Sodium phenylbutyrate: Difference between revisions

{{distinguishDistinguish|Sodium butyrate}}

<!--Clinical dataLegal status -->

| tradenamelegal_AUえーゆー = S4

| legal_UKlegal_NZ = <!-- GSLClass A, B, / P / POM / CDC -->

<!-- Pharmacokinetic data -->

| bioavailability =

| protein_bound =

| metabolism = Hepatic[[Liver]] and renalkidney to [[phenylacetic acid]]

<!-- Identifiers -->

| ATC_prefixCAS_supplemental = A16

| DrugBank = DBSALT002404

<!-- Chemical and physical data -->

| StdInChI = 1S/C10H12O2.Na/c1c11-2-9(10(11)12)8-6-4-37-9-5-72-81-3-6-9;/h3h1-73,9H5-6H,2H24,1H37-8H2,(H,11,12);/q;+1/p-1

| StdInChIKey = RHLFTMGPBSLHRSVPZRWNZGLKXFOE-UHFFFAOYSA-M

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.<ref name=NLM"Buphenyl FDA label">{{cite web | title=Buphenyl- sodium phenylbutyrate tablet Buphenyl- sodium phenylbutyrate powder | website=DailyMed | date=11 March 2020 | url=httphttps://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfodrugInfo.cfm?archiveidsetid=3849|title=Buphenyl|date=September463a36fa-3eb2-4326-8bd0-c8c7a11bca3a 2006|work=DailyMed|publisher=U.S. National Library of Medicine|accessdateaccess-date=2519 October 20132020}}</ref>

Sodium phenylbutyrate is taken orally or by [[nasogastric intubation]] as a tablet or powder, and tastes very salty and bitter. It treats [[urea cycle disorder]]s, genetic diseases in which nitrogen waste builds up in the blood plasma as [[ammonia]] glutamine (a state called [[hyperammonemia]]) due to deficiences in the [[enzyme]]s [[carbamoyl phosphate synthetase I]], [[ornithine transcarbamylase]], or [[argininosuccinic acid synthetase]].<ref name=batshaw/><ref name=NLM"Buphenyl FDA label"/> Uncontrolled, this causes mentalintellectual retardationimpairment and early death.<ref name=NLM"Buphenyl FDA label"/> 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.<ref name=NLM"Buphenyl FDA label"/> Patients may need treatment for all their life.<ref name=NLM"Buphenyl FDA label"/> The treatment was introduced by researchers in the 1990s, and approved by the U.S. [[FDAFood and Drugs Administration]] on(FDA) 13in MayApril 1996.<ref>{{cite web|url=httphttps://www.accessdata.fda.gov/scripts/cder/drugsatfdadaf/index.cfm?fuseactionevent=Searchoverview.Overviewprocess&DrugNameApplNo=BUPHENYL020573|title=Buphenyl: FDA-Approved Drugs|work=Drugs@FDA|publisher=United StatesU.S. [[Food and Drugs Administration]] (FDA) |accessdateaccess-date=26 October 2013}}</ref><ref>{{cite report | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/pre96/020573Orig1s000rev.pdf | title=Buphenyl FDA approval package | work=U.S. [[Food and Drugs Administration]] (FDA) }}</ref>

Nearly {{frac|1/|4}} of women may experience an [[adverse effect]] of [[amenorrhea]] or menstrual dysfunction.<ref name=NLM"Buphenyl FDA label"/> Appetite loss is seen isin 4% of patients. Body odor due to metabolization of pheylbutyratephenylbutyrate 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.<ref name=NLM"Buphenyl FDA label"/> 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.<ref name=batshaw/>

