Tolcapone

K K Jain MD†

Neuropharmacology & Neurotherapeutics

Updated 09.14.2021
Released 12.22.1998
Expires For CME 09.14.2024

Tolcapone

Author: K K Jain MD†

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Tolcapone

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Introduction

Historical note and terminology

Since its demonstration of effectiveness against Parkinson disease in 1961, levodopa has become the mainstay therapy for this disease. However, most orally administered levodopa is converted by catechol-O-methyltransferase into the inactive metabolite 3-O-methyldopa before crossing the blood-brain barrier. The accumulated 3-O-methyldopa then competes with levodopa for the saturable neutral amino acid active transport system in the gut and blood vessel wall, leading to motor fluctuations. The purpose of catechol-O-methyltransferase inhibitors such as entacapone and tolcapone is to inhibit the action of this enzyme.

Catechol-O-methyltransferase is widely distributed in human tissues including glia. Catechol-O-methyltransferase inhibition lowers the circulating levels of 3-O-methyldopa and improves the bioavailability of levodopa. The first-generation, nonselective catechol-O-methyltransferase inhibiting drugs were studied in the 1970s but were abandoned because of toxicity and lack of efficacy. The second-generation catechol-O-methyltransferase inhibitors, which were developed in the late 1980s, are reversible catechol-O-methyltransferase inhibitors and are in clinical trials. Two compounds of this category have been developed, entacapone and tolcapone. The United States Food and Drug Administration approved tolcapone in 1998 and entacapone in 1999. Due to reports of hepatotoxicity, its use was suspended in the European Union and is restricted by a warning in the United States. Tolcapone, however, remains an option in patients with fluctuating Parkinson disease who are receiving levodopa and are not responding to or tolerating other adjunctive treatments. Clinical data obtained by ongoing use of tolcapone in other countries proved that adequate safety can be achieved if liver enzymes are strictly monitored. In 2005, tolcapone was relaunched in the European Union under the prerequisite of biweekly liver enzyme monitoring.

Opicapone is a novel, long-acting, peripherally selective, once-daily, third-generation catechol-O-methyl transferase inhibitor that was approved in the European Union in 2016 as an alternative to tolcapone. It reduces OFF time without increasing ON time with troublesome dyskinesias and has a good drug safety profile (06).

Pharmacology

The chemical name of tolcapone is 3,4-Dihydroxy-4'-methyl-5-nitrobenzophenone.

Tolcapone (chemical structure)

(Contributed by Dr. K K Jain.)

Pharmacodynamics. Tolcapone inhibits the action of the enzyme catechol-O-methyltransferase, which acts to metabolize or degrade catechols that include dopamine, adrenaline, and noradrenaline. Catechol-O-methyltransferase, found in the synaptic cleft of dopaminergic neurons, is the second most significant metabolic pathway for levodopa. O-methylation reactions may influence the response to levodopa in Parkinson disease by the following mechanisms:

	• Catechol-O-methyltransferase in the gut may metabolize levodopa during absorption and, thus, reduce the bioavailability of the drug.
	• O-methylation of levodopa in the systemic circulation can facilitate the elimination of levodopa from plasma and, thus, reduce the plasma half-life of levodopa.
	• O-methylation of levodopa by catechol-O-methyltransferase in the brain capillary endothelial cells further reduces the entry of levodopa into the brain.
	• O-methylation of dopamine terminates the action of the neurotransmitter in the brain.

Accumulation of O-methylated levodopa in the brain was initially considered to inhibit levodopa transport to the brain. Studies with PET show that 3-O-methyldopa does not inhibit the transport of levodopa analog 18F-dopa into the brain. However, catechol-O-methyltransferase inhibition, which successfully blocks O-methylation, is a useful strategy to increase the bioavailability of levodopa. Catechol-O-methyltransferase inhibitors substantially increase the levels of free 18F-dopa in the plasma and the striatum after their administration. Free striatal 18F-dopa storage increases following catechol-O-methyltransferase administration in patients with early Parkinson disease, but there is only a small increase in patients with advanced disease. Therefore, it is likely that in advanced Parkinson disease the benefits of catechol-O-methyltransferase inhibition are likely due to the maintenance of plasma levodopa levels rather than the provision of a greater striatal store of levodopa available for decarboxylation. Further 18F-dopa PET studies have shown that tolcapone has a significant blocking effect on peripheral and central catechol-O-methyltransferase but not dopa decarboxylase activity.

