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Tolcapone
Clinical data
Trade namesTasmar
AHFS/Drugs.comMonograph
MedlinePlusa698036
License data
Pregnancy
category
  • AU: B3
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability65%
Protein binding>99.9%
MetabolismLiver (mainly glucuronidation)
Elimination half-life2–3 hours
ExcretionUrine (60%), feces (40%);
only 0.5% in unmetabolized form
Identifiers
  • (3,4-Dihydroxy-5-nitrophenyl)(4-methylphenyl)methanone
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.222.604 Edit this at Wikidata
Chemical and physical data
FormulaC14H11NO5
Molar mass273.244 g·mol−1
3D model (JSmol)
Melting point143 to 146 °C (289 to 295 °F)
Solubility in waternot 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 checkY
  • Key:MIQPIUSUKVNLNT-UHFFFAOYSA-N checkY
  (verify)

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.

Tolcapone appears to be peripherally selective, but can still cross into the brain in significant amounts and has been found to inhibit COMT centrally as well[clarification needed].[5][6] 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 into the brain, acting both in the central nervous system and in the periphery.[7] However, entacapone is less toxic for the liver.

Medical uses

[edit]

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.[8]

Without administration of tolcapone, the beneficial effects of levodopa tend to wear off more quickly, resulting in motor fluctuations.[9]

Contraindications

[edit]

Combining tolcapone with non-selective monoamine oxidase inhibitors such as phenelzine or tranylcypromine is contraindicated.[10] Tolcapone is also contraindicated for people with liver diseases or increased liver enzymes.[11]

Side effects

[edit]

Tolcapone has demonstrated significant liver toxicity (hepatotoxicity)[12] 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.[13]

Other side effects regard the increase in dopaminergic activity, including digestive symptoms.[11] 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.[13]

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.[10] Urine discoloration comes from yellow tolcapone metabolites being excreted in the urine and is harmless.[11][13]

Interactions

[edit]

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 benserazide, as well as methyldopa, dobutamine, apomorphine, epinephrine (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 norepinephrine reuptake inhibitors; these also showed only slight effects in practice. Combination with non-selective MAO inhibitors might be dangerous.[10][11]

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.[11]

Pharmacology

[edit]

Mechanism of action

[edit]
Rat catechol-O-methyltransferase bound to tolcapone. PDB entry 3s68.[14]

Tolcapone selectively and reversibly[10] 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.[15] 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.[16]

3-O-Methylation of levodopa (3-hydroxy-L-tyrosine) via COMT activity
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).[17]

Pharmacokinetics

[edit]

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.[10][11]

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).[9] 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.[10][11]

Tolcapone and its metabolites. The reduction to the amine and subsequent N-acetylation is putative.[11]

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.[18]

Tolcapone has been said to enter the central nervous system only minimally and hence would appear to be peripherally selective.[5] However, tolcapone is more lipophilic than other COMT inhibitors like entacapone and may be more likely to cross the blood–brain barrier (BBB).[6] A imaging study in humans found that tolcapone also inhibited COMT in the brain to a significant degree.[6]

Chemistry

[edit]

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).[10] Its chemical name is 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone.

Synthesis

[edit]

A synthesis of tolcapone proposed in 2008, begins with a Grignard reaction between 4-Benzyloxy-3-methoxybenzaldehyde [19][20] 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.[21]

Borrowed figure of synthesis scheme.
Synthesis of tolcapone[21]

History

[edit]

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[22] removed the drug from the market. The authorization was then renewed in August 2009.[23]

As a result of reported complications, the US 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.[24] 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.[22]

Research

[edit]

Transthyretin amyloidosis

[edit]

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).[25] However, as of 2015 tolcapone was not FDA approved for the treatment of this disease.[26]

Psychiatric disorders

[edit]

In animal studies, tolcapone shows antidepressant- and anti-anhedonia-like effects, stimulates exploratory behavior, and enhances the locomotor hyperactivity induced by psychostimulants like amphetamine and nomifensine.[27][28][29] Tolcapone has been clinically studied in the treatment of certain psychiatric disorders such as obsessive–compulsive disorder (OCD).[30][31] There is also interest in brain-penetrant COMT inhibitors like tolcapone for the treatment of schizophrenia[30][32] as well as disorders of diminished motivation like apathy.[33]