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 5five patients with hyperammonemia with benzoate and phenylacetate and published a report in ''[[Science (journal)|Science]]''.<ref name=batshaw/><ref>{{cite journal |last vauthors = Brusilow|first=Saul|author2= S, Tinker J, |author3=Batshaw ML |date=8 February 1980|title = Amino acid acylation: a mechanism of nitrogen excretion in inborn errors of urea synthesis | journal = Science |publisher=AAAS| volume = 207 | issue = 4431 | pages =659–61 659–661 | date = February 1980 | pmid = 6243418 |url=http://www.sciencemag.org/content/207/4431/659.long| doi = 10.1126/science.6243418 | bibcode = 1980Sci...207..659B }}</ref> In 1982 and 1984, the researchers published on using benzoate and arginine for urea cycle disorders in the ''[[NEJM]]''.<ref name=batshaw/><ref>{{cite journal |last1 vauthors = Batshaw|first1=Mark L.|last2=ML, Brusilow|first2= S.|last3=, Waber|first3= L.|last4=, Blom|first4= W.|last5=, Brubakk|first5=A.M.|last6= AM, Burton|first6=B.K.|last7= BK, Cann|first7=H.M.|last8= HM, Kerr|first8= D.|last9=, Mamunes|first9= P.|last10=, Matalon|first10= R.|last11=, Myerberg|first11= D.|last12=, Schafer IA |first12 display-authors =I.A.|date=10 June6 1982| title = Treatment of inborn errors of urea synthesis: activation of alternative pathways of waste nitrogen synthesis and excretion | journal =N EnglThe JNew England Journal of Medicine Med| volume = 306 | issue = 23 | pages =1387–92 1387–1392 | date = June 1982 | pmid = 7078580 |url=http://www.nejm.org/doi/full/10.1056/NEJM198206103062303| doi = 10.1056/nejm198206103062303 }}</ref><ref>{{cite journal |last vauthors = Brusilow|first=Saul W.|author2=SW, Danney M, |author3=Waber LJ, |author4=Batshaw M, |author5=Burton B, |author6=Levitsky L, |author7=Roth K, |author8=McKeethren C, |author9=Ward J |date display-authors =21 June6 1984| title = Treatment of episodic hyperammonemia in children with inborn errors of urea synthesis | journal =N EnglThe JNew England Journal of Medicine Med| volume = 310 | issue = 25 | pages =1630–4 1630–1634 | date = June 1984 | pmid = 6427608 |url=http://www.nejm.org/doi/pdf/10.1056/NEJM198406213102503| doi = 10.1056/nejm198406213102503 }}</ref> Use of sodium phenylbutyrate was introduced in the early 1990s, as it lacks the odor of phenylacetate.<ref name=batshaw/><ref>{{cite journal |last vauthors = Brusilow|first=Saul W.|date=FebruarySW 1991| title = Phenylacetylglutamine may replace urea as a vehicle for waste nitrogen excretion | journal =Pediatr. Res.Pediatric Research | volume = 29 | issue = 2 | pages =147–50 147–150 |url date =http://www.nature.com/pr/journal/v29/n2/full/pr199131a.html February 1991 | pmid = 2014149 | doi = 10.1203/00006450-199102000-00009 | doi-access = free }}</ref><ref>{{cite journal |last vauthors = Tuchman|first=Mendel|author2= M, Knopman DS, |author3=Shih VE |date=October 1990|title = Episodic hyperammonemia in adult siblings with hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome | journal =Arch. Neurol.Archives of Neurology | volume = 47 | issue = 10 | pages =1134–7 1134–1137 | date = October 1990 | pmid = 2222247 |url=http://archneur.jamanetwork.com/article.aspx?articleid=590402| doi = 10.1001/archneur.1990.00530100104022 }}</ref>

In [[cystic fibrosis]], a point mutation in the [[Cystic Fibrosis Transmembrane Conductance Regulator]] protein, ΔでるたF508-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.<ref>{{cite journal |last vauthors = Chanoux|first= RA|author2=, Rubenstein RC |date=17 Julytitle 2012|title= Molecular Chaperones as Targets to Circumvent the CFTR Defect in Cystic Fibrosis | journal =Front PharmacolFrontiers in Pharmacology | volume = 3 | issue = 137 |doi pages =10.3389/fphar. 137 | date = 17 July 2012.00137 | pmid = 22822398 |url pmc =http://www.frontiersin.org/Journal/ 3398409 | doi = 10.3389/fphar.2012.00137/full |pmc doi-access =3398409 free }}</ref>

