrolled, this causes intellectual impairment and early death.[1] 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.[1] Patients may need treatment for all their life.[1] The treatment was introduced by researchers in the 1990s, and approved by the U.S. Food and Drugs Administration (FDA) in April 1996.[7][8]
Adverse effects
Nearly 1⁄4 of women may experience an adverse effect of amenorrhea or menstrual dysfunction.[1] Appetite loss is seen is 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.[1] 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.[5]
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 5 patients with hyperammonemia with benzoate and phenylacetate and published a report in Science.[5][9] In 1982 and 1984, the researchers published on using benzoate and arginine for urea cycle disorders in the NEJM.[5][10][11] Use of sodium phenylbutyrate was introduced in the early 1990s, as it lacks the odor of phenylacetate.[5][12][13]
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.[14]
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,[4] and also for the treatment of some sickle-cell disorders as an alternative to hydroxycarbamide due it inducing expression of fetal hemoglobin to replace missing adult hemoglobin.[15][16] 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.[17]
Other
Phenylbutyrate has been associated with longer lifespans in Drosophila.[18]
University of Colorado researchers Dr. 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[update] they plan on testing phenylbutyrate for the treatment of Parkinson's disease in humans.[19]
Pharmacology
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.[20] 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.[1]
A 5g 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.[1]
References
^ abcdefghij"Buphenyl- sodium phenylbutyrate tablet Buphenyl- sodium phenylbutyrate powder". DailyMed. 11 March 2020. Retrieved 19 October 2020.
^"Olpruva - sodium phenylbutyrate kit". DailyMed. 22 December 2022. Retrieved 21 January 2023.
^"Ammonaps EPAR". European Medicines Agency. 17 September 2018. Retrieved 3 January 2023.
^ abcIannitti 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. PMC3586072. PMID 21902286.
^ abcdefBatshaw ML, MacArthur RB, Tuchman M (January 2001). "Alternative pathway therapy for urea cycle disorders: twenty years later". Journal of Pediatrics. 138 (1 Suppl): S46–S54, discussion S54–S55. doi:10.1067/mpd.2001.111836. PMID 11148549.
^Walker V (September 2009). "Ammonia toxicity and its prevention in inherited defects of the urea cycle". Diabetes, Obesity & Metabolism. 11 (9): 823–35. doi:10.1111/j.1463-1326.2009.01054.x. PMID 19531057. S2CID 25998574.
^Brusilow S, Tinker J, Batshaw ML (February 1980). "Amino acid acylation: a mechanism of nitrogen excretion in inborn errors of urea synthesis". Science. 207 (4431): 659–61. Bibcode:1980Sci...207..659B. doi:10.1126/science.6243418. PMID 6243418.
^Batshaw ML, Brusilow S, Waber L, Blom W, Brubakk AM, Burton BK, et al. (June 1982). "Treatment of inborn errors of urea synthesis: activation of alternative pathways of waste nitrogen synthesis and excretion". The New England Journal of Medicine. 306 (23): 1387–92. doi:10.1056/nejm198206103062303. PMID 7078580.
^Brusilow, Saul W.; Danney M; Waber LJ; Batshaw M; Burton B; Levitsky L; Roth K; McKeethren C; Ward J (21 June 1984). "Treatment of episodic hyperammonemia in children with inborn errors of urea synthesis". N Engl J Med. 310 (25): 1630–4. doi:10.1056/nejm198406213102503. PMID 6427608.
^Brusilow, Saul W. (February 1991). "Phenylacetylglutamine may replace urea as a vehicle for waste nitrogen excretion". Pediatr. Res. 29 (2): 147–50. doi:10.1203/00006450-199102000-00009. PMID 2014149.
^Tuchman, Mendel; Knopman DS; Shih VE (October 1990). "Episodic hyperammonemia in adult siblings with hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome". Arch. Neurol. 47 (10): 1134–7. doi:10.1001/archneur.1990.00530100104022. PMID 2222247.
^Chanoux, RA; Rubenstein RC (17 July 2012). "Molecular Chaperones as Targets to Circumvent the CFTR Defect in Cystic Fibrosis". Front Pharmacol. 3 (137): 137. doi:10.3389/fphar.2012.00137. PMC3398409. PMID 22822398.
^Dover, GJ; Brusilow S; Charache S (1 July 1994). "Induction of fetal hemoglobin production in subjects with sickle cell anemia by oral sodium phenylbutyrate". Blood. 84 (1): 339–43. doi:10.1182/blood.V84.1.339.339. PMID 7517215.
^Trompeter, S; Roberts I (2009). "Haemoglobin F modulation in childhood sickle cell disease". British Journal of Haematology. 144 (3): 308–316. doi:10.1111/j.1365-2141.2008.07482.x. PMID 19036119. S2CID 23928373.
