View source for Carbidopa

{{short description|Chemical compound}}
{{Infobox drug
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 460017946
| IUPAC_name = (2''S'')-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoic acid
| image = Carbidopa.svg
| image_class = skin-invert-image
| image2 = Carbidopa ball-and-stick.png
| image_class2 = bg-transparent
<!--Clinical data-->
| tradename = Lodosyn
| Drugs.com = {{drugs.com|monograph|lodosyn}}
| licence_EU = yes
| licence_US = Carbidopa
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_US = <!-- A / B / C / D / X -->
| pregnancy_category =
| legal_AU = <!-- Unscheduled / S2 / S4 / S8 -->
| legal_UK = POM
| legal_US =  Rx-only
| legal_status =
| routes_of_administration =
<!--Pharmacokinetic data-->
| bioavailability =
| protein_bound = 76%
| metabolism = 7 metabolites known, not metabolized extensively
| elimination_half-life = 2 hours
| excretion =
<!--Identifiers-->
| IUPHAR_ligand = 5159
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 28860-95-9
| ATC_prefix =
| ATC_suffix =
| ATC_supplemental =
| PubChem = 34359
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00190
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 31640
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = KR87B45RGH
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00558
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 39585
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 1201236
<!--Chemical data-->
| C=10 | H=14 | N=2 | O=4
| smiles = O=C(O)[C@@](NN)(Cc1cc(O)c(O)cc1)C
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C10H14N2O4/c1-10(12-11,9(15)16)5-6-2-3-7(13)8(14)4-6/h2-4,12-14H,5,11H2,1H3,(H,15,16)/t10-/m0/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = TZFNLOMSOLWIDK-JTQLQIEISA-N
| melting_point     = 203
| melting_high      = 205
}}

'''Carbidopa''', sold under the brand name '''Lodosyn''', is a [[medication]] given to people with [[Parkinson's disease]] in order to inhibit [[peripheral nervous system|peripheral]] [[metabolism]] of [[levodopa]]. This property is significant in that it allows a greater proportion of administered levodopa to cross the [[blood–brain barrier]] for central nervous system effect, instead of being peripherally metabolised into substances unable to cross said barrier.

== Pharmacology ==
Carbidopa [[DOPA decarboxylase inhibitor|inhibits aromatic <small>L</small>-amino-acid decarboxylase]] (DOPA decarboxylase or DDC),<ref name="pmid11106255">{{cite journal | vauthors = Gilbert JA, Frederick LM, Ames MM | title = The aromatic-L-amino acid decarboxylase inhibitor carbidopa is selectively cytotoxic to human pulmonary carcinoid and small cell lung carcinoma cells | journal = Clinical Cancer Research | volume = 6 | issue = 11 | pages = 4365–4372 | date = November 2000 | pmid = 11106255 | url = http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=11106255 }}</ref> an enzyme important in the [[biosynthesis]] of [[serotonin]] from {{Nowrap|[[L-tryptophan|<small>L</small>-tryptophan]]}} and in the biosynthesis of [[dopamine]] (DA) from {{Nowrap|[[L-DOPA|<small>L</small>-DOPA]]}}.  DDC exists both outside of (body periphery) and within the confines of the [[blood–brain barrier]].

Carbidopa is used in the treatment of, among other diseases, Parkinson's disease (PD), a condition characterized by death of dopaminergic neurons in the [[substantia nigra]]. Increased [[dopamine]] availability may increase the effectiveness of the remaining neurons and alleviate symptoms for a time. The pharmacologic objective is to get an exogenous dopamine-precursor known as levodopa/{{Nowrap|<small>L</small>-DOPA}} into the dopamine-deficient brains of PD patients.  Levodopa/{{Nowrap|<small>L</small>-DOPA}} can cross the blood–brain barrier, but dopamine cannot.  The use of carbidopa seems counter-intuitive in Parkinson's disease (PD) in that it prevents DDC conversion of levodopa/{{Nowrap|<small>L</small>-DOPA}} to dopamine.  However, exogenously provided, levadopa/{{Nowrap|<small>L</small>-DOPA}} gets metabolized peripherally to its active metabolite dopamine before reaching the blood–brain barrier. Therefore, the PD brain, which is deficient in dopamine, will not receive as much of its prodrug precursor levodopa/{{Nowrap|<small>L</small>-DOPA}} due to peripheral DDC breakdown. However, carbidopa can decrease peripheral DDC conversion of levodopa/{{Nowrap|<small>L</small>-DOPA}} before it crosses the blood–brain barrier. Carbidopa acts as a peripheral DDC inhibitor, as carbidopa, itself, cannot cross the blood–brain barrier. In other words, carbidopa has no effect on brain DDC conversion of levodopa/{{Nowrap|<small>L</small>-DOPA}} to dopamine. Ultimately, a greater proportion of the exogenously provided levodopa/{{Nowrap|<small>L</small>-DOPA}} reaches the brain.  Commercially, [[carbidopa/levodopa]] combinations are available in the treatment of central dopamine deficiencies.