References

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Tolcapone

View on Grokipedia
from Grokipedia
Tolcapone is a potent, selective, and reversible inhibitor of the enzyme catechol-O-methyltransferase (COMT), used as an adjunctive therapy for Parkinson's disease in patients experiencing end-of-dose wearing-off motor fluctuations while on levodopa/carbidopa treatment. Marketed under the brand name Tasmar, it is administered orally in tablet form (100 mg or 200 mg) three times daily, typically taken separately from levodopa doses to optimize pharmacokinetics. By blocking peripheral COMT activity, tolcapone reduces the O-methylation of levodopa, thereby increasing its plasma half-life, enhancing central nervous system delivery, and extending the duration of levodopa's antiparkinsonian effects without significantly altering its peak concentration. Clinical studies have demonstrated that it can reduce "off" time by approximately 1 to 2 hours per day in advanced Parkinson's patients, potentially allowing for reduced levodopa dosing in some cases. Developed by Roche Laboratories, tolcapone received initial approval from the in late 1997 and from the U.S. (FDA) in March 1998 as an add-on therapy to levodopa for idiopathic . Its chemical structure is a nitrocatechol derivative (3,4-dihydroxy-4'-methyl-5-nitrobenzophenone, C14H11NO5), which contributes to its high potency and ability to cross the blood-brain barrier, though it primarily exerts effects peripherally at therapeutic doses. However, post-marketing surveillance revealed rare but severe cases of , including and fatalities (approximately 1 in 6,000 to 10,000 patients), leading to its voluntary withdrawal from markets in and in November 1998. In the United States, it was not withdrawn but received a black box warning in November 1998, mandating baseline and periodic (every two weeks for the first year, then less frequently), immediate discontinuation if transaminases exceed two times the upper limit of normal, to ensure safe use. Tolcapone was reintroduced in in under strict monitoring via a registry, and it remains available in the U.S. as of 2025, though its use is limited due to these safety concerns and the availability of alternative COMT inhibitors like . Common adverse effects include , , , , and non-traumatic urine discoloration (turning orange-brown), while serious risks beyond encompass hallucinations, , and . Contraindications include active , prior tolcapone-induced hepatocellular injury, or elevated baseline liver enzymes.

Clinical aspects

Medical uses

Tolcapone is indicated as an adjunct therapy to levodopa and carbidopa for the treatment of signs and symptoms of idiopathic , particularly in patients experiencing motor fluctuations such as "wearing-off" phenomena. As a (COMT) inhibitor, it prolongs the effects of levodopa by reducing its peripheral metabolism, thereby helping to stabilize levodopa plasma levels. Clinical trials have demonstrated that tolcapone significantly improves daily "on" time without troublesome in patients with fluctuating . In a multicenter, randomized, -controlled study of 202 patients with wearing-off symptoms, tolcapone at 100 mg or 200 mg three times daily increased "on" time by approximately 1.7 to 2.9 hours per day compared to , while reducing "off" time by 1.6 to 3.0 hours. Similar results were observed in a European trial involving 177 patients, where tolcapone reduced "off" time and enhanced functional status as assessed by the Unified Rating Scale (UPDRS). These benefits are most pronounced in patients who do not respond adequately to other adjunctive therapies. Tolcapone is not recommended for use as monotherapy or as initial therapy in Parkinson's disease, as its efficacy has not been established in these settings. It is specifically targeted at patients with advanced who have developed motor complications, such as end-of-dose wearing-off, rather than those in early-stage disease without fluctuations. Patients should be evaluated for substantial clinical benefit within three weeks of initiation, with discontinuation if none is observed.

Contraindications and precautions

Tolcapone is contraindicated in patients with , in patients who were withdrawn from tolcapone because of evidence of tolcapone-induced hepatocellular injury, or who have demonstrated to the drug or its ingredients. It is also contraindicated in patients with a history of nontraumatic or hyperpyrexia and possibly related to . Precautions are advised when using tolcapone concomitantly with non-selective monoamine oxidase (MAO) inhibitors, such as phenelzine, as this combination may lead to serious adverse effects; selective MAO-B inhibitors like selegiline are considered safe. There are no adequate data on the developmental risks to humans from tolcapone use during pregnancy. Animal reproduction studies have shown no evidence of direct teratogenic effects with tolcapone alone; however, when administered with levodopa/carbidopa, adverse effects on the fetus were observed. Tolcapone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. During breastfeeding, caution is recommended because tolcapone is excreted in the milk of lactating rats, and it is unknown whether it appears in human milk. Do not initiate tolcapone therapy if there is clinical evidence of or if two baseline (ALT) or aspartate aminotransferase (AST) values exceed the upper limit of normal (ULN). Baseline , including ALT and AST, are required before initiating tolcapone therapy, with periodic monitoring every 2 to 4 weeks for the first 6 months and then as clinically indicated thereafter. More frequent testing is necessary if the dose is increased to 200 mg three times daily. Therapy should be discontinued immediately if ALT or AST levels exceed 2 times the ULN, or if any clinical signs of —such as , , or dark —emerge. Discontinuation is also warranted if there is no clinical benefit observed within 3 weeks of starting treatment.

Dosage and administration

Tolcapone is administered orally three times daily as an adjunct to levodopa/carbidopa or levodopa/benserazide therapy in patients with experiencing fluctuations in motor activity. The recommended initial dose for adults is 100 mg, with the first dose taken in the morning alongside the initial daily levodopa dose, followed by subsequent doses approximately 6 and 12 hours later. The tablets may be taken with or without food and should be swallowed whole with a glass of water; they must not be crushed, chewed, or broken. If no substantial clinical benefit is observed after 3 weeks of treatment at the initial dose, tolcapone should be discontinued. For patients who tolerate the 100 mg regimen but demonstrate an insufficient response, the dose may be increased to 200 mg three times daily only if the anticipated clinical improvement justifies the associated risks, with the maximum recommended total daily dose not exceeding 600 mg. Prior to initiation, , including ALT and AST, must be normal, as tolcapone is contraindicated in patients with any evidence of or elevated baseline liver enzymes. Upon starting tolcapone or increasing the dose, the concomitant levodopa dose may require adjustment, typically reduced by about 30% on average, especially if the daily levodopa intake exceeds 600 mg or if moderate to severe dyskinesias emerge. No dosage adjustment is needed for mild to moderate renal impairment ( clearance ≥30 mL/min), but caution is recommended in severe renal impairment ( clearance <30 mL/min), with close monitoring for tolerability. Tolcapone is contraindicated in hepatic impairment, and it is not recommended for use in children or adolescents under 18 years due to lack of safety and efficacy data. Elderly patients follow the standard adult dosing without specific adjustments, provided other criteria are met.