Tolcapone lowers elevated homocysteine levels associated with levodopa treatment in patients with Parkinson disease. This may reduce long-term degenerative changes in the brain associated with hyperhomocysteinemia.

In healthy volunteers, 200 mg doses of tolcapone significantly reduce erythrocyte catechol-O-methyltransferase activity with maximum inhibition at 2 hours that returns to baseline levels within 24 hours. Tolcapone significantly increases the levodopa and dopamine concentrations (80% and 92% respectively) in patients with Parkinson disease and reduces 3-O-methyldopa levels by 80% when given at a dose of 200 mg 3 times daily along with levodopa/carbidopa. Clinical improvement with levodopa under tolcapone can be fully explained by tolcapone-induced changes of peripheral levodopa pharmacokinetics and excludes any central effects of tolcapone on dopa decarboxylase.

Tolcapone is an uncoupler of mitochondrial respiration in isolated mitochondria and markedly inhibits ATP synthesis. This action may be relevant to its effect on liver function, but its toxicity may also involve a mechanism independent of its effects on oxidative phosphorylation.

Pharmacokinetics. Tolcapone is rapidly absorbed when given orally and is rapidly eliminated with a mean half-life of approximately 2 hours. Tolcapone is metabolized to 3-O-methyl-tolcapone, which has an elimination half-life of approximately 30 hours. Bioavailability of tolcapone is 60% following oral administration due to first pass metabolism. Tolcapone is almost completely metabolized and excreted in urine and feces; glucuronidation is the most important route of metabolism. No accumulation of tolcapone or its metabolite occurred when multiple doses of the drug were given to elderly volunteers.

Mass spectrometry has been used on a multiorgan human-on-a-chip system, which includes 7 interacting microphysiological systems -- brain, pancreas, liver, lung, heart, gut, and endometrium -- for the comprehensive study of tolcapone metabolism and metabolite profiling (23). The results showed that oxidation, reduction, and conjugation reactions were the most important routes of tolcapone metabolism.

Formulations. A sustained-release tablet of tolcapone for oral administration, manufactured by direct compression, has a preferred dosage regimen of 1 administration every 12 or 24 hours (17).

Therapeutic drug monitoring. Methods for determining serum levels of tolcapone include high-performance liquid chromatography coupled to ultraviolet detection, electrochemical detection, and mass spectrometry detection (08).

Pharmacogenetics/pharmacogenomics. fMRI studies have revealed that tolcapone improves cognition and cortical information processing in normal human subjects. Individuals with val/val genotypes improve, whereas individuals with met/met genotypes worsen on tolcapone. Although neither COMT genotype nor tolcapone affect brain electrical activity in wakefulness and sleep, val/met heterozygotes produce twice as many lapses after a night without sleep than met/met homozygotes on exposure to tolcapone (22).

Indications

Tolcapone should be used only in patients with Parkinson disease "who do not have any movement abnormalities and who do not respond to, or who are not appropriate candidates for, other available treatments" according to a Food and Drug Administration letter mailed to United States doctors in 1998.

