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Clinical data
Trade names Tasmar
AHFS/ Monograph
MedlinePlus a698036
License data
  • AU:B3
Routes of
By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 65%
Protein binding >99.9%
Metabolism Liver (mainly glucuronidation)
Elimination half-life 2–3 hours
Excretion Urine (60%), feces (40%);
only 0.5% in unmetabolized form
  • (3,4-Dihydroxy-5-nitrophenyl)(4-methylphenyl)methanone
CAS Number
PubChem CID
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.222.604 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C14H11NO5
Molar mass 273.244 g·mol−1
3D model (JSmol)
Melting point 143 to 146 °C (289 to 295 °F)
Solubility in water not soluble
  • [O-][N+](=O)c2cc(C(=O)c1ccc(cc1)C)cc(O)c2O
  • InChI=1S/C14H11NO5/c1-8-2-4-9(5-3-8)13(17)10-6-11(15(19)20)14(18)12(16)7-10/h2-7,16,18H,1H3 Yes check.svgY

Tolcapone, sold under the brand name Tasmar, is a medication used to treat Parkinson's disease (PD). It is a selective, potent and reversible nitrocatechol-type inhibitor of the enzyme catechol-O-methyltransferase (COMT). [4] It has demonstrated significant liver toxicity, which has led to suspension of marketing authorisations in a number of countries.


In comparison with entacapone, another nitrocatechol COMT inhibitor, tolcapone has a longer half life (2.9 hours vs. 0.8 hours) and can better penetrate the blood–brain barrier, acting both in the central nervous system and in the periphery. [5] However, entacapone is less toxic for the liver.

Rat catechol-O-methyltransferase bound to tolcapone. PDB entry 3s68 3s68 tcw.png
Rat catechol-O-methyltransferase bound to tolcapone. PDB entry 3s68

Medical uses

Tolcapone is used in the treatment of Parkinson's disease as an adjunct to levodopa/carbidopa or levodopa/benserazide medications. Levodopa is a prodrug for dopamine, which reduces Parkinson symptoms; carbidopa and benserazide are aromatic L-amino acid decarboxylase (AADC) inhibitors. [7]

Without administration of tolcapone, the beneficial effects of levodopa tend to wear off more quickly, resulting in motor fluctuations. [8]


Combining tolcapone with non-selective monoamine oxidase inhibitors such as phenelzine or tranylcypromine is contraindicated. [9] Tolcapone is also contraindicated for people with liver diseases or increased liver enzymes. [10]

Side effects

Tolcapone has demonstrated significant liver toxicity (hepatotoxicity) [11] that limits the drug's utility. Entacapone is an alternative, largely since it has a more favorable toxicity profile.

The hepatotoxicity can be related to elevated levels of transaminases, but studies have shown that minimal risk exists for those without preexisting liver conditions when their enzyme levels were being monitored. No clear mechanism is implicated, but it has been hypothesized that it has something to do with abnormal mitochondrial respiration due to the uncoupling of oxidative phosphorylation. [12]

Other side effects regard the increase in dopaminergic activity, including digestive symptoms. [10] Treatment with tolcapone runs the risk of eliciting or prolonging dyskinesia; this can be counteracted by decreasing the dose of levodopa. This occurs because the administration of tolcapone results in the accumulation of the biological methyl donor S-adenosyl-L-methionine (SAM) in the striatum that induces Parkinson symptoms. [12]

Digestive symptoms include nausea and diarrhea; further dopaminergic side effects include orthostatic hypotension, dry mouth, sweating and dizziness. Tolcapone causes more severe diarrhea than entacapone; this was the most common reason for therapy termination in studies. [9] Urine discoloration comes from yellow tolcapone metabolites being excreted in the urine and is harmless. [10] [12]


While increase of dopamine levels is a desired interaction, tolcapone can theoretically also increase the levels of other drugs metabolised by COMT, such as the AADC inhibitors carbidopa and benzerazide, as well as methyldopa, dobutamine, apomorphine, adrenaline, and isoprenaline. In studies, a slight interaction with benzerazide was seen, but not with carbidopa. Other interactions with this group of drugs have not been studied. A related type of theoretical interactions is with drugs that increase catecholamine concentrations, such as monoamine oxidase (MAO) inhibitors and noradrenaline reuptake inhibitors; these also showed only slight effects in practice. Combination with non-selective MAO inhibitors might be dangerous. [9] [10]