Adverse effects and safety

Common side effects

Tolcapone, when used as an adjunct to levodopa/carbidopa therapy in Parkinson's disease, commonly causes dopaminergic side effects due to its enhancement of levodopa bioavailability. The most frequent adverse reactions, occurring in more than 10% of patients in pivotal clinical trials, include , , and sleep disorders. In placebo-controlled trials involving patients with Parkinson's disease, dyskinesia was reported in 42% of those receiving tolcapone 100 mg three times daily and 51% receiving 200 mg three times daily, compared to 20% on placebo; this increase is attributable to augmented levodopa effects. Nausea occurred in 30% and 35% of patients on the respective doses versus 18% on placebo, often appearing early in treatment. Sleep disorders, such as insomnia or excessive dreaming, affected 24% and 25% of tolcapone-treated patients compared to 18% on placebo. Other notable effects with 5-10% incidence include dystonia (19-22% vs. 17% placebo), anorexia (19-23% vs. 13%), somnolence (14-18% vs. 13%), diarrhea (16-18% vs. 8%), orthostatic complaints (17% vs. 14%), hallucinations (8-10% vs. 5%), and dry mouth (5-6% vs. 2%). Diarrhea and abdominal pain (5-6% vs. 3%) are gastrointestinal issues that typically emerge within weeks to months, while urine discoloration to a brownish hue occurs in up to 7% of patients on higher doses but is benign and reversible. Management of these effects often involves adjusting concomitant levodopa dosage; for instance, reducing levodopa by approximately 20-30% can mitigate dyskinesia and hallucinations in responsive patients. Nausea may improve with continued use or levodopa titration, and persistent diarrhea warrants clinical evaluation, though most cases resolve upon discontinuation. Overall, these side effects are generally mild and lead to treatment discontinuation in fewer than 10% of cases.
Adverse ReactionPlacebo (%)Tolcapone 100 mg TID (%)Tolcapone 200 mg TID (%)
Dyskinesia204251
Nausea183035
Sleep Disorder182425
Diarrhea81618
Urine Discoloration127

Hepatotoxicity and monitoring

Tolcapone is associated with a rare but potentially fatal risk of acute liver failure, estimated at approximately 1 case per 20,000 patient-years of exposure early on, representing an idiosyncratic reaction that is not clearly dose-dependent. This hepatotoxicity manifests as hepatocellular injury, with serum aminotransferase elevations occurring in 1% to 5% of treated patients, though most are asymptomatic and resolve upon discontinuation. Early post-approval experience showed severe liver injury in approximately 1 in 15,000 patients (4 cases among ~60,000 exposed), while clinical trials reported ALT/AST >3x ULN in 1-4% of patients, contributing to temporary market withdrawals in several countries; rigorous monitoring has since reduced the rate of severe events. Symptoms of tolcapone-induced typically include fatigue, , dark urine, and , often appearing within the first 6 months of therapy, though asymptomatic elevations in liver enzymes such as ALT and AST are more common and can precede clinical manifestations. In severe cases, progression to , confusion, or fulminant failure may occur, as documented in historical reports where lack of early detection led to fatal outcomes. Due to this risk profile, strict monitoring protocols are mandatory for patients on tolcapone. , including ALT and AST, should be performed at baseline, every 2-4 weeks for the first 6 months of treatment, and periodically thereafter; must be discontinued immediately if levels exceed 2 times the upper limit of normal or if any symptoms of emerge. Early case reports were predominantly in elderly women, but no factors have been definitively identified beyond concurrent use of other hepatotoxins or preexisting liver disease; avoid in such patients. These measures, implemented following early post-marketing safety concerns that prompted regulatory actions, have minimized severe outcomes in contemporary use, with no cases reported in post-reintroduction studies as of 2021.

Drug interactions

Pharmacokinetic interactions

Tolcapone inhibits (COMT), which reduces the peripheral metabolism of levodopa to 3-O-methyldopa, thereby increasing levodopa's . When coadministered with levodopa/carbidopa, tolcapone approximately doubles the area under the curve (AUC) of levodopa and extends its terminal elimination from about 2 hours to 3.5 hours, without altering maximum concentration or time to maximum concentration. This pharmacokinetic enhancement often requires a 20-30% reduction in levodopa dosage to prevent excessive levodopa exposure and associated toxicities, such as or . Tolcapone undergoes primary metabolism via to form inactive conjugates, accounting for the majority of its clearance, with minor pathways including COMT-mediated O-methylation and oxidative metabolism potentially involving and CYP2A6. Less than 0.5% of unchanged tolcapone is excreted in urine, and its high protein binding (over 99%) limits efficacy. Tolcapone exhibits no clinically significant inhibition of major (CYP) enzymes, including , , , or , as demonstrated by the absence of pharmacokinetic alterations in probe substrates such as and (), and (), (), and (). Tolcapone is neither a substrate nor an inhibitor of (P-gp), resulting in no clinically significant pharmacokinetic interaction with P-gp substrates such as . For , no pharmacokinetic changes occur, though should be monitored due to sparse clinical interaction data.