Off-label uses

	• Tolcapone also has antidepressant properties, as shown in preclinical studies, but these have not been demonstrated clinically.
	• For improving sleep in patients with advanced Parkinson disease.
	• Kleptomania (09).
	• Catechol-O-methyltransferase (COMT) modulates prefrontal dopamine signaling, and its gene polymorphisms impact cognitive function, pointing to the potential role of catechol-O-methyltransferase inhibitor tolcapone in improving cognitive function in health and disease (02).
	• Tolcapone has been investigated as a smoking cessation aid, but a proof-of-concept study does not provide strong support for further evaluation (01).
	• In an open trial, tolcapone improved symptoms of pathological gambling; the extent of improvement was significantly related to the COMT polymorphism and enhancement of frontoparietal activation as shown by fMRI (10).
	• Chronic drug abuse and alcoholism induce a state of dopamine deficiency in the mesocorticolimbic system in both humans and preclinical rodent models. Experimental data suggest that tolcapone, because of its relative specificity for cortical dopamine systems, may mediate the suppression of drinking behavior (16).
	• An in vitro study has shown that inhibition of catechol-O-methyltransferase can ameliorate HIV-associated neurodegenerative changes that resulted in the decreased expression of the structural and synaptic components, ie, microtubule-associated protein 2 and synaptophysin (15). As HIV-associated dendritic and synaptic damage contribute to HIV-associated neurocognitive disorders, inhibition of catechol-O-methyltransferase may represent a potential neuroprotective strategy for attenuating or preventing some of these disorders.
	• In experimental studies, phencyclidine-induced recognition deficits in rats can be improved with tolcapone, indicating its potential clinical usefulness in cognitive dysfunction related to neuropsychiatric disorders (04).
	• Tolcapone has been repurposed to treat systemic hereditary transthyretin amyloidosis (19). Because tolcapone crosses the blood-brain barrier, it can become a disease-modifying therapy for leptomeningeal amyloidosis.
	• A randomized, double-blind, placebo-controlled, within-subject study of tolcapone was performed in pathological gambling subjects who performed a delay discounting task while functional MRI images were obtained (14). Greater blood-oxygen-level-dependent activity during the placebo condition within the right inferior frontal cortex, a region that is important for inhibitory control, correlated with greater declines in impulsivity on tolcapone versus placebo. This finding has potential for translation for management of gambling disorders and for behavioral addictions in general.
	• Tolcapone is a potent inhibitor of the amyloid aggregation process of the transthyretin protein and acts by stabilizing the structure of the protein, reducing the progression of familial amyloid polyneuropathy.
	• Results of a study of randomized, double-blind crossover administration of tolcapone (100 mg TID for 5 days) on alcohol consumption and laboratory tasks assessing impulsivity show that it may be useful for treating alcohol use disorder (03). A randomized, double-blind, placebo-controlled, crossover study of tolcapone for behavioral variant frontotemporal dementia showed no significant differences in brain imaging but significant differences in Repeatable Battery for the Assessment of Neuropsychological Status (07). Further studies have been suggested.

Adverse effects

Tolcapone as an adjunct to levodopa and carbidopa was well tolerated during clinical trials. Dopaminergic-related adverse events, including dyskinesia and nausea, increased during the initial part of treatment but diminished as levodopa dosages were adjusted. Postural hypotension, dizziness, urine discoloration, insomnia, confusion, and hallucinations were also observed more frequently in tolcapone recipients. Another adverse effect was diarrhea, which either resolved or was mild enough to allow long-term tolcapone treatment.

Tolcapone is a more potent mitochondrial toxicant than entacapone, which is a possible mechanism for tolcapone-associated hepatotoxicity (11). Some recipients developed raised levels of alanine aminotransferase and aspartate aminotransferase. On this basis, it was recommended that liver enzymes be monitored once a month during the first 3 months of treatment and every 6 weeks for the next 3 months of treatment. In clinical use, entacapone has been safe, but tolcapone is under strict regulations on liver enzyme monitoring as, in the early years, a few hepatotoxicity cases appeared, 3 of them with fatal outcome (12).

For details, see the Physicians Desk Reference.