Due to its affinity to the liver enzyme CYP2C9, interactions with drugs being metabolised by this enzyme are also possible, but unlikely. No interaction with tolbutamide, a 2C9 substrate, was observed in studies. [10]


Mechanism of action

Tolcapone selectively and reversibly [9] binds to the catalytic site of COMT in both the periphery and the central nervous system (CNS) with greater affinity than any of the three catecholamines, including levodopa. [13] It thereby prevents the 3-O-methylation of levodopa by COMT in the periphery, which produces 3-O-methyldopa, a major metabolite that competes with levodopa to cross the blood–brain barrier. More of the levodopa that is administered reaches the CNS. Additionally, levodopa that has already reached the CNS, after being converted to dopamine, will not be degraded as quickly when tolcapone inhibits COMT activity. Thus, tolcapone improves the bioavailability and reduces the clearance of levodopa and subsequently dopamine from the CNS. [14]

3-O-Methylation of levodopa (3-hydroxy-L-tyrosine) via COMT activity COMT activity.svg
3-O-Methylation of levodopa (3-hydroxy-L-tyrosine) via COMT activity

The strength of the binding affinity of tolcapone, represented by the inhibition constant Ki (2.5 nM), can be thought of as the dissociation constant for enzyme and inhibitor complex kinetics. Maximum catalytic activity denotes the efficacy of tolcapone (Vmax = 58.4 pmol/min·mg). [15]


Tolcapone is quickly absorbed from the gut to about 85%. It has an absolute bioavailability of 65%, which is only slightly decreased when taken with food. The substance reaches highest blood plasma concentrations after about two hours. When in the bloodstream, it is almost completely (>99.9%) bound to plasma proteins, primarily albumin. The main inactivation step is glucuronidation; other processes are methylation by COMT, hydroxylation by CYP3A4 and CYP2A6 with subsequent oxidation to a carboxylic acid, and possibly a minor path with reduction to an amine with subsequent acetylation. [9] [10]

The half-life of tolcapone is two to three hours, the volume of distribution (Vd) being 0.3 L/kg (21 L in an average 70 kg person). [8] 60% of the metabolites are excreted via the urine and 40% via the feces. Only 0.5% of the drug are excreted in unchanged form via the urine. [9] [10]

Tolcapone and its metabolites. The reduction to the amine and subsequent N-acetylation is putative. Tolcapone metabolism.svg
Tolcapone and its metabolites. The reduction to the amine and subsequent N-acetylation is putative.

99% of tolcapone is in monoanionic form in the body because the physiological pH is 7.4. Tolcapone penetrates the blood–brain barrier much better than two other nitrocatechols, nitecapone and entacapone, because it has higher lipophilicity due to its R-substituent.[ vague ] Partition coefficients quantify the ability of the molecule to cross the blood–brain barrier. LogPIdce= 0.2, –1.4, –0.4 for tolcapone, nitecapone and entacopone respectively. Partition coefficients in this case were measured in 1,2-dichloroethane/H2O solution which caused molecules to be in ionized form. There is no current explanation for how these charged molecules permeate the blood–brain barrier. [16]


Tolcapone is an intensely yellow, odorless, bitter tasting, non-hygroscopic, crystalline compound with a relative molecular mass of 273.25 g/mol. It melts at 143 to 146 °C (289 to 295 °F), is practically insoluble in water and acids but soluble in 0.1  M aqueous sodium hydroxide solution. The pKa values are 4.5 and 10.6 for the two phenyl groups; and the maximum absorption is at 268  nm (in 0.1 M hydrochloric acid / ethanol). [9] Its chemical name is 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone.