Pharmacodynamic interactions

Tolcapone, as a (COMT) inhibitor, exhibits additive pharmacodynamic effects when combined with levodopa, enhancing activity in the brain and potentially leading to increased dyskinesias or hallucinations. These effects arise because tolcapone prolongs levodopa's duration of action by inhibiting its peripheral , necessitating dose adjustments of levodopa by approximately 25-30% to mitigate excessive motor fluctuations or psychiatric symptoms. Concomitant use of tolcapone with non-selective inhibitors (MAOIs), such as , is contraindicated due to synergistic inhibition of catecholamine metabolism, which can result in excessive accumulation of norepinephrine and , precipitating a . This interaction heightens the risk of severe cardiovascular events, including dangerously elevated and , and requires complete avoidance of such combinations. Caution is advised when tolcapone is used with selective MAO-B inhibitors like , as both agents inhibit breakdown, potentially leading to excessive stimulation and an increased risk of . While coadministration is permissible at standard doses, close monitoring for signs of or other neuropsychiatric effects is recommended to prevent exacerbation of symptoms. Tolcapone can enhance the hypotensive effects of antihypertensives or antipsychotics through additive impacts on regulation, particularly when combined with levodopa's orthostatic effects. This interaction may manifest as increased , requiring monitoring and possible dose titration of concomitant agents. Tolcapone shows no significant pharmacodynamic interactions with other dopaminergics such as beyond the expected synergistic enhancement of antiparkinsonian effects.

Tolcapone is a selective, reversible, and potent inhibitor of (COMT), an responsible for the O-methylation of catecholamines such as levodopa, , norepinephrine, and epinephrine. By competitively binding to the COMT , tolcapone prevents the transfer of a from the cofactor S-adenosylmethionine (SAM) to these substrates, thereby inhibiting their degradation. Its nitrocatechol structure facilitates this binding, forming hydrogen bonds and coordinating with a magnesium ion in the enzyme's catalytic pocket, as demonstrated in crystallographic studies of COMT-tolcapone complexes. The inhibition constant (K_i) for tolcapone against human COMT is approximately 0.3 nM, indicating high potency. This inhibition occurs both peripherally and centrally, as tolcapone penetrates the blood-brain barrier, unlike peripherally restricted COMT inhibitors such as . In the periphery, tolcapone blocks the conversion of levodopa to 3-O-methyldopa (3-OMD), a major metabolite that competes with levodopa for across the blood-brain barrier via the large neutral transporter. Consequently, tolcapone prolongs the plasma half-life of levodopa by 1.5- to 2-fold and increases its , allowing more levodopa to reach the brain for conversion to . In the , tolcapone inhibits brain COMT, enhancing synaptic levels without directly agonizing or affecting other systems. Overall, these actions augment transmission in patients receiving levodopa therapy, extending the duration of therapeutic effects and reducing motor fluctuations. Tolcapone's dual peripheral and central inhibition distinguishes it from , which primarily acts outside the brain and requires more frequent dosing to maintain efficacy.

Pharmacokinetics

Tolcapone is rapidly absorbed following , with an absolute of approximately 65%. Peak plasma concentrations (T_max) are typically reached within 2 hours. Food intake delays the rate of absorption but does not substantially affect the overall extent of , which remains at 80-90% relative to fasting conditions. The steady-state for tolcapone is approximately 9 L. It is highly bound to plasma proteins (>99.9%), primarily to . Tolcapone penetrates the blood-brain barrier, achieving concentrations sufficient for central inhibition of COMT. Tolcapone undergoes extensive hepatic , with the primary pathway being to form an inactive conjugate, independent of enzymes. Minor oxidative occurs via and , leading to negligible active metabolites. The elimination of tolcapone is 2-3 hours, with systemic clearance around 7 L/h. Approximately 60% of the dose is excreted in the urine (primarily as the ) and 40% in the , with less than 0.5% eliminated unchanged. There is no accumulation upon thrice-daily (TID) dosing, which supports its use for sustained peripheral and central COMT inhibition. In patients with hepatic impairment, the of tolcapone is prolonged and clearance reduced by about 50% in moderate cases (e.g., Child-Pugh class B), leading to higher unbound concentrations; use is contraindicated in any . In renal impairment, are mildly altered with reduced clearance in severe cases (creatinine clearance <30 mL/min), though no dose adjustment is typically required for mild to moderate impairment.

Chemistry

Chemical structure and properties

Tolcapone has the molecular formula C14H11NO5 and a molecular weight of 273.24 g/mol. The of tolcapone is that of a 3,4-dihydroxy-5-nitrobenzophenone featuring a at the 4' position on the unsubstituted phenyl ring; the nitrocatechol moiety is central to its molecular architecture. Tolcapone appears as a crystalline with a of approximately 145°C. It is sparingly soluble in , with a reported solubility of about 0.057 mg/mL at neutral . The phenolic groups exhibit pKa values of approximately 4.5 and 9.8, reflecting the acidity of the catechol-like hydroxyls. Tolcapone is light-sensitive and should be stored at , protected from moisture to maintain stability. In pharmaceutical-grade preparations, potential impurities arising from synthesis are closely monitored to ensure purity.