This severe hepatic adverse effect has not been seen thus far with the other catechol-O-methyltransferase inhibitor, entacapone. The mechanism of hepatotoxicity of tolcapone is uncoupling of oxidative phosphorylation in vivo, which does not occur with entacapone. The mechanism of tolcapone-induced liver toxicity has been studied both in vitro and in vivo, but no clear explanation has emerged. A pharmacogenetic basis is suggested by the finding that single nucleotide polymorphisms located within the UDP-glucuronosyltransferase 1A gene complex, which codes for the enzymes involved in the main elimination pathway of tolcapone, are significantly associated with the occurrence of elevated liver transaminase levels. Theoretically, genotyping should identify the patients susceptible to this adverse effect so that the use of tolcapone in these patients can be avoided. This approach has not been used in practice so far.

References

01: Ashare RL, Wileyto EP, Ruparel K, et al. Effects of tolcapone on working memory and brain activity in abstinent smokers: a proof-of-concept study. Drug Alcohol Depend 2013;133(3):852-6. PMID 24095246
02: Bitsios P, Roussos P. Tolcapone, COMT polymorphisms and pharmacogenomic treatment of schizophrenia. Pharmacogenomics 2011;12(4):559-66. PMID 21521027
03: Coker AR, Weinstein DN, Vega TA, Miller CS, Kayser AS, Mitchell JM. The catechol-O-methyltransferase inhibitor tolcapone modulates alcohol consumption and impulsive choice in alcohol use disorder. Psychopharmacology (Berl) 2020. PMID 32617646
04: Detrait ER, Carr GV, Weinberger DR, Lamberty Y. Brain catechol-O-methyltransferase (COMT) inhibition by tolcapone counteracts recognition memory deficits in normal and chronic phencyclidine-treated rats and in COMT-Val transgenic mice. Behav Pharmacol 2016;27(5):415-21. PMID 26919286
05: Eggert K, Oertel WH, Lees AJ, German Competence Network on Parkinsons disease. Safety and efficacy of tolcapone in the long-term use in Parkinson disease: an observational study. Clin Neuropharmacol 2014;37(1):1-5. PMID 24434524
06: Fabbri M, Rosa MM, Ferreira JJ. Clinical pharmacology review of opicapone for the treatment of Parkinson's disease. Neurodegener Dis Manag 2016;6(5):349-62. PMID 27599671
07: Fremont R, Manoochehri M, Armstrong NM, et al. Tolcapone treatment for cognitive and behavioral symptoms in behavioral variant frontotemporal dementia: a placebo-controlled crossover study. J Alzheimers Dis 2020;75(4):1391-403. PMID 32444540
08: Goncalves D, Alves G, Soares-da-Silva P, Falcão A. Bioanalytical chromatographic methods for the determination of catechol-O-methyltransferase inhibitors in rodents and human samples: a review. Anal Chim Acta 2012;710:17-32. PMID 22123108
09: Grant JE. Kleptomania treated with tolcapone, a catechol-O-methyl-transferase (COMT) inhibitor. Prog Neuropsychopharmacol Biol Psychiatry 2011;35(1):295-6. PMID 21062636
10: Grant JE, Odlaug BL, Chamberlain SR, Hampshire A, Schreiber LR, Kim SW. A proof of concept study of tolcapone for pathological gambling: relationships with COMT genotype and brain activation. Eur Neuropsychopharmacol 2013;23(11):1587-96. PMID 23953269
11: Grünig D, Felser A, Bouitbir J, Krähenbühl S. The catechol-O-methyltransferase inhibitors tolcapone and entacapone uncouple and inhibit the mitochondrial respiratory chain in HepaRG cells. Toxicol In Vitro 2017;42:337-47. PMID 28526448
12: Haasio K. Toxicology and safety of COMT inhibitors. Int Rev Neurobiol 2010;95:163-89. PMID 21095462
13: Katsaiti I, Nixon J. Are there benefits in adding catechol-O methyltransferase inhibitors in the pharmacotherapy of Parkinson's disease patients? A systematic review. J Parkinsons Dis 2018;8(2):217-31. PMID 29614697
14: Kayser AS, Vega T, Weinstein D, Peters J, Mitchell JM. Right inferior frontal cortex activity correlates with tolcapone responsivity in problem and pathological gamblers. Neuroimage Clin 2016;13:339-48. PMID 28066708
15: Lee TT, Chana G, Gorry PR, et al. Inhibition of catechol-O-methyl transferase (COMT) by tolcapone restores reductions in microtubule-associated protein 2 (MAP2) and synaptophysin (SYP) following exposure of neuronal cells to neurotropic HIV. J Neurovirol 2015;21(5):535-43. PMID 26037113
16: McCane AM, Czachowski CL, Lapish CC. Tolcapone suppresses ethanol intake in alcohol-preferring rats performing a novel cued access protocol. Alcohol Clin Exp Res 2014;38(9):2468-78. PMID 25257296
17: Nardi-Ricart A, Nofrerias-Roig I, Suñé-Pou M, et al. Formulation of sustained release hydrophilic matrix tablets of tolcapone with the application of sedem diagram: influence of tolcapone's particle size on sustained release. Pharmaceutics 2020;12(7):674. PMID 32708961
18: Nyholm D, Johansson A, Lennernäs H, Askmark H. Levodopa infusion combined with entacapone or tolcapone in Parkinson disease: a pilot trial. Eur J Neurol 2012;19(6):820-6. PMID 22136163
19: Pinheiro F, Varejão N, Esperante S, et al. Tolcapone, a potent aggregation inhibitor for the treatment of familial leptomeningeal amyloidosis. FEBS J 2021;288(1):310-24.** PMID 32324953
20: Ries V, Selzer R, Eichhorn T, et al; German Tolcapone Study Group. Replacing a dopamine agonist by the COMT-inhibitor tolcapone as an adjunct to L-dopa in the treatment of Parkinson's disease: a randomized, multicenter, open-label, parallel-group study. Clin Neuropharmacol 2010;33(3):142-50. PMID 20502133
21: Sethi K, Factor S, Watts R. Quality of life in Parkinson's disease patients following adjunctive tolcapone therapy: results of an open-label, multicenter, community-based trial. CNS Spectr 2010;15(1):27-32. PMID 20394182
22: Valomon A, Holst SC, Borrello A, et al. Effects of COMT genotype and tolcapone on lapses of sustained attention after sleep deprivation in healthy young men. Neuropsychopharmacology 2018;43(7):1599-607. PMID 29472644
23: Wang X, Cirit M, Wishnok JS, Griffith LG, Tannenbaum SR. Analysis of an integrated human multiorgan microphysiological system for combined tolcapone metabolism and brain metabolomics. Anal Chem 2019;91(13):8667-75. PMID 31181164
24: References especially recommended by the author or editor for general reading.