^Moumné, L; Betuing, S; Caboche, J (2013). "Multiple aspects of gene dysregulation in Huntington's disease". Front Neurol. 4: 127. doi:10.3389/fneur.2013.00127. PMC3806340. PMID 24167500.
^Kang, H. L.; Benzer, S.; Min, K. T. (2002). "Life extension in Drosophila by feeding a drug" (PDF). Proc. Natl. Acad. Sci. U.S.A. 99 (2): 838–843. Bibcode:2002PNAS...99..838K. doi:10.1073/pnas.022631999. PMC117392. PMID 11792861.
^Iannitti T, Palmieri B (September 2011). "Clinical and experimental applications of sodium phenylbutyrate". Drugs in R&D. 11 (3): 227–49. doi:10.2165/11591280-000000000-00000. PMC3586072. 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]
^Kormanik, Kaitlyn; Kang, Heejung; Cuebas, Dean; Vockley, Jerry; Mohsen, Al-Walid (1 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. ISSN 1096-7206. PMC3504130. PMID 23141465.
External links
"Sodium phenylbutyrate". Drug Information Portal. U.S. National Library of Medicine.
sodium, phenylbutyrate, confused, with, sodium, butyrate, sold, under, brand, name, buphenyl, among, others, salt, aromatic, fatty, acid, phenylbutyrate, phenylbutyric, acid, compound, used, treat, urea, cycle, disorders, because, metabolites, offer, alternati. Not to be confused with Sodium butyrate 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 4 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 5 6 Sodium phenylbutyrateClinical dataTrade namesBuphenyl Pheburane Ammonaps othersAHFS Drugs comMicromedex Detailed Consumer InformationLicense dataEU EMA by INN US DailyMed Sodium phenylbutyratePregnancycategoryAU B3Routes ofadministrationBy mouthATC codeA16AX03 WHO Legal statusLegal statusAU S4 Prescription only US only 1 2 EU Rx only 3 In general Prescription only Pharmacokinetic dataMetabolismLiver and kidney to phenylacetic acidElimination half life0 8 hours phenylbutyrate 1 15 1 29 hours phenylacetate ExcretionUrine 80 100 as phenylacetylglutamine IdentifiersIUPAC name Sodium 4 phenylbutanoateCAS Number1716 12 7 NPubChem CID5258DrugBankDBSALT002404 YChemSpider5068 NUNIINT6K61736TKEGGD05868ChEBICHEBI 75316 NChEMBLChEMBL1746 NCompTox Dashboard EPA DTXSID7040948ECHA InfoCard100 130 318Chemical and physical dataFormulaC 10H 11Na O 2Molar mass186 186 g mol 13D model JSmol Interactive imageSMILES Na O C O CCCC1 CC CC C1InChI 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 YKey VPZRWNZGLKXFOE UHFFFAOYSA M Y N Y what is this verify 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 4 Contents 1 Structure and properties 2 Uses 2 1 Medical uses 2 1 1 Adverse effects 2 2 Research 2 2 1 Urea cycle disorders 2 2 2 Chemical chaperone 2 2 3 Histone deacetylase inhibitor 2 2 4 Other 3 Pharmacology 4 References 5 External linksStructure and properties EditSodium 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 1 Uses EditMedical uses Edit 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 5 1 Uncontrolled this causes intellectual impairment and early death 1 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 1 Patients may need treatment for all their life 1 The treatment was introduced by researchers in the 1990s and approved by the U S Food and Drugs Administration FDA in April 1996 7 8 Adverse effects Edit Nearly 1 4 of women may experience an adverse effect of amenorrhea or menstrual dysfunction 1 Appetite loss is seen is 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 1 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 5 Research Edit Urea cycle disorders Edit 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 5 patients with hyperammonemia with benzoate and phenylacetate and published a report in Science 5 9 In 1982 and 1984 the researchers published on using benzoate and arginine for urea cycle disorders in the NEJM 5 10 11 Use of sodium phenylbutyrate was introduced in the early 1990s as it lacks the odor of phenylacetate 5 12 13 Chemical chaperone Edit In cystic fibrosis a point mutation in the Cystic Fibrosis Transmembrane Conductance Regulator protein DF508 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 14 Histone deacetylase inhibitor Edit 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 4 and also for the treatment of some sickle cell disorders as an alternative to hydroxycarbamide due it inducing expression of fetal hemoglobin to replace missing adult hemoglobin 15 16 