Synthesis

Tolcapone, chemically known as 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone, can be prepared through several synthetic routes, with methods focusing on from commercial precursors and emphasizing and impurity control. A convenient laboratory synthesis begins with 4-benzyloxy-3-methoxybenzaldehyde, which undergoes a Grignard reaction with p-tolylmagnesium bromide to form the corresponding alcohol, followed by Oppenauer oxidation to yield the protected benzophenone intermediate. Debenzylation provides 4-hydroxy-3-methoxy-4'-methylbenzophenone, which is regioselectively nitrated at the 5-position using nitric acid, and subsequent O-demethylation with hydrogen bromide in acetic acid affords tolcapone in an overall yield of 60%. This route avoids complex separations and uses mild conditions for the key nitration step. The original synthesis, patented by in the 1980s (Australian Patent AU-B-69764/87), and refined industrial processes employ a Friedel-Crafts as the core step. Starting from veratrol (1,2-dimethoxybenzene) and 4-methylbenzoyl chloride (derived from 4-methylacetophenone), the is catalyzed by aluminum trichloride in at 25-30°C to produce 3,4-dimethoxy-4'-methylbenzophenone. Selective cleavage of one using excess aluminum trichloride at 32-35°C yields 4-hydroxy-3-methoxy-4'-methylbenzophenone after isolation via selective of its sodium salt (overall yield for this stage: 50-64%). Regioselective with 65% in glacial acetic acid at 20-25°C introduces the nitro group at the 5-position (yield: 80-87%), directed ortho to the methoxy . Final demethylation with aluminum trichloride in triethylamine and , followed by acidic , provides tolcapone (yield: 72-85%), achieving an overall process yield of approximately 70-80%. Key challenges in these syntheses include preventing over-nitration or formation of di-nitro byproducts during the nitration step, which is mitigated by controlling temperature and using acetic acid as solvent to favor mono-substitution. Purification typically involves recrystallization from ethanol-water mixtures to achieve high purity (>99%) and reduce impurities such as regioisomers. Subsequent patents have introduced variations aimed at minimizing impurities and improving yield for production.

History

Development and initial approval

Tolcapone was developed by F. Hoffmann-La Roche Ltd. in the 1980s as a selective inhibitor of (COMT), marking the first compound in a new generation of potent, reversible nitrocatechol-based agents designed to enhance levodopa therapy in (PD) following earlier non-selective prototypes. In preclinical studies, tolcapone demonstrated high potency against COMT, with IC50 values ranging from 18 to 130 nM across species and tissues, consistently below 50 nM in key assays for soluble and membrane-bound forms. Animal models, including rats, confirmed its ability to prolong levodopa's plasma half-life by up to 90% and potentiate its antiparkinsonian effects, such as reversing induced by dopamine antagonists when combined with levodopa/carbidopa. These findings supported advancement to clinical development as an adjunct to levodopa for managing motor fluctuations in PD. Pivotal phase III trials conducted in the 1990s, involving over 500 patients with fluctuating PD, evaluated tolcapone (100 mg or 200 mg three times daily) as an add-on to levodopa/carbidopa. In a multicenter, randomized, -controlled study of 177 patients over three months, tolcapone significantly reduced daily "off" time by 1.7 hours (from a baseline of approximately 6.6 hours) compared to 0.7 hours with placebo, representing a 25% improvement, while increasing "on" time without troublesome . Similar results were observed in two additional 13-week trials and a 6-week study, with overall "off" time reductions of 20-30% across 594 patients, alongside decreased levodopa requirements by 20-30%. Tolcapone was well tolerated, with common adverse events including , , and , but no fatal reported during these trials. Tolcapone received initial regulatory approval as Tasmar for use as an adjunct to levodopa/decarboxylase inhibitor therapy in PD patients experiencing end-of-dose wearing-off, without initial black box warnings for liver toxicity. The European Medicines Agency granted marketing authorization on August 27, 1997, following the phase III data demonstrating efficacy in motor fluctuations unresponsive to other therapies. The U.S. Food and Drug Administration approved it on January 29, 1998, with initial labeling recommending liver enzyme monitoring every two weeks for the first year due to observed elevations in 1-3% of patients, but no contraindication for those with two elevated values or clinical liver disease at launch. By the late 1990s, Tasmar was marketed in over 30 countries worldwide, including major European markets and the United States.