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Tolcapone

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Entacapone
Levodopa
Opicapone

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Tolcapone

Trial description	Result/reference
In a 10-week, randomized, open-label, parallel-group trial, Parkinson disease patients on a stable regimen of l-dopa/ decarboxylase inhibitor in combination with bromocriptine, lisuride, or pergolide were switched to tolcapone.	Switch from a dopamine agonist to tolcapone is well tolerated and can be done safely within a few days (20).
A short-term, randomized, crossover clinical trial with levodopa/carbidopa intestinal gel combined with oral entacapone and tolcapone to find if levodopa dose can be reduced by 20% without worsening of motor fluctuations.	Plasma levodopa levels were maintained with no worsening of motor fluctuations, but the levels were significantly higher using tolcapone, and it was concluded the dose of tolcapone could be reduced (18).

Tolcapone

Tolcapone

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Table 1. Clinical Trials of Tolcapone

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

Media

References

Contributors

Author

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Also in This Category

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Tolcapone

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Table 1. Clinical Trials of Tolcapone

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

Media

References

Contributors

Author

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Hemifacial spasm

Wilson disease

Acupuncture

Neuroacanthocytosis

Restless legs syndrome

Dementia in Parkinson disease

ALS-like disorders of the Western Pacific

Illicit drug use: neurologic complications

This is an article preview.
Start a Free Account
to access the full version.