A synthesis of tolcapone proposed in 2008, begins with a Grignard reaction between 3-Benzyloxy-4-methoxybenzaldehyde [17] [18] and p-tolyl magnesium bromide. The alcohol thus produced is then converted to a ketone using sodium t-butoxide. The benzyl protecting group is removed by palladium-catalyzed hydrogenation in the presence of ammonium formate. A nitro group is introduced at the 5-position adjacent to the hydroxyl group unmasked in the cleavage of the benzyl ether. The synthesis ends with cleavage of the methoxy group using aluminum chloride to yield the product alcohol. [19]

Synthesis of tolcapone Tolcapone synthesis.svg
Synthesis of tolcapone


Tolcapone was introduced into the European market in August 1997, and subsequently into the United States market in March 1998. Liver toxicity was reported in four people who were administered tolcapone, three people died due to complications. Consequentially, the marketing authorization of tolcapone was suspended from December 1998 until August 2004 when it was lifted. In November 1998, the company that manufactured tolcapone voluntarily [20] removed the drug from the market. The authorization was then renewed in August 2009. [21]

As a result of reported complications, the U.S. Food and Drug Administration (FDA) issued a black box warning for tolcapone and label revisions that aimed to regulate the monitoring of those prescribed tolcapone for Parkinson's disease in November 1998. [22] A number of other countries withdrew tolcapone from the market; Australia in February 1999, Bulgaria in April 1999, Iceland in November 1998, Lithuania in December 1998. [20]


Because of preliminary data suggesting the drug may have activity, the U.S. FDA in 2013 granted tolcapone "orphan drug status" in studies aiming at the treatment of transthyretin familial amyloidosis (ATTR). [23] However, as of 2015 tolcapone was not FDA approved for the treatment of this disease. [24]

Related Research Articles

<span class="mw-page-title-main">Monoamine oxidase inhibitor</span> Type of medication

Monoamine oxidase inhibitors (MAOIs) are a class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressants, especially for treatment-resistant depression and atypical depression. They are also used to treat panic disorder, social anxiety disorder, Parkinson's disease, and several other disorders.

<span class="mw-page-title-main">Catecholamine</span> Class of chemical compounds

A catecholamine is a monoamine neurotransmitter, an organic compound that has a catechol and a side-chain amine.

Catechol-<i>O</i>-methyltransferase Class of enzymes

Catechol-O-methyltransferase is one of several enzymes that degrade catecholamines, catecholestrogens, and various drugs and substances having a catechol structure. In humans, catechol-O-methyltransferase protein is encoded by the COMT gene. Two isoforms of COMT are produced: the soluble short form (S-COMT) and the membrane bound long form (MB-COMT). As the regulation of catecholamines is impaired in a number of medical conditions, several pharmaceutical drugs target COMT to alter its activity and therefore the availability of catecholamines. COMT was first discovered by the biochemist Julius Axelrod in 1957.

<small>L</small>-DOPA Chemical compound

l-DOPA, also known as levodopa and l-3,4-dihydroxyphenylalanine, is an amino acid that is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize l-DOPA, make it via biosynthesis from the amino acid l-tyrosine. l-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline), which are collectively known as catecholamines. Furthermore, l-DOPA itself mediates neurotrophic factor release by the brain and CNS. l-DOPA can be manufactured and in its pure form is sold as a psychoactive drug with the INN levodopa; trade names include Sinemet, Pharmacopa, Atamet, and Stalevo. As a drug, it is used in the clinical treatment of Parkinson's disease and dopamine-responsive dystonia.

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

Carbidopa (Lodosyn) is a drug given to people with Parkinson's disease in order to inhibit 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.

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

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<span class="mw-page-title-main">Dopaminergic</span> Substance related to dopamine functions

Dopaminergic means "related to dopamine" (literally, "working on dopamine"), dopamine being a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic brain pathways facilitate dopamine-related activity. For example, certain proteins such as the dopamine transporter (DAT), vesicular monoamine transporter 2 (VMAT2), and dopamine receptors can be classified as dopaminergic, and neurons that synthesize or contain dopamine and synapses with dopamine receptors in them may also be labeled as dopaminergic. Enzymes that regulate the biosynthesis or metabolism of dopamine such as aromatic L-amino acid decarboxylase or DOPA decarboxylase, monoamine oxidase (MAO), and catechol O-methyl transferase (COMT) may be referred to as dopaminergic as well. Also, any endogenous or exogenous chemical substance that acts to affect dopamine receptors or dopamine release through indirect actions (for example, on neurons that synapse onto neurons that release dopamine or express dopamine receptors) can also be said to have dopaminergic effects, two prominent examples being opioids, which enhance dopamine release indirectly in the reward pathways, and some substituted amphetamines, which enhance dopamine release directly by binding to and inhibiting VMAT2.