Market withdrawal and reintroduction

In late 1998, post-marketing surveillance identified three cases of fatal fulminant hepatic failure associated with tolcapone use in patients with , prompting the (EMA) to suspend marketing authorization across on December 11, 1998, and to voluntarily withdraw the drug from markets in and several other countries. These events occurred shortly after tolcapone's initial approval in 1997 () and 1998 (), highlighting rare but severe risks not fully evident in pre-approval trials. Subsequent investigations by the FDA and EMA reviewed post-marketing data, identifying approximately 11 serious cases of , including the initial fatalities, with an estimated incidence of fulminant hepatic failure ranging from 1:6,000 to 1:10,000 exposed patients—substantially higher than background rates in the general population. In the United States, where full market withdrawal did not occur, implemented severe restrictions, including a black box warning on the label emphasizing the risk of and mandatory intensive liver function monitoring (ALT/AST tests every two weeks for the first year, then monthly). In 2006, the FDA approved label changes that reduced the intensity of required liver function monitoring while retaining the black box warning, based on post-marketing data showing low risk with adherence. Tolcapone was reintroduced in on , , following the lifting of the EMA suspension, with centralized approval and similar restrictions, limiting use to patients with fluctuating Parkinson's symptoms unresponsive to other therapies and mandating immediate discontinuation if ALT/AST exceeds three times the upper limit of normal. It was reintroduced across the , including in the and , under strict monitoring protocols. Post-marketing surveillance, including a 2021 systematic review covering over 23 years, has reported only seven cases of severe liver injury worldwide (three fatal, all in non-compliant patients), indicating a very low incidence under strict monitoring. Earlier data from 2005 noted over 40,000 patient-years of exposure with minimal severe events. As of 2025, no additional fatalities have been reported in compliant patients. Ongoing pharmacovigilance by Roche and regulatory agencies continues to emphasize adherence to monitoring to mitigate risks. These events led to a significant decline in tolcapone sales, with entacapone emerging as the preferred catechol-O-methyltransferase (COMT) inhibitor due to its lack of associated hepatotoxicity.

Society and culture

Brand names and availability

Tolcapone is marketed primarily under the brand name Tasmar by Companies Inc. (previously under and Valeant Pharmaceuticals), with generic formulations of tolcapone available in select markets since the U.S. (FDA) approved the first generic version in 2018. The medication is available exclusively as oral tablets in two strengths: 100 mg pale yellow hexagonal tablets and 200 mg yellow-orange hexagonal tablets. In the United States, Tasmar and its generics are subject to restricted availability due to the risk of severe, potentially fatal ; distribution requires prescriber enrollment in a monitoring program, baseline and regular (every two weeks for the first year, then monthly), and documented patient before initiation. In the , Tasmar holds conditional marketing authorization from the , permitting use only in patients with fluctuating unresponsive to other therapies, with mandatory biweekly liver enzyme monitoring during the first year and precautions against use in those with liver impairment or elevated enzymes. Availability varies by member state, with the drug authorized in the under prescription-only medicine (POM) status as of 2025. Availability in is limited, with approval in select countries such as , though primarily restricted to specialized settings due to concerns. As of 2025, a typical monthly supply (90 tablets of 100 mg generic tolcapone) in the costs between $1,000 and $2,000 without insurance, though discount programs can lower this to around $1,000; patient assistance options, including co-pay support, are provided through manufacturer programs for eligible uninsured or underinsured patients. Occasional supply disruptions occur due to low market demand and stringent manufacturing controls related to safety monitoring requirements. In the United States, tolcapone is approved by the (FDA) as a prescription-only for use as an adjunct to levodopa/carbidopa in patients with experiencing motor fluctuations, and it is not classified as a . It carries a black box warning highlighting the risk of potentially fatal acute fulminant , with the drug recommended only for patients unresponsive to or intolerant of other adjunctive therapies. Treatment requires baseline (including ALT and AST levels) prior to initiation, followed by monitoring every 2-4 weeks for the first 6 months and periodically thereafter, with immediate discontinuation if enzyme levels exceed twice the upper limit of normal or signs of hepatic dysfunction appear; patients must provide written acknowledgment of these risks after physician discussion. In the , the (EMA) granted marketing authorization for tolcapone (as Tasmar) on August 27, 1997, which was suspended on December 11, 1998, due to reports of fatal liver injuries but lifted on August 31, 2004, under strict conditions. It is authorized for use with levodopa/benserazide or levodopa/carbidopa in patients with motor fluctuations who are unresponsive or intolerant to other (COMT) inhibitors, but not as first-line therapy owing to hepatotoxicity risks; it is contraindicated in patients with , , , or a history of , , or . Prescription and supervision must be by physicians experienced in management, with mandatory liver function monitoring similar to U.S. requirements. Tolcapone has been withdrawn or banned in several other countries due to hepatotoxicity concerns, including Canada (suspended in 1999 after a fatal liver failure case), Australia (withdrawn in February 1999), Bulgaria (April 1999), Iceland (November 1998), and Lithuania (1999). In regions where it remains available, such as parts of and select Asian countries, access is restricted to specialist use with rigorous monitoring protocols as of 2025. As of 2025, there have been no new regulatory approvals for tolcapone globally, and it retains its over-the-counter ineligible status worldwide, remaining prescription-only where authorized. The FDA continues to oversee post-marketing data on through reporting, with no changes to the existing . The original patents for tolcapone expired in 2010, enabling generic versions to enter the market in both the and the , where FDA and EMA approvals for generics have been granted, though commercial availability may vary by pharmacy and region.