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]],<ref name=r&d/> 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.<ref>{{cite journal |last vauthors = Dover|first= GJ|author2=, Brusilow S, |author3=Charache S |date=1 July 1994|title = Induction of fetal hemoglobin production in subjects with sickle cell anemia by oral sodium phenylbutyrate | journal = Blood | volume = 84 | issue = 1 | pages =339–43 339–343 | date = July 1994 | pmid = 7517215 |url doi =http:/ 10.1182/bloodjournalblood.hematologylibraryV84.org/content/84/1/.339.long339 | doi-access = free }}</ref><ref>{{cite journal |last vauthors = Trompeter|first= S|author2=, Roberts I |year=2009| title = Haemoglobin F modulation in childhood sickle cell disease | journal = British Journal of Haematology | volume = 144 | issue = 3 | pages = 308–316 |doi date =10.1111/j.1365-2141.2008.07482.x February 2009 | pmid = 19036119 |url=http://onlinelibrary.wiley.com/ doi/ = 10.1111/j.1365-2141.2008.07482.x/full |issue s2cid =3 23928373 }}</ref> 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.<ref>{{Citecite journal | vauthors = Moumné L, Betuing S, Caboche J | title = Multiple aspectsAspects of geneGene dysregulationDysregulation in Huntington's diseaseDisease | pmc=3806340journal | pmid=24167500 |Frontiers doi=10.3389/fneur.2013.00127in Neurology | volume=4 | year=2013 | journal=Front Neurol4 | pages=127 | last1 = Moumné127 | first1date = LOctober 2013 | last2pmid = Betuing24167500 | first2pmc = S3806340 | last3doi = Caboche10.3389/fneur.2013.00127 | first3doi-access = Jfree }}</ref>

Phenylbutyrate has been associated with longer lifespans in ''[[Drosophila]]''.<ref>{{cite journal |last1 vauthors = Kang|first1=H. L.|last2=HL, Benzer|first2= S.|last3=, Min KT |first3=K. T.|title = Life extension in Drosophila by feeding a drug | journal =Proc. Natl.Proceedings Acad.of Sci.the U.S.A.National Academy of Sciences of the United States of America | volume = 99 | issue = 2 | pages = 838–843 |year date = January 2002 | pmid = 11792861 | pmc = 117392 | doi = 10.1073/pnas.022631999 |pmc doi-access =117392 free |url bibcode =http://authors 2002PNAS.library.caltech.edu/1617/1/KANpnas0299.pdf.838K }}</ref>

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|1=July 2011}} they plan on testing phenylbutyrate for the treatment of Parkinson's disease in humans.<ref name="pmid21902286">{{cite journal | vauthors = Iannitti T, Palmieri B | title = Clinical and experimental applications of sodium phenylbutyrate | journal = Drugs in R&D | volume = 11 | issue = 3 | pages = 227–49227–249 | date = September 2011 | pmid = 21902286 | pmc = 3586072 | doi = 10.2165/11591280-000000000-00000 | layurl=http://www.denverpost.com/business/ci_18407428#ixzz1RFVzEItR | laysource=Denver Post |laydate=7 March 2014 | quote = 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] }}</ref>

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, [[phenylacetic acid|phenylacetate]].<ref name=":0">{{Citecite journal |last vauthors = Kormanik|first=Kaitlyn|last2= K, Kang|first2=Heejung|last3= H, Cuebas|first3=Dean|last4= D, Vockley|first4=Jerry|last5= J, Mohsen AW |first5=Al-Walid|date=2012-12-01| title = Evidence for involvement of medium chain acyl-CoA dehydrogenase in the metabolism of phenylbutyrate | journal = Molecular Genetics and Metabolism | volume = 107 | issue = 4 | pages = 684–689 | date = December 2012 | pmid = 23141465 | pmc = 3504130 | doi = 10.1016/j.ymgme.2012.10.009|issn=1096-7206|pmc=3504130|pmid=23141465 }}</ref> 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.<ref name=NLM"Buphenyl FDA label"/>

A 5g tablet or powder of sodiumSodium phenylbutyrate taken by mouth can be detected in the blood within 15fifteen minutes, and reaches peak concentration in the bloodstream within an hour. It is metabolized into phenylacetate within half an hour.<ref name=NLM"Buphenyl FDA label"/>

== References ==