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

Entacapone, sold under the brand name Comtan among others, is a medication commonly used in combination with other medications for the treatment of Parkinson's disease. Entacapone together with levodopa and carbidopa allows levodopa to have a longer effect in the brain and reduces Parkinson's disease signs and symptoms for a greater length of time than levodopa and carbidopa therapy alone.

<span class="mw-page-title-main">Dopamine agonist</span> Compound that activates dopamine receptors

A dopamine agonist(DA) is a compound that activates dopamine receptors. There are two families of dopamine receptors, D2-like and D1-like, and they are all G protein-coupled receptors. D1- and D5-receptors belong to the D1-like family and the D2-like family includes D2, D3 and D4 receptors. Dopamine agonists are primarily used in the treatment of Parkinson's disease, and to a lesser extent, in hyperprolactinemia and restless legs syndrome. They are also used off-label in the treatment of clinical depression. The use of dopamine agonists is associated with impulse control disorders and dopamine agonist withdrawal syndrome (DAWS).

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Catechol-<i>O</i>-methyltransferase inhibitor

A catechol-O-methyltransferase(COMT) inhibitor is a drug that inhibits the enzyme catechol-O-methyltransferase. This enzyme methylates catecholamines such as dopamine, norepinephrine and epinephrine. It also methylates levodopa. COMT inhibitors are indicated for the treatment of Parkinson's disease in combination with levodopa and an aromatic L-amino acid decarboxylase inhibitor. The therapeutic benefit of using a COMT inhibitor is based on its ability to prevent the methylation of levodopa to 3-O-methyldopa, thus increasing the bioavailability of levodopa. COMT inhibitors significantly decrease off time in people with Parkinson's disease also taking carbidopa/levodopa.