Research directions

Transthyretin amyloidosis

Tolcapone has been repurposed for the treatment of transthyretin (TTR) amyloidosis due to its ability to bind the TTR tetramer with high affinity (Kd ≈ 20 nM), thereby inhibiting tetramer dissociation and subsequent amyloid fibril formation. This binding occurs at the thyroxine (T4) pockets of TTR, stabilizing the native tetrameric structure more effectively than tafamidis in ex vivo plasma assays, where tolcapone demonstrated superior inhibition of TTR aggregation. Unlike its primary role as a catechol-O-methyltransferase (COMT) inhibitor, this mechanism is independent of COMT activity and targets the amyloidogenic process central to ATTR amyloidosis. Preclinical studies have provided structural and functional supporting tolcapone's . Crystal structures from 2024 reveal that tolcapone and its analogs bind specifically to TTR's T4-binding pockets, forming key hydrogen bonds and hydrophobic interactions that enhance tetramer stability. In mouse models of ATTR variant (ATTRv) and (ATTR-P), tolcapone administration reduced fibrillogenesis and TTR deposition in tissues, demonstrating stabilization of the tetramer without significant off-target effects. A Phase I (NCT03591757, completed in 2023) evaluated tolcapone in a small cohort of 10 patients with leptomeningeal ATTR , showing short-term stabilization of TTR tetramers in both plasma (55% increase in stabilized fraction) and (48% decrease in unstable monomers). Notably, no was observed in this group, suggesting tolerability at tested doses despite prior concerns from use. Recent advances from 2024–2025 include biophysical studies using and simulations, which confirm tolcapone's tetramer stabilization and highlight its lack of negative compared to other stabilizers. Ongoing efforts focus on optimizing analogs, such as 3-O-methyltolcapone, which exhibits comparable binding affinity (Kd ≈ 33 nM) and improved pharmacokinetic profiles to enhance penetration and reduce . As of November 2025, Corino Therapeutics is conducting a Phase II trial of a modified-release formulation of tolcapone (CRX-1008) for ATTR , including potential applications in ATTR (ATTR-CM), with completion expected in mid-2025. However, tolcapone's dose is limited by potential , prompting exploration of derivatives for broader application.

Psychiatric disorders

Tolcapone, a (COMT) inhibitor, has been explored for its potential therapeutic effects in various psychiatric disorders, primarily due to its ability to modulate prefrontal levels, which can enhance cognitive functions such as and executive control. Research indicates that tolcapone's cognitive benefits are most consistent in improving , particularly in individuals with the Val/Val COMT , who exhibit lower baseline prefrontal and thus may benefit from increased signaling under the inverted-U optimization model. However, effects on other domains like sustained or are mixed, with some studies showing impairments, and overall evidence remains limited by small sample sizes and short durations. In obsessive-compulsive disorder (OCD), tolcapone has demonstrated preliminary efficacy in reducing symptoms. A randomized, double-blind, -controlled crossover involving 20 adults with OCD found that 100 mg twice daily for two weeks significantly decreased Yale-Brown Obsessive Compulsive Scale (YBOCS) scores by 16.4% compared to 3.6% with (p=0.0409), though no changes were observed in anxiety or depression measures. This suggests tolcapone may target OCD through enhanced prefrontal regulation, but limitations include the short treatment period and mild symptom severity in participants. For alcohol use disorder (AUD), tolcapone shows promise in improving behavioral control rather than directly reducing cravings. A 2025 study from the University of Colorado Anschutz Medical Campus reported that tolcapone enhances activation, thereby increasing over alcohol-related behaviors in individuals with AUD, potentially including those with comorbid ADHD. This mechanism positions tolcapone as a novel adjunctive therapy for substance use disorders by addressing . Investigations into schizophrenia-related deficits highlight tolcapone's potential to ameliorate sensorimotor gating and working memory impairments. In a double-blind crossover study of 25 healthy men, 200 mg tolcapone improved prepulse inhibition (PPI) and n-back task performance in participants with the low-dopamine G/G COMT rs4818 genotype, supporting its utility for prodromal or deficit symptoms in schizophrenia, though effects were genotype-specific. Broader cognitive enhancements, including executive function and verbal episodic memory, have been observed in healthy subjects, with fMRI evidence of improved prefrontal efficiency during working memory tasks. In behavioral variant (bvFTD), a form of (FTLD), tolcapone's effects on cognitive and behavioral symptoms are less conclusive. A randomized, placebo-controlled crossover with 28 bvFTD patients showed improvements from baseline in neuropsychiatric symptoms (NPI-Q, p=0.04) and global clinical impression (CGI, p=0.035) after 7 days of treatment, but no significant impact on primary outcomes or compared to . The drug was well-tolerated, though 21% experienced transient liver elevations. Despite these potential benefits, tolcapone is contraindicated in patients with major psychotic disorders due to the risk of exacerbating , including hallucinations and paranoid ideation, as noted in clinical trials (incidence 8-10%) and post-marketing reports. Further large-scale trials are needed to establish its and in psychiatric populations.