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 17 Other Edit Phenylbutyrate has been associated with longer lifespans in Drosophila 18 University of Colorado researchers Dr 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 update they plan on testing phenylbutyrate for the treatment of Parkinson s disease in humans 19 Pharmacology Edit 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 20 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 1 A 5g 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 1 References Edit 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 Olpruva sodium phenylbutyrate kit DailyMed 22 December 2022 Retrieved 21 January 2023 Ammonaps EPAR European Medicines Agency 17 September 2018 Retrieved 3 January 2023 a b c Iannitti T Palmieri B September 2011 Clinical and Experimental Applications of Sodium Phenylbutyrate Drugs in R amp D 11 3 227 249 doi 10 2165 11591280 000000000 00000 PMC 3586072 PMID 21902286 a b c d e f Batshaw ML MacArthur RB Tuchman M January 2001 Alternative pathway therapy for urea cycle disorders twenty years later Journal of Pediatrics 138 1 Suppl S46 S54 discussion S54 S55 doi 10 1067 mpd 2001 111836 PMID 11148549 Walker V September 2009 Ammonia toxicity and its prevention in inherited defects of the urea cycle Diabetes Obesity amp Metabolism 11 9 823 35 doi 10 1111 j 1463 1326 2009 01054 x PMID 19531057 S2CID 25998574 Buphenyl FDA Approved Drugs U S Food and Drugs Administration FDA Retrieved 26 October 2013 Buphenyl FDA approval package PDF U S Food and Drugs Administration FDA Report Brusilow S Tinker J Batshaw ML February 1980 Amino acid acylation a mechanism of nitrogen excretion in inborn errors of urea synthesis Science 207 4431 659 61 Bibcode 1980Sci 207 659B doi 10 1126 science 6243418 PMID 6243418 Batshaw ML Brusilow S Waber L Blom W Brubakk AM Burton BK et al June 1982 Treatment of inborn errors of urea synthesis activation of alternative pathways of waste nitrogen synthesis and excretion The New England Journal of Medicine 306 23 1387 92 doi 10 1056 nejm198206103062303 PMID 7078580 Brusilow Saul W Danney M Waber LJ Batshaw M Burton B Levitsky L Roth K McKeethren C Ward J 21 June 1984 Treatment of episodic hyperammonemia in children with inborn errors of urea synthesis N Engl J Med 310 25 1630 4 doi 10 1056 nejm198406213102503 PMID 6427608 Brusilow Saul W February 1991 Phenylacetylglutamine may replace urea as a vehicle for waste nitrogen excretion Pediatr Res 29 2 147 50 doi 10 1203 00006450 199102000 00009 PMID 2014149 Tuchman Mendel Knopman DS Shih VE October 1990 Episodic hyperammonemia in adult siblings with hyperornithinemia hyperammonemia and homocitrullinuria syndrome Arch Neurol 47 10 1134 7 doi 10 1001 archneur 1990 00530100104022 PMID 2222247 Chanoux RA Rubenstein RC 17 July 2012 Molecular Chaperones as Targets to Circumvent the CFTR Defect in Cystic Fibrosis Front Pharmacol 3 137 137 doi 10 3389 fphar 2012 00137 PMC 3398409 PMID 22822398 Dover GJ Brusilow S Charache S 1 July 1994 Induction of fetal hemoglobin production in subjects with sickle cell anemia by oral sodium phenylbutyrate Blood 84 1 339 43 doi 10 1182 blood V84 1 339 339 PMID 7517215 Trompeter S Roberts I 2009 Haemoglobin F modulation in childhood sickle cell disease British Journal of Haematology 144 3 308 316 doi 10 1111 j 1365 2141 2008 07482 x PMID 19036119 S2CID 23928373 Moumne L Betuing S Caboche J 2013 Multiple aspects of gene dysregulation in Huntington s disease Front Neurol 4 127 doi 10 3389 fneur 2013 00127 PMC 3806340 PMID 24167500 Kang H L Benzer S Min K T 2002 Life extension in Drosophila by feeding a drug PDF Proc Natl Acad Sci U S A 99 2 838 843 Bibcode 2002PNAS 99 838K doi 10 1073 pnas 022631999 PMC 117392 PMID 11792861 Iannitti T Palmieri B September 2011 Clinical and experimental applications of sodium phenylbutyrate Drugs in R amp D 11 3 227 49 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 Kormanik Kaitlyn Kang Heejung Cuebas Dean Vockley Jerry Mohsen Al Walid 1 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 ISSN 1096 7206 PMC 3504130 PMID 23141465 External links Edit Sodium phenylbutyrate Drug Information Portal U S National Library of Medicine Portal Medicine Retrieved from https en wikipedia org w index php title Sodium phenylbutyrate amp oldid 1134873598, wikipedia, wiki, book, books, library,