Along with carbidopa, other [[DDC inhibitor]]s are [[benserazide]] (Ro-4-4602), [[difluoromethyldopa]], and [[α-methyldopa]].

== Pharmacology 2 ==

Carbidopa, an inhibitor of aromatic amino acid decarboxylation, is a white, crystalline compound, slightly soluble in water, with a molecular weight of 244.3. It is designated chemically as ''N''-amino-α-methyl-3-hydroxy-L-tyrosine monohydrate. Its empirical formula is C<sub>10</sub>H<sub>14</sub>N<sub>2</sub>O<sub>4</sub>•H<sub>2</sub>O. Used in tandem with {{Nowrap|<small>L</small>-DOPA}} (also known as levodopa, a dopamine precursor converted in the body to dopamine), it increases the plasma half-life of levodopa from 50 minutes to 1½ hours. Carbidopa cannot cross the blood–brain barrier, so it inhibits only peripheral DDC. It thus prevents the conversion of {{Nowrap|<small>L</small>-DOPA}} to dopamine peripherally. This reduces the side effects caused by [[dopamine]] on the periphery, as well as increasing the concentration of L-DOPA and dopamine in the brain.

The combination of [[carbidopa/levodopa]] carries the brand names of '''Kinson''', '''Sinemet''', '''Pharmacopa''' and '''Atamet'''; while '''[[Stalevo]]''' is a combination with [[entacapone]], which enhances the bioavailability of carbidopa and levodopa.

Carbidopa is most commonly used as a method to inhibit the activity of DOPA decarboxylase. This is an enzyme that breaks down {{Nowrap|<small>L</small>-DOPA}} in the periphery and converts it to dopamine. This results in the newly formed dopamine being unable to cross the blood–brain barrier and the effectiveness of {{Nowrap|<small>L</small>-DOPA}} treatments is greatly decreased. Carbidopa reduces the amount of levodopa required to produce a given response by about 75% and, when administered with levodopa, increases both plasma levels and the plasma half-life of levodopa, and decreases plasma and urinary dopamine and homovanillic acid. Elimination half-life of levodopa in the presence of carbidopa is about 1.5 hours. Following SINEMET CR, the apparent half-life of levodopa may be prolonged because of continuous absorption. This is extremely useful in the treatment of Parkinsons disease symptoms because the amount of levodopa administered to the patient can be greatly reduced. This reduction in dosage is extremely useful due to the side effects that may occur from an overdose of {{Nowrap|<small>L</small>-DOPA}} within the body.

Carbidopa is also used in combination with [[5-hydroxytryptophan|5-hydroxytryptophan (5-HTP)]], a naturally occurring amino acid which is a precursor to the neurotransmitter [[serotonin]] and an intermediate in [[tryptophan]] metabolism. Carbidopa, which is used in PD to prevent conversion of the levodopa to dopamine, prevents the metabolism of 5-HTP in the liver and causes decreased levels of serotonin
in the blood.{{citation needed|date=September 2021}} Research shows that co-administration of 5-HTP and carbidopa greatly increases plasma 5-HTP levels. Several cases of [[scleroderma]]-like illness have been reported in patients using carbidopa and 5-HTP.<ref>{{cite web|url=http://www.truestarhealth.com/Notes/1339004.html |title=Join Truestar now and achieve total health and weight loss now! |access-date=2014-01-09 |url-status=dead |archive-url=https://web.archive.org/web/20140108185248/http://www.truestarhealth.com/Notes/1339004.html |archive-date=2014-01-08 }}</ref> In Europe, 5-HTP is prescribed with carbidopa to prevent the conversion of 5-HTP into serotonin until it reaches the brain.{{citation needed|date=September 2013}}