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  1. Anvisa (31 March 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 4 April 2023). Archived from the original on 3 August 2023. Retrieved 16 August 2023.
  2. "Tasmar 100 mg film-coated tablets - Summary of Product Characteristics (SmPC)". (emc). 9 October 2020. Retrieved 28 November 2022.
  3. "Tasmar- tolcapone tablet, film coated". DailyMed. U.S. National Library of Medicine. 2 October 2020. Retrieved 28 November 2022.
  4. Antonini A, Abbruzzese G, Barone P, Bonuccelli U, Lopiano L, Onofrj M, et al. (February 2008). "COMT inhibition with tolcapone in the treatment algorithm of patients with Parkinson's disease (PD): relevance for motor and non-motor features". Neuropsychiatric Disease and Treatment. 4 (1): 1–9. doi: 10.2147/NDT.S2404 . PMC   2515921 . PMID   18728767.
  5. Forsberg M, Lehtonen M, Heikkinen M, Savolainen J, Järvinen T, Männistö PT (February 2003). "Pharmacokinetics and pharmacodynamics of entacapone and tolcapone after acute and repeated administration: a comparative study in the rat". The Journal of Pharmacology and Experimental Therapeutics. 304 (2): 498–506. doi:10.1124/jpet.102.042846. PMID   12538800. S2CID   24863335.
  6. Ellermann M, Lerner C, Burgy G, Ehler A, Bissantz C, Jakob-Roetne R, et al. (March 2012). "Catechol-O-methyltransferase in complex with substituted 3'-deoxyribose bisubstrate inhibitors". Acta Crystallographica. Section D, Biological Crystallography. 68 (Pt 3): 253–60. doi:10.1107/S0907444912001138. PMID   22349227.
  7. Dingemanse J, Jorga K, Zürcher G, Schmitt M, Sedek G, Da Prada M, Van Brummelen P (September 1995). "Pharmacokinetic-pharmacodynamic interaction between the COMT inhibitor tolcapone and single-dose levodopa". British Journal of Clinical Pharmacology. 40 (3): 253–62. doi:10.1111/j.1365-2125.1995.tb05781.x. PMC   1365105 . PMID   8527287.
  8. 1 2 Jorga KM, Fotteler B, Heizmann P, Zürcher G (July 1998). "Pharmacokinetics and pharmacodynamics after oral and intravenous administration of tolcapone, a novel adjunct to Parkinson's disease therapy". European Journal of Clinical Pharmacology. 54 (5): 443–7. doi:10.1007/s002280050490. PMID   9754991. S2CID   19203574.
  9. 1 2 3 4 5 6 7 Dinnendahl V, Fricke U, eds. (1998). Arzneistoff-Profile (in German). Vol. 10 (13 ed.). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN   978-3-7741-9846-3.
  10. 1 2 3 4 5 6 7 8 "Tasmar: EPAR – Product Information" (PDF). European Medicines Agency. 3 August 2016.
  11. Olanow CW, Watkins PB (2007). "Tolcapone: an efficacy and safety review (2007)". Clinical Neuropharmacology. 30 (5): 287–94. doi:10.1097/wnf.0b013e318038d2b6. PMID   17909307. S2CID   19148461.
  12. 1 2 3 Truong DD (2009). "Tolcapone: review of its pharmacology and use as adjunctive therapy in patients with Parkinson's disease". Clinical Interventions in Aging. 4: 109–13. doi: 10.2147/CIA.S3787 . PMC   2685232 . PMID   19503773.
  13. Deleu D, Northway MG, Hanssens Y (2002). "Clinical pharmacokinetic and pharmacodynamic properties of drugs used in the treatment of Parkinson's disease". Clinical Pharmacokinetics. 41 (4): 261–309. doi:10.2165/00003088-200241040-00003. PMID   11978145. S2CID   39359348.
  14. Jorga K, Fotteler B, Heizmann P, Gasser R (October 1999). "Metabolism and excretion of tolcapone, a novel inhibitor of catechol-O-methyltransferase". British Journal of Clinical Pharmacology. 48 (4): 513–20. doi:10.1046/j.1365-2125.1999.00036.x. PMC   2014389 . PMID   10583021.
  15. Forsberg MM, Huotari M, Savolainen J, Männistö PT (April 2005). "The role of physicochemical properties of entacapone and tolcapone on their efficacy during local intrastriatal administration". European Journal of Pharmaceutical Sciences. 24 (5): 503–11. doi:10.1016/j.ejps.2005.01.005. PMID   15784340.
  16. Novaroli L, Bouchard Doulakas G, Reist M, Rolando B, Fruttero R, Gasco A, Carrupt PA (2006). "The Lipophilicity Behavior of Three Catechol-O-methyltransferase (COMT) Inhibitors and Simple Analogues". Helvetica Chimica Acta. 89 (1): 144–152. doi:10.1002/hlca.200690007.
  17. "3-Benzyloxy-4-methoxybenzaldehyde". PubChem. U.S. National Library of Medicine.
  18. Manikumar G, Jin C, Rehder KS (2008). "Convenient Synthesis of Tolcapone, a Selective Catechol‐O‐methyltransferase Inhibitor". Synthetic Communications. 38 (5): 810–815. doi:10.1080/00397910701821077. S2CID   94242335.
  19. 1 2 Manikumar G, Jin C, Rehder KS (2008). "Convenient Synthesis of Tolcapone, a Selective Catechol‐O‐methyltransferase Inhibitor". Synthetic Communications. 38 (5): 810–815. doi:10.1080/00397910701821077. S2CID   94242335.
  20. 1 2 "2001 Pharmaceuticals: Restrictions in Use and Availability". World Health Organization. Archived from the original on 12 June 2011. Retrieved 31 October 2012.
  21. "Tasmar tolcapone EPAR summary for the public" (PDF). European Medicine Agency. Retrieved 31 October 2012.
  22. Press Office, U.S. Department of Health and Human Services. "FDA Talk Paper". New Warnings for Parkinson's Drug, Tasmar. Food and Drug Administration.
  23. "Tolcapone". FDA: Search Orphan Drug Designations and Approvals. 1 January 2013.
  24. Reig N, Ventura S, Salvadó M, Gámez J, Insa R (2015). "SOM0226, a repositioned compound for the treatment of TTR amyloidosis". Orphanet J Rare Dis. 10 (Suppl 1): P9. doi: 10.1186/1750-1172-10-s1-p9 . PMC   4642128 .