References

  1. https://www.ncbi.nlm.nih.gov/books/NBK560593/
  2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/020697s010lbl.pdf
  3. https://pmc.ncbi.nlm.nih.gov/articles/PMC2685232/
  4. https://jamanetwork.com/journals/jamaneurology/fullarticle/775949
  5. https://pubchem.ncbi.nlm.nih.gov/compound/Tolcapone
  6. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf
  7. https://pubmed.ncbi.nlm.nih.gov/9339691/
  8. https://www.ema.europa.eu/en/documents/product-information/tasmar-epar-product-information_en.pdf
  9. https://www.ncbi.nlm.nih.gov/books/NBK548573/
  10. https://www.sciencedirect.com/topics/medicine-and-dentistry/tolcapone
  11. https://link.springer.com/article/10.1007/s00228-020-03081-x
  12. https://go.drugbank.com/drugs/DB00323
  13. https://reference.medscape.com/drug/tasmar-tolcapone-343053
  14. https://ec.europa.eu/health/documents/community-register/2016/20160822135663/anx_135663_en.pdf
  15. https://www.drugs.com/monograph/tolcapone.html
  16. https://www.rcsb.org/structure/3S68
  17. https://onlinelibrary.wiley.com/doi/10.1111/j.1527-3458.2007.00020.x
  18. https://pubmed.ncbi.nlm.nih.gov/15784340/
  19. https://pubmed.ncbi.nlm.nih.gov/10451758/
  20. https://www.medicines.org.uk/emc/product/11830/smpc
  21. https://bpspubs.onlinelibrary.wiley.com/doi/10.1046/j.1365-2125.2000.00113.x
  22. https://www.accessdata.fda.gov/drugsatfda_docs/nda/98/20697_Tasmar_EAfonsi.pdf
  23. https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1046/j.1365-2125.1999.00036.x
  24. https://www.chemicalbook.com/ProductChemicalPropertiesCB9302569_EN.htm
  25. https://pmc.ncbi.nlm.nih.gov/articles/PMC2014389/
  26. https://patents.google.com/patent/US5877353A/en
  27. https://www.tandfonline.com/doi/abs/10.1080/00397910701821077
  28. https://www.orientjchem.org/vol38no6/development-of-a-novel-one-pot-process-for-the-synthesis-of-tolcapone/
  29. https://patents.google.com/patent/WO2014147464A2/en
  30. https://www.researchgate.net/publication/229576071_Catechol-O-methyltransferase-Inhibiting_Pyrocatechol_Derivatives_Synthesis_and_Structure-Activity_Studies
  31. https://www.clinician.com/articles/39784-tolcapone-tablets-tasmar-roche-pharmaceuticals
  32. https://www.tandfonline.com/doi/full/10.1080/00498254.2020.1853850
  33. https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2125.1995.tb05781.x
  34. https://www.accessdata.fda.gov/drugsatfda_docs/nda/98/20697_Tasmar_medr_P1.pdf
  35. https://jamanetwork.com/journals/jamaneurology/fullarticle/774131
  36. https://pubmed.ncbi.nlm.nih.gov/9708959/
  37. https://www.ema.europa.eu/en/medicines/human/EPAR/tasmar
  38. https://www.accessdata.fda.gov/drugsatfda_docs/nda/98/20697_Tasmar.cfm
  39. https://pmc.ncbi.nlm.nih.gov/articles/PMC11091965/
  40. https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/catechol-methyltransferase-inhibitor
  41. https://www.mdedge.com/content/tolcapones-approved-label-changes-mean-less-liver-enzyme-monitoring
  42. https://ec.europa.eu/health/documents/community-register/2006/2006080412493/anx_12493_en.pdf
  43. https://www.parkinsons.org.uk/information-and-support/comt-inhibitors
  44. https://pmc.ncbi.nlm.nih.gov/articles/PMC8128808/
  45. https://pubmed.ncbi.nlm.nih.gov/17909307/
  46. https://pmc.ncbi.nlm.nih.gov/articles/PMC6494077/
  47. https://www.drugs.com/availability/generic-tasmar.html
  48. https://parkinsonsnewstoday.com/tasmar/
  49. https://fda.report/NDC/50742-193
  50. https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=a0e47a9d-78e7-4523-983a-aa259f221736
  51. https://www.mims.com/singapore/drug/info/tolcapone
  52. https://www.goodrx.com/tolcapone
  53. https://www.drugpatentwatch.com/p/bulk-api/TASMAR
  54. https://www.drugs.com/pro/tolcapone.html
  55. https://www.fda.gov/drugs/drug-safety-and-availability/drug-safety-communications
  56. https://www.nature.com/articles/ncomms10787
  57. https://pubs.acs.org/doi/10.1021/acs.jmedchem.2c01195
  58. https://www.mdpi.com/1422-0067/25/1/479
  59. https://clinicaltrials.gov/study/NCT03591757
  60. https://fapnewstoday.com/news/clinical-trial-data-provide-proof-of-concept-for-crx-1008-treatment-for-leptomeningeal-fap/
  61. https://journals.lww.com/nrronline/fulltext/2025/04000/design_and_redesign_journey_of_a_drug_for.24.aspx
  62. https://www.pharmaceutical-technology.com/data-insights/tolcapone-corino-therapeutics-amyloidosis-likelihood-of-approval/
  63. https://doi.org/10.1017/S1092852924000130
  64. https://doi.org/10.1097/YIC.0000000000000368
  65. https://doi.org/10.1016/j.bpsc.2025.06.003
  66. https://doi.org/10.1016/j.biopsych.2009.07.008
  67. https://doi.org/10.1038/sj.npp.1301227
  68. https://doi.org/10.3233/JAD-191265
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