== Synthesis ==
[[File:Carbidopa synthesis.svg|class=skin-invert-image|thumb|center|999px|Carbidopa synthesis:<ref>{{cite journal | vauthors = Sletzinger M, Chemerda JM, Bollinger FW | title = Potent Decarboxylase Inhibitors. Analogs of Methyldopa | journal = Journal of Medicinal Chemistry | volume = 6 | issue = 2 | pages = 101–103 | date = March 1963 | pmid = 14188777 | doi = 10.1021/jm00338a003 }}</ref><ref>{{Cite journal|doi=10.1021/jo00813a023|title=Synthesis of D- and L-α-(3,4-dihydroxybenzyl)-α-hydrazinopropionic acid via resolution|journal=The Journal of Organic Chemistry|volume=36|issue=14|pages=1946–1948|year=1971| vauthors = Karady S, Ly MG, Pines SH, Sletzinger M }}</ref><ref>{{Cite journal|doi=10.1021/jo00813a024|title=Synthesis of L-α-(3,4-dihydroxybenzyl)-α-hydrazinopropionic acid from optically active precursors by N-homologization|journal=The Journal of Organic Chemistry|volume=36|issue=14|pages=1949–1951|year=1971| vauthors = Karady S, Ly MG, Pines SH, Sletzinger M }}</ref>

;<ref>{{Cite patent|country=GB|number=940596|pubdate=1963-10-30|title=α-hydrazino acids|assign=[[Merck & Co. Inc.]]|inventor = Chemerda JM, Sletzinger M, Bollinger FW }}</ref> Chemerda et al., {{US patent|3462536}} (to [[Merck & Co.]]). L-form.<ref>{{Cite patent|country=DE|number=2062285|pubdate=1971-07-01|title=L-α-Hydrazino-β-phenylpropionsäure-Verbindungen enthaltendes Arzneimittel [L-alpha-hydrazino-beta-phenylpropionic acid compounds, decarboxylase inhibitors]|assign=[[Merck & Co. Inc.]]| inventor = Karady S, Pines SH, Ly MG, Sletzinger M, Allegretti JE, Wildman Jr AS }}</ref><ref>{{Cite patent|country=DE|number=2062332|pubdate=1971-07-15|title=L-α-Hydrazino-β-phenylpropionsäure-Verbindungen und Verfahren zu deren Herstellung[L-alpha-hydrazino-beta-phenylpropionic acid compounds and processes for their preparation]|assign=[[Merck & Co. Inc.]]| inventor = Karady S, Pines SH, Ly MG, Sletzinger M, Allegretti JE, Wildman Jr AS }}</ref>]]
The synthesis begins with a modified [[Strecker amino acid synthesis|Strecker reaction]] using [[hydrazine]] and [[potassium cyanide]] on {{chem name|arylacetone}} ('''1''') to give '''2'''. This is then hydrolyzed with cold HCl to give carboxamide '''3'''. More vigorous hydrolysis with 48% HBr cleaves the amide bond and the aryl ether group to produce carbidopa ('''4''').

== References ==
{{Reflist}}

== External links ==
* [https://web.archive.org/web/20080227161318/http://packageinserts.bms.com/pi/pi_lodosyn.pdf Lodosyn prescribing information]
* [https://web.archive.org/web/20050115124132/http://www.medsafe.govt.nz/Profs/datasheet/s/Sinemettab.htm Sinemet datasheet for New Zealand]

{{Antiparkinson}}
{{Monoamine metabolism modulators}}
{{Hydrazines}}

[[Category:Aromatic L-amino acid decarboxylase inhibitors]]
[[Category:Antiparkinsonian agents]]
[[Category:Catecholamines]]
[[Category:Peripherally selective drugs]]
[[Category:Phenethylhydrazines]]